Ms Ii - Exam 1

Front 1

What does etiology stand for and what are the two major classes?

Back 1

study of the cause of disease

Intrinsic (genetic)
Aquired

Front 2

What is hypertrophy and what is a classic example of a cell that often undergoes hypertrophy?

Back 2

increase in cell size

example: cardiac myocyte

Front 3

What is hyperplasia and what are the two main types?

Back 3

increase in cell number

Physiologic hyperplasia - normal hormonal (at puberty) and compensatory (due to damage)

Pathological Hyperplasia - abnormal (still responds to regulatory mechanism)

Front 4

In what organ do hyperplasia and hypertrophy happen without being considered pathologic?

Back 4

Gravid uterus

Front 5

What is atrophy and what are some of the common causes?

Back 5

decrease in cell size

decreased workload, denervation, decreased blood supply, aging, inadequate nutrition, loss of endocrine stim, pressure

Front 6

What is the main mechanism of atrophy and how does this work in the cell?

Back 6

imbalance b/w protein synthesis and degradation (proteolysis)

- proteolysis can be caused by lysosomes or the ubiquitin-proteasome pathway

Front 7

What is a typical morphologic finding in a cell undergoing atrophy?

Back 7

autophagic vacuoles (contain degraded cell components)

Front 8

What is metaplasia, by what mechanisms does it occur, and what is the classic example?

Back 8

change is cell type due to the reprogramming of tissue stem cells

example: Barrett's esophagus

Front 9

Which factors affect the programming of cells undergoing metaplasia and what can persistent metaplasia lead to?

Back 9

cytokines, growth factors, extracellular matrix components

persistent exposure to these factors may cause malignant transformation of metaplastic epithelium

Front 10

What cellular characteristics may be seen in REVERSIBLE cell injury?

Back 10

loss of microvilli, cell swelling, blebs, swelling of the mitochondria and ER, clumping of chromatin, autophagic vacuoles

Front 11

What additional cellular characteristics may be seen in cells once they undergo IRREVERSIBLE cell injury?

Back 11

in addition to Loss of microvilli, cell swelling, blebs, swelling of the mitochondria and ER, clumping of chromatin, autophagic vacuoles . . . .

loss of ribosomes from ER, kysosome rupture, myelin figures, nuclear condensation/fragmentation, amorphous densities in swollen mito

Front 12

Which characteristic of cell injury is especially indicative of an IRREVERSIBLE process?

Back 12

rupture of the lysosomes

Front 13

How does the end result of necrosis differ from that of apoptosis?

Back 13

necrosis: enzymatic digestion and leakage of cellular contents

apoptosis: phagocytosis of apoptotic cells and fragments

Front 14

Is apoptosis a reversible process?

Back 14

no

Front 15

What are the four major abnormalities that can lead to cell damage?

Back 15

decrease in ATP
membrane damage
increase in intracellular calcium
reactive oxygen species

Front 16

How does ATP depletion cause cell death?

Back 16

- decrease in Na/K pump = cell/organelle swelling
- increase in anaerobic glycolysis = decrease in pH (via lactic acid) causing clumping of chromatin
- detachment of ribosomes = decreased protein synthesis and lipid deposition

Front 17

What causative agents can lead to mitochondrial damage?

Back 17

increased cytosolic calcium, oxidative stress, lipid perioxidation

Front 18

Which compound is associated with mitochondrial death?

Back 18

cytochrome C (causes mitochondrial permeability transition - MTP)

Front 19

What enzymes are activated due to increased cytosolic calcium and what is each associated with?

Back 19

- ATPase --> decreased ATP
- Phospholipase --> decreased phospholipids = memb damage
- Protease --> disruption of membrane and cytoskeleton proteins
- Endonuclease --> nucleus chromatin damage

Front 20

How is oxidative stress defined?

Back 20

imbalance b/w free radical-generating and radical scavenging systems in the cell

Front 21

What effects do reactive oxygen species have on the cell?

Back 21

membrane lipid peroxidation (attack the unsat. FA in cell memb), DNA fragmentation (nuclear and mito), protein damage (oxidation of a.a. residues, formation of S-S bonds b/w proteins, protein fragmentation, enhance protein degradation)

Front 22

What defines a free radical?

Back 22

molecule with single unpaired electron in outer orbit which is highly reactice and propagates to create more free radicals in new compounds

Front 23

What can cause the formation of free radicals?

Back 23

absorbant radiant energy (UV, X-ray), drug and xenophobic metabolism, normal metabolic processes (energy metab., inflammation, intracellular oxidates), catalyzation by transition metals, nitric oxide

Front 24

How do free radicals cause damage to lipids and proteins, specifically?

Back 24

lipids - attack unsaturated fatty acids in the cell memb

proteins - oxidation of amino acid residues, formation of disulfide bones, protein fragmentation/degradation

Front 25

By what mechanisms can membrane damage occur?

Back 25

- mitochondrial dysfunction
- decreased phospholipids
- cytoskeletal damage
- ROS
- products of lipid breakdown

Front 26

How do a decrease in oxygen and increase in calcium lead to membrane damage, respectively?

Back 26

Decrease in oxygen --> mitochondrial dysfunction --> decrease in phospholipid deacylation/synthesis --> phospholipid loss

Increase in calcium --> phospholipase activation --> increase in phospholipid degradation --> phospholipid loss and formation of lipid breakdown products (cause damage by inserting themselves in the cell memb and changing the permeability)

increased calcium also leads to membrane damage by activating proteases which cause cytoskeletal damage

Front 27

When does cell injury become irreversible?

Back 27

inability to reverse mitochondrial dysfunction; profound disturbances in memb fcn (esp. lysosomal memb damage causing an influx of calcium or leakage of cell contents)

Front 28

What is meant by the time lag of irreversible injury?

Back 28

irreversible injury occurs before light microscopic changes appear (ultrastructural changes occur after cell death)

Front 29

Which ultrastructural changes are seen in REVERSIBLE cell injury?

Back 29

- distortion of microvilli
- blebs on memb
- loosening of intracellular adhesions
- myelin figures
- mito swelling /rarefaction/ amorphous densities
- dilation of ER
- nuclear changes (less granular/fibrillar)

Front 30

What are the microscopic features of necrosis?

Back 30

- eosinophilic cytoplasm (loss of cytoplasmic RNA/denatured proteins bind to eosin)
- homogenous, glassy cytoplasm
- vacuolated cytoplasm
- calcification of cells

Front 31

What three nuclear changes are seen in necrosis?

Back 31

- Karolysis = decreased number of basophilia
- Pyknosis = decreased nuclear size but increased nuclear basophilia
- Karyorrhexis = nuclear fragmentation

Front 32

What type of necrosis is seen after ischemic injury (e.g. MI) to the cell and what classifies its morphology?

Back 32

coagulative necrosis - cell outlines are preserved

Front 33

What type of necrosis is seen with bacterial infection and ischemic injury to the brain?

Back 33

liquefactive necrosis

Front 34

What are the three historic forms of necrosis and what characterizes each?

Back 34

1. Caseous (cheese-like) necrosis = same as coagulative but w/ loss of cell outlines and thick white appearance

2. Fat Necrosis = enzymes digest (saponify) fat

3. Gangraeous Necrosis = ischemia of limbs (wet = with bacterial involvement; dry = without)

Front 35

What is the classic example of caseous necrosis?

Back 35

tuberculosis

Front 36

What disease often leads to fat necrosis of surrounding structures?

Back 36

pancreatitis (release lipases that digest fats causing saponification

Front 37

What is tested for when determining whether necrosis has occurred in a patient?

Back 37

increased leakage of enzymes (e.g. CK, LDH)

Front 38

What is the key difference in hypoxia and ischemia concerning cell injury?

Back 38

Hypoxia: damage caused by reduced oxygen availability

Ischemia: damage caused by reduced blood flow leading to decreased aerobic AND decreased anaerobic metabolism (also, toxic metabolites accumulate since blood cant carry them away)

Front 39

How does reperfusion of tissue after ischemia cause damage?

Back 39

- reoxygenation means an influx of oxygen which causes an increase in ROS
- inflammation caused by the immune system in blood damages cells
- complement in blood binds the IgM deposited during ischemia and leads to further cell injury and inflammation

Front 40

What are the two types of chemical injury and what are some examples associated with each?

Back 40

1. Direct Actors (no metabolism needed)
- examples: mercuric chloride in GI/kidney, lead in blood/GI/nervous system, antibiotics, chemotherapy drugs

2. Indirect Actors (metabolites do the damage)
- example: CCl4 which generates free radicals in the liver

Front 41

What can a substance that causes necrosis at high doses lead to when given at low doses?

Back 41

apoptosis (programmed cell death)

Front 42

What are the general features of apoptosis?

Back 42

- plasma memb remains intact
- dead cell is rapidly cleared
- can be physiologic (part of normal process) or pathologic

Front 43

What are some examples of physiologic apoptosis?

Back 43

- embryogenesis
- hormone-dependent involution
- cell deletion in dividing populations
- eliminatino of self-targeting lymphoctes
- death caused by cytotoxic T-lymphocytes (including elimination of tumors, virus-infected cells, and transplants, so long as not part of pathologic condition)

Front 44

What are some examples of pathologic apoptosis?

Back 44

- self-destruction of injured/virus-infected cells (as part of the disease process)
- pathologic atrophy following duct obstruction
- tumor cell death
- cell death due to mito permeability changes

Front 45

What morphologic characteristics are seen in apoptosis?

Back 45

- cells shrink
- chromatin condenses (nucleus may fragment)
- cytoplasmic blebs (leading to apoptotic bodies)

Front 46

What happens to apoptotic bodies?

Back 46

they express a receptor that causes them to be digested by phagocytes

Front 47

What is the distinguishing feature of DNA on electrophoresis between a cell that underwent apoptosis vs. necrosis?

Back 47

Apoptosis: laddering of DNA due to othe effect of endonucleases

Necrosis: general dissolution of DNA creating a homogenous band

Front 48

What are caspases and which caspase functions as an endonuclease?

Back 48

Cystein-aspartic acid proteases; Capase 3 is an endonuclease

Front 49

What types of injury can cause apoptosis at low doses?

Back 49

radiation, toxins, free radicals - cause DNA damage; apoptosis is initiated through p53

Front 50

What are the two pathways of apoptosis and how do they differ?

Back 50

1. Extrinsic: death receptors on cell surface are activated (FAS, TNFalpha) which activate initiator capases (8-10), and subsequent executioner caspases (3)

2. Intrinsic: signals that stop apoptosis (Bcl-2/Bcl-x) are silenced and signals that promote apoptosis (Bax, Bak, Bim) begin; involves increased mito permeability which leads to the release of cytochrome C which activates initator caspase

Front 51

What molecule is associated with the bypass pathway of apoptosis, what secretes it, and how does it cause apoptosis?

Back 51

Granzyme B; secreted by cytotoxix T lymphocytes through pores (perforin) in the cell membrane

- granzyme B directly activates executioner caspases

Front 52

Is the Bcl-2 family of genes pro-apoptotic or anti-apoptotic?

Back 52

both, depending on the circulating form

Pro = Bax, Bak, Bim
Anti = Bcl-2, Bcl-x

Front 53

What are the subcellular responses seen in cell injury?

Back 53

lysosomal catabolism, induction of sER, mitochondrial changes, cytoskeletal abnormalities

Front 54

What are the two types of lysosomal catabolism and what defines each?

Back 54

1. Heterophagy: catabolism of extracellular material via phagocytosis or pinocytosis

2. Autophagy: catabolism of intracellular material via autophagic vacuoles

Front 55

What are the possible end-results of heterophagy and what class of disease is caused by a failure of these mechanisms?

Back 55

phagocytosed materials form a residual body which either be exocytosed or become a lipofuscin pigment granule

failure of these systems leads to lysosomal storage disease

Front 56

When cells are exposed to toxins (e.g. polycyclic aromatic hydrocarbons from cigarette smoke), what is induced?

Back 56

formation of lots of sER as well as cytochrome p450 (molecule that metabolizes many toxins)

Front 57

What damaging side-effects can occur due to the metabolism of certain compounds?

Back 57

metabolite can be more toxic than original compund; ROS are often formed in the process

Front 58

In what disease are megamitochondria seen?

Back 58

alcoholic liver disease

Front 59

What cytoskeletal components are affected by toxins and what toxins specifically affect each?

Back 59

- thin filaments: affected by phalloidin of Amanita phalloides

- microtubules: affected by some anti-neoplastic agents

- intermediate filaments: affected by alcohol (causes formation of Mallory bodies = keratin intermediate filaments)

Front 60

What are three major processes by which intracellular accumulations occur and what are examples for each?

Back 60

1. Inadequate rate of metabolism of a normal substance (protein reabsorption droplets in renal tubules)

2. Defective Metabolism, packaging, transport or secretion of a normal substance (storage disease)

3. Accumulation of exogenous substances (silica, asbestos)

Front 61

What specific mechanisms can lead to intracellular accumulations?

Back 61

abnormal metabolism, defective protein folding/transport, lack of an enzyme, ingestion of indigestible materials

Front 62

What causes fatty liver?

Back 62

any defect in the pathway from free fatty acid uptake by the liver to lipid secretion; most common in excessive alcohol use

Front 63

What pathologies can result from the accumulation of cholesterol and cholesterol esters?

Back 63

- atherosclerosis (accumulation in tunica intima)

- Xanthomas (in hyperlipidemic state)

- Inflammation and necrosis

- cholesterolosis (in gall bladder)

- genetic disease (e.g. Niemann-Pick disease, type C)

Front 64

What are three causes of excess protein accumulation?

Back 64

1. reabsorption

2. excess secretion/production

3. defects in protein folding (leading to defects in transport/secretion and aggregation of abnormal protein)

Front 65

What is the function of chaperones?

Back 65

assist in proper protein folding (i.e. creating the correct tertiary structure)

example: heat shock proteins

Front 66

What is the pathophysiology of cystic fibrosis?

Back 66

defective intracellular transport

- a genetic mutation delays the dissociation of a chloride channel protein from its chaperone, causing abnormal folding of the channel

Front 67

Defective secretion of which protein can lead to a severe form of emphysema?

Back 67

alpha1-antitrypsin

Front 68

What does an accumulation of unfolded proteins in the ER lead to?

Back 68

increase in chaperone production, decrease in protein translation, and possibly caspase activation if other safety mechanisms fail

Front 69

What is the pathophysiology of amyloidosis?

Back 69

aggregation of abnormal proteins (beta-pleated sheets)

Front 70

In what diseases can glycogen accumulation occur and how does it show up on light microscopy?

Back 70

diabetes mellitus and glycogen storage diseases - appears in muscle as less defined lipid vacuoles

Front 71

What exogenous pigment is found occupationally in WV and what is the associated disease?

Back 71

coal dust - excessive inhalation leads to anthracosis (better known as coal worker's pneumoconiosis)

Front 72

What is lipofuscin and what is its presence indicative of?

Back 72

an endogenous pigment consisting of lipid/phospholipid protein

does not cause damage itself but is indicative of free radical injury and lipid peroxidation

Front 73

What is hemosiderin and what results from excess and extreme accumulation of this substance?

Back 73

endogenous pigment composed of iron oxide - excess hemosiderin leads to hemosiderosis, whereas extremem accumulation in the liver, heat, and pancreas cause hemochromatosis

Front 74

What is the distinguishing feature on light microscopy between lipofuscin and hemosiderin?

Back 74

lipofuscin accumulates perinuclear whereas hemosiderin is found throughout the cell

Front 75

Abnormal accumulation of what pigment causes jaundice?

Back 75

bilirubin

Front 76

In pathology, what is referred to as hyaline change?

Back 76

a homogenous, glassy, pink appearance within or around the cell

Front 77

What is the cause of metastatic calcification and what pathologies does it result from?

Back 77

hypercalcemia w/ tissue deposition

caused by increased PTH, bone destruction, vitamin D, related disorders, and renal failure

Front 78

Accumulation of what substance often results from sarcoidosis?

Back 78

vitanim D (precursor form activated macrophages inside the granulomas)

Front 79

How does dystrophic calcification differ from the metastatic form and what are its causes and effects?

Back 79

- does not correlate with increased blood calcium levels --> caused by prior necrosis

- formation of crystalline calcium phospahte initiated intracellularly by mitochondria in dead/dying cells and extracellularly by phospholipids of membrane-bound vesicles

- propagation of abnormal crystallization can cause organ dysfunction

Front 80

What biochemical changes are associated with aging cells?

Back 80

- reduced mitochondrial oxidative phosphorylation

- reduced synthesis of proteins, nucleic acids, and transcription factors

- reduced chromosomal repair

- decreased nutrient uptake

Front 81

What structural changes are associated with aging cells?

Back 81

- mitochondrial pleomorphism and vacuolation

- abnormally shaped nuclei

- decreased ER

- distorted golgi

- increased lipofuscin

- glycation end-products and cross-linked proteins

- abnormal protein folding

Front 82

What is meant by replicative senescence, what causes it and what disease exemplifies this process?

Back 82

a decrease in population doubling level with increased cellular age, caused by a decrease in telomere length

exemplified in Werner syndrome (caused by defective DNA repair)

Front 83

What is a common feature regarding telomeres in cells that have undergone malignant transformation?

Back 83

telomerase reactivation (telomerase is not found in normal somatic cells)

Front 84

What results from a decrease in IGF-1 signaling?

Back 84

a leaner person w/ increased lifespan (lifespan also thought to increase from a decreased caloric intake)

Front 85

What metabolic events are associated with a decreased lifespan?

Back 85

oxidative damage, DNA damage, declining proteasomic fcn (causes damaged proteins and organelles)

Front 86

Who wrote the first work on immunity to disease and what disease was it concerned with

Back 86

Edward Jenner - small pox

Front 87

Who coined the term pathogen, and who developed the first vaccine?

Back 87

pathogen: Robert Koch

vaccine: Louis Pasteur

Front 88

Who discovered antibodies and antigens?

Back 88

Emil von Behring

Front 89

What are the two types of immune responses and what characterizes each?

Back 89

1. Innate Immune Response: nonspecific, not altered by exposure, rapid response, dominated by phagocytic cells

2. Aquired/adaptive Immune Response: specific, memory following exposure, slow response, dominated by lymphocytes

Front 90

What do the innate and acquired immune responses have in common?

Back 90

they have common effector mechanisms for the destruction of pathogens

Front 91

What are the anatomical barriers of the innate immune system?

Back 91

- skin (mechanical barrier)

- mucous membranes (trap and remove invaders)

Front 92

What are the physiological barriers of the innate immune system?

Back 92

- temperature (fever inhibits bacterial growth)

- low pH (acidity not conducive to bacterial growth)

- chemical mediators (lysozyme, interferon, complement)

Front 93

When a pathogen gets past the anatomical and physiological barriers of the innate immune system, what barrier it encounter last?

Back 93

phagocytic cell barrier

Front 94

What did Eli Metchnikoff discover?

Back 94

phagocytosis by leukocytes; specifically macrophages (activated monocyte) and microphages (neutrophils or polymorphonuclear cells - PMN)

Front 95

What is the acquired immune response solely dependent on?

Back 95

lymphocytic cells and their products

Front 96

Who discovered the purpose of lymphocytes?

Back 96

Bruce Glick and his chickens

Front 97

What are the two types of acquired immunity?

Back 97

1. Humoral immunity (in the blood)

2. Cell-mediated immunity (in the cells)

Front 98

Where do myeloid and lymphoid immune cells come from?

Back 98

both are produced in the bone marrow

Front 99

Which hematopoietic cell is the precursor to all others and what characterizes this cell?

Back 99

Pluripotent hematopoietic stem cell - 1/100,000 cells in bone marrow

can be transported to reform the entire hematopoietic system without losing its ability to self-renew

Front 100

Which cells are the immediate offspring of the pluripotent hematopoietic stem cells and what do those cells give rise to?

Back 100

committed stem cells (limited renewal) - give rise to progenitor cells (no renewal) which then form the functional end cells

Front 101

What does it mean, clinically, when you have marrow with a left shift?

Back 101

there are more immature hematopoietic cells than found in the normal individual

Front 102

What are bone marrow stromal cells also known as and what is their purpose?

Back 102

adventitial reticular cells - secrete cytokines that sim blood cell production in response to the humoral environment

Front 103

What are the cytokines called that are produced by bone marrow stromal cells and what function do these cytokines have?

Back 103

Colony Stimulating Factors (CSF) - stimulate the production of colonuy-forming units in culture (CFU-C)

CSF are also known as interleukins

Front 104

What happens to hematopoietic cells that fail to be stimulated by appropriate survival signals (cytokines, adhesion contacts, etc.)?

Back 104

they die via apoptosis

Front 105

From what precursor are the bone marrow stromal cells derived?

Back 105

Mesenchymal stem cells (these are also responsible for the formation of osteogenic cells, adipocytes, and chondrogenic cells)

Front 106

From what embryonic region do hematopoietic stem cells originate and where do they migrate to?

Back 106

Splanchnopleura and AGM region --> migrate to the yolk sac and fetal liver

Front 107

To what organs do the hematopoietic stem cells migrate after leaving the liver (in mice)?

Back 107

thymus (to make T-lymphocytes) and spleen

from the spleen they migrate to the bone marrow (this occurs just before birth in mice - whereas in humans the migration is finisehed at the end of the 1st trimester)

Front 108

Where do the hematopoietic stem cells of the bone marrow arise from?

Back 108

NOT from the yolk sac! instead from the fetal liver

Front 109

Removal of which part of the immune system has the most lethal impact on patients?

Back 109

removal of the innate immune system (seen w/ radiation/chemotherapy)

removal of the aquired immune system still provides the initial protection, but the disease continues for a long time

Front 110

What distinguishes the immediate innate immune response from the early induced innate immune response?

Back 110

immediate (0-4 hours): macrophages and preformed chemical mediators respond
early induced (4-96 hours): inflammation recruitment and activation of effector cells

Front 111

What is meant by the microbiological aspect of innate immunity?

Back 111

the normal flora of the skin and gut provide a layer of protection against pathogens by competing for the same nutrient and space

Front 112

Which is the most numerous leukocyte in circulation and what is its lifespan?

Back 112

polymorphonuclear neutrophil (PMN), comprises 70% of leukocytes, have a lifespan of 12 hours in circulation (36 hour total lifespan)

Front 113

In which disease is there a deficiency in neutrophils that occurs every 21 days?

Back 113

cyclic neutropenia (result of autosomal dominantly inherited mutations in ELA2, the gene encoding neutrophil elastase)

Front 114

What is the primary cytokine that stimulates proliferation and differentiation of neutrophils?

Back 114

G-CSF (granulocyte colony stimulating factor); can be used therapeutically (Neupogen)

Front 115

What characterizes colony stimulating factors and what are the different types?

Back 115

small peptide formed by bone marrow stromal cells;
stimulates proliferation and differentiation of cells with the receptor to the specfic CSF;
M-CSF: monocytes
G-CSF: neutrophils
GM-CSF: monocytes and neutrophils
Stem cell factor: mixed myeloid cells

Front 116

What is the immediate response when bacteria enter the body through a break in the skin?

Back 116

tissue macrophages recognize structures on the cell surface of bacteria and secrete cytokines (vasoactive and chemotactic factors) which cause inflammation of the surrounding tissues

Front 117

Which cells are the first to respond to cytokines released by macrophages after its exposure to a pathogen and what do these cells do once stimulated?

Back 117

Neutrophils - they attach themselves to the surrounding endothelial cells (margination), then squeeze through the vessel wall (extravasation - made possible by dilation of capillaries in response to cytokines), they migrate to the site of infection and finally phagocytose the microorganism

Front 118

What is the purpose of complement and how does it achieve this?

Back 118

complement is involved in pathogen recognition mechanisms - in the presence of a pathogen, the complement is enzymatically cleaved; one part of the complement attaches to the pathogen while the other serves as a chemotatic factor which signals effector cells (phagocytes) that a pathogen is present

Front 119

What are the cardinal physical signs of inflammation?

Back 119

pain, redness, heat, swelling

Front 120

What is the lifespan of a monocytes/macrophage, what are some of the different types of macrophages and where are they located?

Back 120

lifespan = weeks
Alveolar macrophages (lung)
Kupffer cells (liver)
Histiocytes (CT)
Mesangial Cells (kidney)
Microglial cells (brain)

Front 121

When a macrophage is stimulated by a pathogen, what does it release?

Back 121

pro-inflammatory cytokines (interleukins, TNF-alpha); these are also released by dendritic cells

Front 122

Where are natural killer cells produced, and what do their cell surface receptors respond to?

Back 122

produced in the bone marrow, they respond especially to virus-infected cells; they are also called lymphokine-activated killer cells since they response to IL-2

Front 123

What is the main purpose of eosinophils, basophils, and (to a certain extent) mast cells, and what complications are associated with them?

Back 123

they fcn in the killing of parasites - however, the substances they release (e.g. histamine) can cause severe complications regarding allergies

Front 124

Where are dendritic cells produced and what are some examples of the different types?

Back 124

produced in the bone marrow
Langerhans cells (skin)
Interstitial Dendritic cells (organs: heart, liver, kidneys, etc.)
Interdigitating dendritic cells (follicles of Lymph nodes)
Circulating dendritic cells (blood)

Front 125

What is the main purpose of dendritic cells, and especially that of the Langerhans cell?

Back 125

recognition of foreign invaders - Langerhans cells engulf a foreing invaders, travel to a lymphoid organ and activate the aquired immune system (it is the connection b/w the innate and aquired immune systems)

Front 126

What are Toll-like receptors and where are they found?

Back 126

very primative and highly conserved receptors on innate immunity cells that recognize foreign materials; they are found on both the outside and inside of the cell

Front 127

What makes IL-1, IL-6, and TNF-α especially important cytokines?

Back 127

they induce acute-phase protein secretion (incl. complement) which is essential for the inflammatory phase of the innate immune response

Front 128

In a patient with hypoalbuminemia, what must be taken into account when giving drugs?

Back 128

The patients free drug concentration will be higher than in normal individual

Front 129

What is the major organ of drug excretion?

Back 129

kidney

but in the case of inhalational anesthetics it will be the lungs

Front 130

What is meant by enteral administration of a drug?

Back 130

administration via the GI: oral, sublingual, rectal

Front 131

What is IT drug administration?

Back 131

intrathecal: into the spine

Front 132

What are four factors affecting the absorption from the GI tract?

Back 132

acidity, gastric emptying time, motility, GI content

Front 133

Which compound will be absorbed easier by the GI tract, a weak acid or a weak base?

Back 133

a weak acid, since it will be neutral when protonated by the slightly acidic environment of the GI tract

Front 134

How do the GI contents affect absorption?

Back 134

content can either impede absorption or it can enhance it by stimulating acid secretion and blood flow

Front 135

What factors can reduce the efficiency of absorption of orally ingested medications?

Back 135

inactivation by the intestinal enzymes, transport of absorbed drugs back into the intestine, metabolism in the liver due to the first-pass effect

Front 136

What are the advantages of sublingual and rectal administration of certain drugs, respectively?

Back 136

sublingual: rich in blood supply, no first-pass effect

rectal: useful when drugs not tolerated orally, for heavily sedated patients, when site of action is rectal, to avoid injection, and to avoid first-pass effect

Front 137

What are some of the advantages and disadvantages of parenteral routes of drug administration?

Back 137

advantages: rapid effect, maximizes bioavailabilty

disadv: once injected, cannot get back or retard its absorption, overdose may be a problem

Front 138

What are some special features of IM drug administration?

Back 138

drug absorption is affected by blood flow, so vasodilation/constriction can change absorption; lateral diffusion can be changed (e.g. with hyaluronidase); a disadvantage is local tissue damage and pain due to alkaline formation

Front 139

How does subcutaneous drug administration differ from IM?

Back 139

generally slower absorption due to less lateral diffusion and lower blood flow

Front 140

What form of drug administration will result in the most rapid increase in concentration of that drug in plasma, and which methods are slower?

Back 140

IV>IM>SC>PO

Front 141

What are topical routes of drug administration and what are some of the features of each?

Back 141

Percutaneous: thick skin and lipid poor stratum corneum are barriers to penetration (highly lipid soluble drugs pass through epidermis most easily; Mucous membranes: includes local anesthetics for operative manipulations, and nasal sprays for common cold; Corneal application: for ophthalmologic drugs

Front 142

What are some of the advantages to inhalational drug administration?

Back 142

High surface area, rich blood supply, and thin epithelium allow for rapid absorption

Front 143

What are the two major types of lymphocytes and what is their classification?

Back 143

B-Lymphocytes (humoral immunity)
T-Lymphocytes (cell-mediated immunity)

Front 144

What is the difference between primary/central and secondary/peripheral lymphoid tissue?

Back 144

primary/central: bone marrow and thymus
secondary/peripheral: adenoid, tonsil, lymph node, appendix, spleen, NOT blood

Front 145

Once B-lymphocytes in secondary lymphoid tissue have been activated and become plasma cells, where do they travel?

Back 145

to bone marrow

Front 146

When lymphoid cells are in peripheral tissue, what happens to their cell cycle?

Back 146

they are stuck in G0, if their cognate antigen is presented within 2-7 days, they will become activated and proliferates; if not they will undergo apoptosis

Front 147

What are the two types of cells that are created after a B-lymphocyte has undergone clonal expansion?

Back 147

Effector cells (make antibodies)
Memory cells (reside in the body for a long time)

Front 148

How does lymph flow through the lymph node?

Back 148

from afferent vessels, through the cortex (packed w/ lymphocytes), into the paracortex and medulla (contain macrophages and plasma cells), ending at the hilus in an efferent lymphatic vessel

Front 149

What is the difference between the primary and secondary follicles (germinal centers) in the lymph node?

Back 149

primary: accumulation of lymphocytes
secondary: location of stimulated lymphocytes (follicle has a germinal center)

Front 150

What are the characteristics of the post-capillary venule of a lymph node?

Back 150

high cuboidal epithelium
contain cell adhesion molecules (vascular addressins/homing receptors)
Integrin on lymphocytes attach to post-capillary venules

Front 151

How does the spleen differ from the lymph node?

Back 151

does not have lymphatic input
recognizes antigens in the vascular space (NOT in the tissue space)

Front 152

Where in the spleen are the lymphoid cells found?

Back 152

in the white pulp (around the arterioles)
bulk of the lymphocytes are found in the periarterial lymphatic sheath (PALS) where they await antigens

Front 153

Where is mucosal lymphoid tissue found and what specific cell type do they possess?

Back 153

Oral cavity (tonsils)
brochial associated lymphoid tissue (BALT)
gut associated lymphoid tissue (GALT)
they have M cells which allow antigens to pass into them so they can be identified

Front 154

Where are Peyer’s patches found?

Back 154

in the small intestine (mainly jejunum), under the lamina propria; a layer of M cells lies directly above the Peyer's patch to import foreign antigens

Front 155

What are the receptors that recognize antigen called on B cells vs. those on T cells?

Back 155

B Cells: immunoglobulins
T Cells: T cell receptor (TCR)

Front 156

What is the difference in function between T-helper cells and T-cytotoxic cells?

Back 156

T Helper Cells: release cytokines in response to a foreign antigen that pull in T-cytotoxic cells and B lymphocytes
T Cytotoxic Cells: recognize and immediately destroy foreign antigen

Front 157

What co-receptor is found on T-helper cells and T-cytotoxic cells, respectively?

Back 157

T-Helper: CD4
T-cytotoxic: CD8

Front 158

What is meant by the T-suppressor cell?

Back 158

it is not a cell in itself, but rather a fcn of T-cytotoxic cells

Front 159

What is the difference in the variable and constant regions of the antibody?

Back 159

variable region: antigen-binding site
constant regoin: effector fucntion (signals celll that an antigen has been recognized)

Front 160

How does antigen recognition differ between B cells and T cells?

Back 160

B Cell: recognizes native antigen
T Cell: recognizes "chewed up" antigen

Front 161

What two signals are needed for lymphocyte activation for B cell and T cells, respectively?

Back 161

B Cell: antigen receptor binding and activation by a T-Helper cell
T Cell: recognition of a peptide of antigen that is expressed on the surface of another cell (antigen-presenting cell) and activation by the APC

Front 162

What is the anamnestic response?

Back 162

secondary immune response of the aquired immune system to a particular antigen (much greater response than primary immune response)

Front 163

What is presented by MHC-I and MHC-II, respectively, and which T cell interacts with each?

Back 163

MHC-I: present foreign protein made inside the cell (i.e. viral protein) which is recognized by T-cytotoxic cells
MHC-II: presents a phagocytosed peptide which is recognized by T-helper cells

Front 164

What is the subset of MHC-I and on which cells is it expressed?

Back 164

HLA-A, HLA-B, HLA-C
expressed on ALL nucleated cells (since all cell can become infected w/ a virus)

Front 165

What is the subset of MHC-II and on which cells is it expressed?

Back 165

HLA-DP, HLA-DQ, HLA-DR
expressed on macrophages, dendritic cells, and B cells (i.e. antigen-presenting cells)

Front 166

What are the two different results that can occur when a free antibody binds to a pathogen?

Back 166

Neutralization: antibodies prevent pathogen from infecting host cells
Opsonization: macrophages bind to the constant region of the antibody and phagocytose it along w/ pathogen

Front 167

What is the specificity for an Ig with a valence of 10?

Back 167

1 - every Ig, no matter what the valence, has a specificity of one

Front 168

What does polyclonal antibodies refer to?

Back 168

a polyclonal response of many monoclonal antibodies to an antigen with multiple epitopes

Front 169

What is known, in general terms, about the genes that comprise the variable region of Ig?

Back 169

they consist of a V gene, which codes for the bulk of the variable region, and a J gene, which codes for a small portion of the variable region; the J gene is found separate on the human genome from the V gene

Front 170

What changes does germline DNA undergo while forming the light chain of Ig?

Back 170

Germline DNA undergoes somatic recombination which removes the DNA b/w the V and J genes --> this piece of DNA is then transcribed into a primary RNA transcripts --> mRNA splicing removes the RNA b/w the V-J genes and the C gene --> the formed mature RNA transcript is then translated to form the actual polypeptide chain of the Ig

Front 171

What is meant by the 12-23 rule regarding the recombination signal sequence?

Back 171

Each V/J gene has a DNA sequence consisting of a heptamer (conserved) - 12/23 nucleotide spacer - nonamer (conserved)
recombination can only happen b/w a gene w/ a 12 nucleotide spacer and another with a 23 nucleotide spacer (i.e. 1 turn of the helix vs. 2 turns of the helix)

Front 172

What are the enzymes in lymphocytes called that activate the recombination signal sequence and how do they function?

Back 172

RAG1/RAG2 (recombinase activating genes)
two RAG enzymes attach themselves to the V and J regions and subsequently combine
all of the genetic material b/w the V and J regions forms a loop which is cleaved off by RAG
the loop (singal joint) is then degraded by endonucleases

Front 173

How is the V-J coding joint formed by RAG?

Back 173

RAG complex binds to and randomly cleaves recombination signal sequences to yield a DNA hairpin --> RAG-mediated cleavage of hairpin generates palindromin P-nucleotides --> the enzyme TdT adds N-nucleotides to the ends of the P-nucleotides --> strands are paired, unpaired nucleotides removed (by exonucleases) and the gaps are filled by DNA synthesis

Front 174

What is the DNA polymerase called that only functions in lymphocytes and what is characteristic of it?

Back 174

TdT (terminal deoxynucleotidal transferase) - polymerases nucleotides without template

Front 175

What are the three hypervariable regions of Ig comprised of, respectively?

Back 175

2 of the regions are coded for by V genes and 1 is generated randomly by TdT

Front 176

What portion of the rearrangements of an Ig gene are abortive and why?

Back 176

~50% - occurs b/c when TdT adds nucleotides it causes a frameshift in 2/3 of the Ig genes, generating a stop codon in about half of all sequences

Front 177

What enhances transcription of an Ig gene?

Back 177

rearrangement if the Ig gene brings the enhancer closer to the promoter, resulting in enhanced transcription

Front 178

How does the diversity region of the heavy chain gene get incorporated into its variable region?

Back 178

by the 12-23 rule (RAG1-2) where J and D recombine first, followed by recombination of of V with the new J-D region

Front 179

What is the key feature that distinguishes the heavy chain variable region from the light chain variable region?

Back 179

the heavy chain variable region has V, J, and D segments, wheras the light chain variable region only has V and J segments

Front 180

How is it possible that different isotypes possess the same idiotype?

Back 180

After the VJD region has recombined to determine idiotype, the CH genes on chromosome 14 can recombine to form any isotype

Front 181

Which is the first Ig isotype expressed and which is subsequently expressed?

Back 181

IgM is first, then IgD (can be expressed in the bone marrow or shortly after leacing the bone marrow, but it is expressed PRIOR to antigen binding)

Front 182

What characterizes IgD as opposed to other immunoglobulins?

Back 182

it is never found in secretion, but only in its membrane-bound form (function is unknown)

Front 183

Which two Ig isotypes can be expressed at the same?

Back 183

IgM and IgD (only possibility) b/x they are expressed on the same strand of RNA

Front 184

What keeps the Ig attached to the cell surface of a B cell?

Back 184

IgAlpha and IgBeta

Front 185

What happens if a B cell undergoes an abortive rearrangement?

Back 185

it either recombines until a proper protein has been made (it senses the presence of the protein in the cytoplasm) or it dies by apoptosis

Front 186

What is the difference between immunoglobulin and antibody?

Back 186

Immuniglobulins are expressed on B cells but they do not necessarily recognize any available antigen
Antibodies are secreted from plasma cells (activated B cells) and they will respond to the antigen that activated the original B cell

Front 187

Which of the globulins is immunoglobulin?

Back 187

Gamma-globulin

Front 188

Which parts of the immunoglobulin have an identical structure and where are the disulfide bonds located?

Back 188

each light chain is identical and each heavy chain is identical
2 disulfide bonds are found b/w the heavy chains, and 1 b/w each heavy chain and light chains

Front 189

Which end of the immunoglobulin is the variable region and what parts of the immunoglobulin does it comprise?

Back 189

the amino end is variable and it comprises the ends of both the light and heavy chains

Front 190

What are the 6 domains of immunoglobulin?

Back 190

Variable: VH, VL
Constant: CL, CH1, CH2, CH3

Front 191

What gives the immunoglobulins their strength and stability in a noxious environment?

Back 191

they are mainly composed of beta-pleated sheets

Front 192

Where on the immunoglobulin is the antigen-binding site found and what is the part of the antigen called that binds here?

Back 192

between the VH and VL domains on each arm
this is where the epitope binds

Front 193

What is the valence of IgG and what does this mean?

Back 193

Valence = 2, this means that there are 2 binding sites on the immunoglobulin

Front 194

What aspect of the immunoglobulin allows it the flexibility to bind multiple antigens at variable angles?

Back 194

the hinge regions (located b/w CH1 and CH2)

Front 195

What different parts does immunoglobulin divide into after proteolytic cleavage by papain and pepsin, respectively?

Back 195

Papain: 2 Fab (antibody binding fragment) and Fc (crystallizable fragment)
Pepsin: F(ab)2 (both antibody binding regions still attached together) and pFc (chewed up crystallizable fragment)

Front 196

What are the 5 different heavy chain immunoglobulin isotypes (classes) and on what chromosome are they all coded?

Back 196

IgG, IgM, IgD, IgA, IgE, all coded on chromosome 14

Front 197

What are the 2 light chain immunoglobulin isotypes (classes) and on what chromosome is each coded?

Back 197

Kappa on chromosome 2
Lambda on chromosome 22

Front 198

What does the concept of allelic exclusion refer to regarding heavy and light chains?

Back 198

Heavy Chain: only one chromosome is used to create heavy chains of immunoglobulin (the other is silent)
Light Chain: either kappa or lamba is expressed on onlyy one chromosome (the other is silent)

Front 199

What are allotypes in regard to the heavy chain of immunoglobulin?

Back 199

differences in the variable region of Ig within the individual

Front 200

What does idiotype refer to?

Back 200

differences in the sequence of the heavy chain b/w individuals

Front 201

What is the most common immunoglobulin found in serum and what are some of its characteristics?

Back 201

IgG - it has 4 subclasses (IgG1-4) and a valance of 2; its MW is 160,000

Front 202

What is the only immunoglobulin expressed on the cell surface in bone marrow and what are some of its characteristics?

Back 202

IgM (first Ig expressed on cell memb) - 5-10% of total serum Ig, MW 180,000

Front 203

How does IgM differ when found on the surface of lymphocytes vs. secreted IgM?

Back 203

it appears on the surface of lymphocytes as a monomer (MW 180,000) but is a pentamer in its secreted form ((MW 9000,000 with a valence of 10); the monomers are polymerized by J chain (which is made by B cells) and the pentamer cannot cross the placenta because of its large size

Front 204

Which is the primary Ig made in the lymphoid tissues and what are some of its characteristics?

Back 204

IgA: 10-15% of serum Ig, predominant Ig in secretions, polymerized by J chain to form a dimer (MW 600,000 with a valence of 4); has 2 subclasses (IgA1-2)

Front 205

What happens to dimeric IgA after it is secreted, as it moves from the basolateral surface to the lumen?

Back 205

it binds to a poly-Ig receptor as it tracels through the epithelial cell; part of this receptor remians attached to the IgA as it exits the cell and is known as the "secretory piece"

Front 206

Which Ig is responsible for symptoms of allergy, hives, and asthma, and what are some of its characteristics?

Back 206

IgE - has very low serum concentrations; normally binds to receptors on mast cells causing degranulation and histamine release

Front 207

How does the FcεR1 receptor on mast cells differ from almost all other Fc receptors?

Back 207

it can bind IgE before the IgE has come in contact with its specific epitope; all other Fc receptors can only bind Ig that has already contacted its epitope

Front 208

What kinds of forces are involved with antigen-antibody interactions and how do these relate to antibody affinity?

Back 208

non-covalent forces: electrostatic forces, H-bonds, van der Waals forces, Hydrophobic forces
Anitbody affinity depends on the precise fit and forces elicited when the antigen comes in contact with the antibody (this can range from high to low affinity)

Front 209

What are hypervariable regions and how many exist on each variable Ig domain?

Back 209

regions of variable Ig domains that express a large amount of variability (also known as complementarity-determining regions); they comprise the actual antigen-binding site; there are three of these variable regions per variable domain (HV1-3)

Front 210

What is the difference between a linear and a discontinuous epitope?

Back 210

linear: antibody binds a linear, continous sequence of amino acids on the antigen
Discontinuous: antibody binds amino acids from different parts of the antigen

Front 211

How are monoclonal antibodies created and what is their purpose?

Back 211

B cells from a mouse are immunized with a specific antigen --> these cells are fused with myeloma cells to make them immortal --> they are grown in drug-containing medium so that only hybrid cells survive --> antigen-specific hybridomas (B cell + myeloma cell) are selected and used to clone massive amounts of antigen-specidic antibodies

Front 212

What are the components of a T cell receptor (TCR)?

Back 212

Variable region with antigen-binding site
constant region
transmembrane region
cytoplasmic tail
the receptor is composed of an alpha and beta chain (broke down in Valpha/Calpha/Vbeta/Cbeta)
together they have a similar structure to the Fab component of the B cell Ig

Front 213

What post-translational modification is found on the TCR and what bond is found in the hinge region between the constant and transmembrane regions?

Back 213

post-translational modification: hlycosylation of all variable/constant regions
bond: a disulfide bond connects the two segments of the hinge region

Front 214

In regard to the genes used to produce the α and β chains, how do they compare to those used to make the light and heavy chains of the Ig molecule?

Back 214

alpha: similar to the light chain, but found on chrom 14
beta: similar to heavy chain but found on chrom 7

Front 215

Which segment of the TCR undergoes recombination first?

Back 215

beta first (D-J, then V-DJ); then alpha (V-J)

Front 216

When comparing Ig to TCR, what are some of the noticeable differences seen?

Back 216

the beta chain only has 2 D segments (vs. 25 for heavy chain)
beta chain is often read in all three reading frames (vs. rarely for heavy chain)
alpha/beta junctional diversity is much greater than that of the heavy/light chain

Front 217

What are the two classes of TCRs and what differentiates them?

Back 217

alpha beta TCR and gamma delta TCR
there is much greater variability in the alpha beta TCR
gamma delta TCR are more commonly used in mucosal tissues and they appear to be used in innate immunity as well

Front 218

Where on the genome is the δ-chain locus found and what is important about this location?

Back 218

on chrom 14 b/w the V and J genes of the alpha chain locus
after the first rearrangement of the alpha chain. the delta chain locus is excised

Front 219

What is the difference between the exocytic and endocytic pathways of antigen presentation using the major histocompatability complex (MHC)?

Back 219

exocytic: peptides from endogenous proteins (and sometimes exogenous proteins) are presented by MHC-I to cytotoxic T cells
Endocytic: peptides from exogenous proteins are endocytosed and presented by MHC-II to helper T cells

Front 220

When a pathogen is taken up in an endocytic vesicle of a macrophage, what causes its degradation?

Back 220

a combination of low pH and acid activated proteases

Front 221

When CD4+ T cells respond to a peptide presented on an MHC-II protein, what results?

Back 221

either activation to kill the intravesicular bacteria/parasites; or activation of B cells to secrete Ig to eliminate extracellular bacteria/toxins

Front 222

What is the importance of the highly polymorphic nature of MHC proteins?

Back 222

their variability ensures that they can bind to many different types of foreign peptides as well as a wide variety of T cells

Front 223

What is the key morphologic difference between the MHC-I and MHC-II?

Back 223

MHC-I is anchored by one transmembrane tail, whereas MHC-II is anchored by two

Front 224

How do MHC-I and MHC-II expression differ among cells and tissues?

Back 224

MHC-I: found mostly on T cells, B cells, macrophages (and other APCs) and neutrophils
MHC-II: found primarily on B cells, macrophages (and other APCs) and epithelial cells of the thymus, but also on activated T cells

Front 225

Which cells do not express MHCs?

Back 225

RBCs (i.e. non-nucleated cells)

Front 226

What are the major structural characteristics of MHC-I?

Back 226

composed of one single heavy chain (alpha chain) with three domains (alpha 1-3), one signle light chain (beta 2- microglobulin - Beta 2 m); only alpha 3 is inserted into the cell membrane; the peptide binding cleft is formed by the alpha helical regions of the alpha 1 and alpha 2 domains with their underlying beta sheaths

Front 227

What are the structural differences of MHC-II in comparison to MHC-I?

Back 227

MHC-II consists of a two-chain heterodimer (alpha and beta chains), both of which are inserted into the cell memb (via alpha 2 and beta 2) ; the peptide binding cleft is made by the alpha 1 and beta 1 domains and presents peptides that are 13-17 residues long (vs. 8-9 for MHC-I)

Front 228

By what process does MHC-I antigen processing and presentation occur?

Back 228

intracellular antigen is degraded by a proteosome and enters the ER --> MHC-I in the ER binds the antigen --> it is transported through the Golgi and eventually presented on the EC surface

Front 229

How does MHC-II antigen processing and presentation differ from that of MHC-I?

Back 229

the foreign antigen enters the cell through an endocytic vesicle --> this antigen is processed in a phagolysosome --> MHC-II travels from the ER through the Golgi and eventually meets up with this antigen containing vesicle --> once they fuse, MHC-II binds the antigen and travels to the EC surface

Front 230

What is the importance of the concept that MHC-II picks up antigen from a phagolysosome and not in the ER?

Back 230

it prevents MHC-II from binding MHC-I antigen

Front 231

In which MHC pathway does the proteasome play an integral part and what is its function?

Back 231

MHC-I; it contains about 28 catalytic sites which cleave unfolded protein as it passes through the proteasome; the cleaved peptides are then transported into the ER where they bind MHC-I

Front 232

What structure is utilized to transport the antigen product of the proteasome from the cytosol into the ER and what are its components?

Back 232

TAP (transporter associated with antigen processing) - consists of 2 ATP-binding cassette (ABC) domains and 2 hydrophobic transmembrane domains; the 4 domains assemble into a heterodimer with the ABCs on the cytostolic side and the hydrophobic tails in the ER

Front 233

How is the TAP transporter able to transport a wide variety of antigens in the ER?

Back 233

both its domains (TAP1-2) are coded for in two different alleles which allows for some selective variation

Front 234

What is MHC-I heavy chain bound to until β2-microglobulin binds it, and which chaperone proteins bind subsequently?

Back 234

the MHC-I heavy chain is bound to calnexin; when beta2m binds, calnexin releases and the chaperones calreticulin and Erp57 take its place; tapasin binds the complex as well on the side of the beta2m domain and creates connections b/w MHC-I and TAP

Front 235

When does MHC-I folding complete and what happens afterwards?

Back 235

folding is complete when TAP delivers a peptide that binds MHC-I; when folding has copmleted, the MHC-I is released from TAP and exported to the cell surface

Front 236

What activates the proteases found in early endosomes and what is their purpose?

Back 236

as early endosomes become late endosomes. the pH drops significantly, activating the endosomal proteasomes; these proteasomes degrade foreign antigen which is presented to MHC-II once the endosome fuses with an MHC-II vesicle

Front 237

How is MHC-II prevented from binding antigen in the ER and how is this process reversed when MHC-II leaves the trans-Golgi in its own vesicle?

Back 237

the invariant chain binds to the cleft outside of MHC-II, blocking the antigen-binding cleft; once in its own cesicle, invarient chain is cleaved, but it leaves behind CLIP fragments in its antigen-binding cleft

Front 238

How is the CLIP fragment removed from the antigen-binding cleft of MHC-II?

Back 238

when the MHC-II vesicle fuses with an endosome, HLA-DM is activated and induces opening of the MHC-II antigen-binding cleft, this releases the CLIP fragment and allows antigen to bind instead

Front 239

In what form can the invariant chain binding MHC-II be found, and where can they become dissociated from MHC-II?

Back 239

invariant chain can form a trimer, binding three MHC-II compounds at once; they can become dissociated from MHC-II in the MIIC (MHC-II compartment)

Front 240

Why does the MHC-I antigen-binding cleft bind residues that are almost exclusively 8-10 amino acids long?

Back 240

because the cleft has strong anchoring sites on each end (or on the floor of the cleft) that determine residue interactions' since there are only two anchoring sits, antigen length is restricted to 8-10 residues long

Front 241

What is the main difference between the MHC-II cleft anchoring sites and those of MHC-I?

Back 241

they are anchored throughout the entire length of the cleft, allowing for greater differences in antigen binding length; MHC-II binds to a certain core sequence deep inside of its cleft

Front 242

How are MHC-I and MHC-II genes organized on the HLA complex on chromosome 6?

Back 242

they are located on different parts of the chrom, but the components that code for TAP and the proteasome (involved in MHC-I antigen binding) are found in between the genes that code for different MHC-II compinds

Front 243

What is the meant by the fact that HLA expression is co-dominant?

Back 243

Offspring will inherit either one of the HLA alleles from each of the parents, and both acquired alleles are expressed equally in the child

Front 244

What accounts for the large diversity in MHC expression?

Back 244

Polymorphism (individuals are heterozygous for HLA genes – i.e. they have two different copies)
Polygeny (duplication of the HLA genes – i.e. there is HLA-A, HLA-B, HLA-C, HLA-DP, etc.)

Front 245

Where on the MHC molecules is the allelic variation found?

Back 245

Almost entirely on the antigen-binding cleft – on both sides of the cleft for MHC-I, but mainly on the β chain for MHC-II

Front 246

Which HLA isotypes are the most highly polymorphic?

Back 246

The classical isotypes: HLA-A, HLA-B, HLA-C and HLA-DP, HLA-DQ, HLA-DR

Front 247

Who discovered the function of the thymus, and who gave the first description of B and T cells?

Back 247

Thymus: Good and Miller
B/T cells: Raff

Front 248

What did Dennis Osmond discover in ’72?

Back 248

that B lymphocytes differentiate from stem cells EXCLUSIVELY in the bone marrow

Front 249

When hematopoietic stem cells differentiate into early pro-B cells, what detectable change occurs?

Back 249

D-J rearrangment occurs in the heavy chain genes

Front 250

When early pro-B cells differentiate into late pro-B cells, what change happens?

Back 250

V-DJ rearrangment occurs

Front 251

The presence of which cell type is absolutely essential for B cell differentiation?

Back 251

bone marrow stromal cells

Front 252

What relationship between the stromal cells and pro-B cells is required for differentiation to take place?

Back 252

the pro-B cells (and stem cells) must be directly attached to the layer of bone marrow stromal cells

Front 253

What are the different types of adhesion contacts between bone marrow stromal cells and pro-B cells and why are they important?

Back 253

VCAM-1/VLA-4
Fibronectin/FN-receptor
CD44-CD44
ckit-ligand (SCF)/ckit
the adhesions are important b/c they allow survival and proliferative signals to be sent from the stromal cells to the pro-B cells
the ckit connections are especially important

Front 254

Which free flowing cytokines, secreted by bone marrow stromal cells, cause tremendous proliferation of pro-B cells?

Back 254

IL-7
IGF-1 in response to GH (IGF-1 is also required for pro-B cells to release from the stromal cells)

Front 255

When VDJ is fully arranged and pro-B cells become large pre-B cells, what is the pre-B cell receptor composed of and what is the purpose of this receptor?

Back 255

a fully formed heavy chain composed of the mu isotype (IgM) and two associated molecules which comprise the light chain (i.e. lamba5 and VpreB) - the presence of this surface receptors stops rearrangment by RAG1-2 and signals to the cell that everything is going ok (otherwise apoptosis follows)

Front 256

What occurs after the μ chain is expressed on the large pre-B cell and the cell differentiates into a small pre-B cell?

Back 256

RAG1-2 are reactivated (slightly) and V-J rearrangement occurs on the light chain genes; this is followed expression of the mu isotype in both the cytoplasm and cell surface
when VJ rearrangment is completed, the cell becomes an immature B cell with its IgM expressed on the cell surface

Front 257

Which cytokine is required for pre-B cells to differentiate into immature B cells and where is this cytokine produced?

Back 257

IL-4 secreted from T cells (IL-4 is a necessary survival signal)

Front 258

What has to occur for immature B cells to differentiate into mature B cells?

Back 258

IgD has to be expressed alongside IgM (the cells is now ready to respond to antigen)

Front 259

What is the consequence of the fact that TdT expression is strong during heavy chain rearrangement but weak during light chain rearrangement?

Back 259

heavy chain variable regions have large N regions (lots of N-nucleotide addition) whereas light chain variable regions have an almost non-existent N region

Front 260

How does the concept of allelic exclusion apply to heavy chain rearrangement in the late pro-B cell?

Back 260

after both chromosoms have undergone D-J rearrangment, V-DJ rearrangement occurs in only one chromosome
if this rearrangement is productive, the other chromosome will not rearrange
however, if it is not productive, the second chromosome will undergo rearrangement and if this fails as well, the cell dies by apoptosis

Front 261

What is the sequence by which light chain rearrangement occurs in pre-B cells?

Back 261

Rearrangement of the κ gene on the first chromosome is usually step 1
if this fails, rearrangement on the second chromosome will occur
if this fails as well, the process will repeat itself but this time with the λ gene
if failure occurs twice here, the cell will die by apoptosis

Front 262

How is it possible for one κ or λ gene to undergo multiple rearrangements and why is this not possible on the heavy chain?

Back 262

If, after the first V-J rearrangement, there are still V and J genes remaining (i.e. they were not lost in the signal joint), RAG1-2 can cause additional rearrangements until no more available Vs and Js remain; this is not possible on the heavy chains, because a second rearrangement would get rid of the D region

Front 263

In the first several hours after formation of the immature B cell, what happens when this B cell encounters a multivalent self-antigen vs. a soluble self-antigen?

Back 263

Multivalent: the B cell is destroyed by apoptosis
Soluble: the B cell becomes anergic (it can’t generate a response to antigen)

Front 264

What can happen when an immature B cell encounters a self-antigen while RAG1-2 are still active?

Back 264

Light chain rearrangement can continue and cause the B cell to express a different idiotype (very rare event)

Front 265

What two functional regions are found in each lobe of the thymus and what is found within each of these functional regions?

Back 265

cortex: immune thymocytes and cortical epithelial cells
Medulla: mature thympcytes, medullary epithelial cells, macrophages, dendritic cells

Front 266

What happens to the vast majority of thymocytes in the thymus?

Back 266

they die by apoptosis

Front 267

On what T cells are the surface molecules CD3, CD4, and CD8 found, respectively?

Back 267

CD3: all T cells
CD4: T helper cells
CD8: cytotoxic T cells

Front 268

What is the region called where thymocytes first enter the thymus and what are they called at this point?

Back 268

subcapsular region - they are called double-negative thymocytes because they have neither CD4 nor CD8 (nor CD3)

Front 269

When double-negative thymocytes travel deeper into the cortex, what happens to them?

Back 269

they become double positive thymocytes (they gain CD4 and CD8 - as well as CD3) mediated by the cortical epithelial cells

Front 270

What is the most critical transition for the thymocytes and what happens at this transition?

Back 270

cortico-medullary junction: dendritic cells mediate negative selection creating mature CD4+ or CD8+ thymocytes by destroying self-reactive thymocytes

Front 271

What genetic rearrangements occur, and in what order, as the thymocytes goes from double-negative to double-positive?

Back 271

first, there is D-J rearrangement in the beta chain creating CD25+, CD44low double-negative thymocytes --> these thymocytes then undergo V-DJ rearrangement and produce beta chain protein --> at this point CD4/CD8 induction occurs and transcription of un-rearranged alpha chain begins (called pTalpha) --> eventually V-J rearrangment takes place on the alpha chain, and surface expression of alpha:beta:CD3 complex is seen

Front 272

What is the purpose of positive selection?

Back 272

it allows thymocytes the chance to express a functional T cell receptor before undergoing negative selection in which self-reactive thymocytes are destroyed

Front 273

What is meant by self MHC restriction?

Back 273

a T lymphocyte will only respond to a peptide antigen on the same MHC type encountered during its selection process in the thymus (i.e. it will not react with any other native/foreign MHC molecule)

Front 274

At which point does the thymocyte become either CD4 or CD8 single positive and what determines its fate?

Back 274

during its interaction with the cortical epithelial cells
if the thymocyte comes in contact with an MHC-I molecule, it will continue to express CD8 but not CD4 (becoming a cytotoxic T cell)
if it comes in contact with an MHC-II molecule, it will continue to express CD4 but not CD8 (becoming a T Helper cell)

Front 275

What must be true of a thymocyte for it to pass through positive and negative selection without dying by apoptosis?

Back 275

positive and negative selection must have different specificity and avidity (binding strength)
also during positive selection, the self-antigen on the MHC must be recognized poorly by the thymocyte and deliver a partial signal (if it is not recognized well, the thymocute will die by apoptosis)

Front 276

As T cells enter the lymph node, where do they go?

Back 276

They interact with dendritic cells in an attempt to recognize their specific antigen
if this does not occur, they will move back into circulation and out of the lymph node
however, if they do encounter their antigen, they will stay in place, proliferate, and differentiate into effector T cells

Front 277

Which cell-surface adhesion molecules are important for initiating the interactions of lymphocytes with APCs?

Back 277

(T-cell:APC) CD2:LFA-3
LFA-1:ICAM-1
LFA-1:ICAM-1
ICAM-3:DC-SIGN

Front 278

Once LFA-1 on the T cell binds with ICAM-1 on the APC, what does it allow for?

Back 278

It brings the TCR and MHC-II closer together so that they can recognize each other; if recognition occurs, a signal will be sent by the T cell that induces a conformational change in LFA-1, increasing its affinity for ICAM-1 and prolonging cell-cell contact

Front 279

When the TCR makes contact with an MHC molecule, how do they align?

Back 279

The TCR will lie across diagonally with its α and β chain CDR3 loops contacting the center of the peptide
the CDR1 and CDR2 of the α chain contact the MHC helices at the amino terminus whereas the CDR1 and CDR2 of the β chain contact the MHC helices at the carboxyl terminus

Front 280

What two events must occur for normal T-cell recognition of peptides to occur?

Back 280

The T cell must be both antigen-specific and self-MHC restricted (i.e. it has to fit together with both the antigen and the MHC molecule)

Front 281

How does T-cell recognition occur in the case of alloreactivity?

Back 281

It involves direct recognition of a foreign MHC-peptide complex
this can involve peptide-dominant or MHC-dominant binding (i.e. the T cell binds strongly to either the foreign peptide or to the foreign MHC molecule)

Front 282

How is a superantigen able to activate large numbers of T cells?

Back 282

After binding the MHC-II molecule, the superantigen is able to activate TCRs on the basis of their Vβ region, not their hypervariable regions
since Vβ regions are much less specific than hypervariable regions, the superantigen can activate many T cells that share a similar structure in this region

Front 283

What are some classic examples of superantigens?

Back 283

Staphylococcal enterotoxins, toxic shock syndrome toxin (TSST), MMTV-7 (mammary tumor virus)

Front 284

Where do the CD4 and CD8 receptors of T cells bind the MHC molecule?

Back 284

CD4: binds MHC-II β2 domain
CD8: binds MHC-I α3 domain

Front 285

What parts make up the T cell receptor complex?

Back 285

Antigen-recognition proteins (i.e. the α and β chain); Invariant signaling proteins (i.e. CD3 complex: ε, γ, δ, and ζ chains)

Front 286

How is activation of the CD3 complex achieved?

Back 286

CD45 is a phosphatase which dephosphorylates Fyn and Lck, taking away their inhibition
clustering and activation of the TCR/co-receptors activates Fyn and Lck, allowing them to phosphorylate tyrosine residues on the CD3ε and ζ chain ITAMs; this allows ZAP-70 to bind and become phosphorylated
ZAP-70 then goes on to phosphorylate other molecules which in effect alters gene expression in the nucleus

Front 287

What two signals are required to activate a naïve T cell and what happens when only one of these signals is present?

Back 287

TCR/co-receptor binding to the MHC/peptide complex AND interaction between the T-cell CD28 with B7 on a dendritic cell (for example); if only the co-stimulators bind (CD28/B7) there is no effect, but if the TCR/co-receptor binds with the MHC/peptide complex without the co-stimulators, anergy of the T cell results (i.e. the T cell will no longer respond to antigen)

Front 288

What happens after the initial cross-linking of CD28 with B7 in T cell activation?

Back 288

Expression of CTLA-4 is induced; CTLA-4 binds B7 more avidly than CD28 did and delivers inhibitory signals to the activated T cell

Front 289

What is the distribution of dendritic cells, macrophages, and B cell in lymph nodes, respectively?

Back 289

Dendritic cells: cortex T-cell areas (not in follicles); Macrophages: throughout cortex and follicles; B cells: mainly in follicles

Front 290

How do immature dendritic cells differ from their mature form?

Back 290

They are located in peripheral tissues and are very phagocytic; once they have taken up foreign antigen, they migrate to the lymphoid tissues, lose their phagocytic function, and become much more potent antigen-presenting cells

Front 291

How does the response of macrophages differ when taking up a nonbacterial protein vs. bacteria?

Back 291

In the case of a nonbacterial protein, the macrophage will not express the B7 molecule and so any T cell that interacts with it will become anergic; however, when the macrophage takes up bacteria, it will express B7 and T cells will become activated – in certain cases, a macrophage can take up a nonbacterial protein and bacteria at the same time, in which case T cells will become activated in response to the nonbacterial protein as well

Front 292

On what cells are high-affinity IL-2 receptors found and what is the response from the cell when this receptor becomes activated?

Back 292

Only found on activated T cells – these activated T cells secrete high amounts of IL-2 and activate their own receptor in an autocrine fashion; activation of the IL-2 receptor leads to T-cell proliferation

Front 293

After proliferation of naïve T cells, what type of cells do they differentiate into?

Back 293

immature effector T cell (TH0); this cell differentiaties into either a TH1 or a TH2 cell

Front 294

What is the difference between the TH1 and TH2 cells?

Back 294

TH1: activates macrophages, induces B cells to produce opsonizing antibody
TH2: activates B cells to make neutralizing antibody, has various effects on macrophages

Front 295

By what mechanisms can CD4 T cells cause activation of CD8 T cells?

Back 295

if the CD4 T cell is an effector T cell (i.e. it has already encountered its antigen), it will activate the APC which in turn will broduce B7 which can co-stimulate the naive CD* T cell
alternatively, if a naive CD$ T cell (TH1) encounters its MHC/peptide complex and is co-stimulated by B7, it will begin to secrete IL-2, which in turn can activate a naive CD8 T cell without being co-stimulated by B7

Front 296

What is the process by which a CD8 T cell (cytotoxic T cell) causes destruction of a cell?

Back 296

the T cell makes nonspecific adhesions to its target cell --> if recognition occurs, redistribution of the cytoskeleton and cytoplasm of the T cell takes place, leading to the release of lytic granules at the site of cell contact --> this leads to destruction of the target cell (e.g. by apoptosis)

Front 297

What distinct set of effector molecules is produced by cytotoxic T cells, TH1, and TH2 cells, respectively?

Back 297

cytotoxic: perforin, granzymes, granulysin, Fas ligand
TH1: IFN-gamma, GM-CSF, TNF-alpha, CD40L, Fas ligand
TH2: IL-4, IL-5, CD40L

Front 298

What are the effects of the lytic granules perforin, granzymes, and granulysin, respectively?

Back 298

perforin: polymerizes to form a pore in the target membrane
granzymes: serine proteases which activate apoptosis once in the cytoplasm of the target cell
granulysin: induces apoptosis

Front 299

How do cytotoxic T cells prevent from killing cells that neighbor its target cell?

Back 299

they have a very polar/focused mode of secretion

Front 300

When a T H1 cell causes activation of a macrophage, what changes take place in the macrophage?

Back 300

they greatly increase their microbicidal effectiveness and amplify the immune response by presenting a large number of new molecules on their surface, such as CD40, B7, TNF-alpha, MHC-I and MHC-II

Front 301

What happens when a T H1 cell secretes IFN-γ and CD40, and what is the effect of that T H1 cell secreting Fas ligand or TNF-β?

Back 301

IFN-gamma/CD40: activates macrophages to destroy engulfed bacteria
Fas ligand/TNF-beta: kills chronically infected cells, releasing bacteria, to be destroyed in fresh microphages

Front 302

What results when an intracellular pathogen or its constituents cannot be totally eliminated from the macrophage?

Back 302

formation of a granuloma, which has a central portion that contains a still infected multi-nucleated giant cell, surrounded by a mass of T cells

Front 303

When B cells become activated after their Ig binds epitope, what sequence of events takes place, eventually resulting in changes of gene expression?

Back 303

The B cell receptors (Ig) cluster and cross-link --> this allows receptor-associated kinases (e.g. Blk, Fyn, Lyn) to phosphorylate the ITAMs (immunoreceptor tyrosine-based activation motif) on IgAlpha and IgBeta --> the tyrosine kinase, Syk, then binds to the doubly-phosphortlated ITAMs and is activated --> activation of the tyrosine kinase sends signals to the nucleus where changes in gene expression take place

Front 304

Where is CD45 found and what is its purpose?

Back 304

it is a tyrosine phosphatase found on all leukocytes which augments the activation of receptor-associated kinases (Blk, Fyn, Lyn) upon activation of B cells by antigen

Front 305

What are the B cell co-receptors and by what mechanism do they enhance B cell activation?

Back 305

CD81, CD19, CD2 (CD21)
when the complement C3d binds to a pathogen, it can interact with CR2 and by means of the co-receptors enhance B cell activation

Front 306

What function does CD22 serve?

Back 306

it is a negative regulator of B cell activation

Front 307

What are the two parts of lymphocyte activation and what signal is responsible for each?

Back 307

Competence (lymphocyte activation: caused by a naive lymphocyte in G0 binding to its antigen
Progression (lymphocyte proliferation/differentiation): induced by signals from T-helper cells --> causes S-phase entry of a B lymphocyte in late G1

Front 308

What is meant by the concept of linked recognition?

Back 308

in order to have a TD (thymus dependent) antibody response, the B cells and their associated T-helper cells must respond to the same antigen

Front 309

Once a B cell has bound its antigen, by what mechanism does the T-helper cell cause activation of the B cell?

Back 309

after capping of Ig on the B cell (Ig converges and cross-links in one area of the B cell), the antigen is endocytosed and degraded --> MHC-II binds peptides from the degraded antigen and moves to the surface --> T-helper cells recognize the peptides on MHC-II and bind --> it then produces CD40L (which binds the CD40 on the B cell) and cytokines causing proliferation and differentiation of the B cell

Front 310

What does the increase in ICAM-1 due to CD40L binding cause and what is its purpose?

Back 310

ICAM-1 is an intergrin which binds to the environment causing the B cell to stay put in close proximity to where it was activated, thus making time for the antibody response to take place

Front 311

In general terms, what happens after the B cell has been activated the second time?

Back 311

it divides about 6-10 times and differentiates to become a mass producer of antibody

Front 312

What do the terms hapten and carrier refer to and what is their experimental significance?

Back 312

Hapten: an epitope of an antigen recognized by B cells
Carrier: an epitope of the same antigen recognized by T-helper cells - if an antigen is so small that the B cell can recognize it (i.e. the hapten is antigenic) but the T-helper cell cant find an epitope to bind to, the hapten is not immunogenic (since it cant elicit an immune response)

Front 313

What happens in terms of differentiation of the B cell when CD40L binding occurs?

Back 313

the B cell switches from making IgM to making a different Ig isotype

Front 314

What is the first cytokine released by the T-helper cell in response to its activation and from what location of the T-helper cell is it released?

Back 314

IL-4
all of the organelles of the T-helper cell undergo capping and the secretory apparatus of the cell aligns so that the cytokines are only excreted where the B and T cells connect

Front 315

After IL-4 has been produced by the T-helper cell following its activation, what other cytokines are formed and what is the function of all of these cytokines?

Back 315

Proliferation Cytokines: IL-2, IL-4, IL-5
Differentiation Cytokines: IL-2, IL-4, IL-5, IFN-gamma, TGF-beta

Front 316

How do activated B cells and T-helper cells meet in the lymph node?

Back 316

B cells leak out of the high endothelial venules (HEV) and meet up with T-Helper cells which have been activated by the same antigen because of their interaction with a dendritic/Langerhans cell
Once they meet and interact, they form a primary locus/follicle in the lymph node where proliferation/differentiation of B cells occurs

Front 317

Once a primary lymph follicle has been created in the T-cell area, what happens next?

Back 317

The primary follicle migrates to the B-dependent area where it becomes a secondary germinal center

Front 318

What are the various parts of a secondary follicle/germinal center?

Back 318

Dark Zone: lymphocyte proliferation
Light Zone: contains a large amount of follicular dendritic cells
Mantle Zone: contains mature lymphocytes (e.g. plasma cells)

Front 319

When do germinal centers begin to appear, comparing primary vs. secondary exposure?

Back 319

Primary: ~ 1 week
Secondary: 2-3 days

Front 320

What three key events occur in the germinal center?

Back 320

B cell proliferation
Isotype switching (mostly to IgG)
Affinity Maturation (affinity get stronger as the B cell matures)

Front 321

How do follicular dendritic cells help to prolong an immune response?

Back 321

They have Fc receptors and complement receptors (CR2) which can hold the immune complex (iccosomes = antibody + antigen) in place so that B cells can contine to get stimulated; once B cells lose stimulation by antigen, they die by apoptosis

Front 322

What is the half-life of a B cell comparing those that successfully enter lymphoid follicles (i.e. they have encountered antigen) and those that fail to enter?

Back 322

Fail to enter: ~ 3 days
Successfully enter: ~ 2 weeks

Front 323

How do general capillaries and brain capillaries differ?

Back 323

General Capillaries: discontinuous and relatively permeable to unbound drugs
Brain Capillaries: physically joined and creat a significant barrier for drugs

Front 324

What are some common ways for drugs to travel through cell membranes and what are examples of drugs that use those mechanisms?

Back 324

Endocytosis (e.g. absorption of complexes of iron and proteins - transferrin)
Facilitated Diffusion (e.g. glucose and Vit B12)
Active Transport (e.g. Levo-Dopa and Gabapentin)
Diffusion (most important mechanism - required non-ionized moiety that is lipophilic)

Front 325

What forms of a drug can move by bulk flow to the interstitial space?

Back 325

both the ionized and unionized forms (but NOT hte bound forms)

Front 326

In what case is it possible for protein-bound drug to diffuse through the discontinuities of general capillaries?

Back 326

during inflammation

Front 327

By what mechanisms can drugs flow across the blood-brain barrier?

Back 327

by diffusion if the drug is unionized
through endocytosis of the ionized/unionized forms
during infammation

Front 328

What two factors does the drug ionization of a weak base or a weak acid depend on?

Back 328

pKa (-log of H+ dissociation constant) and pH (H+ concentration of the biophase in which it exists)

Front 329

What does a high pKa indicate for any given compound?

Back 329

that it easily attracts a hydrogen ion

Front 330

8. What are the normal pH values for blood, CSF, gastric fluid, intestinal fluid, glomerular filtrate, and urine?

Back 330

blood: 7.4
CSF: 7.2
gastric fluid: 1-2
intestinal fluid: 5-6
glomerular filtrate: 7.4
urine: 6

Front 331

At a low pH, in what form are drugs found that are either a weak base or a weak acid?

Back 331

Weak Base: ionized
Weak Acid: unionized

Front 332

What is the Henderson-Hasselbach equation?

Back 332

pH = pKa + log (A-/HA) and pH = pKa + log (B/HB+) for a weak acid and weak base, respectively

Front 333

At what point is 50% of a drug found in its ionized form?

Back 333

when their pKa is equivalent to the pH of their environment

Front 334

What is meant by the term ion trapping?

Back 334

it describes the unequal division of ions b/w different compartments in the body (i.e. the ionized form gets trapped in one compartment because of the pH in that compartment) - for a weak acid, the ions get trapped in the compartment with the higher pH whereas with a weak base the ions will be trapped in the compartment with the lower pH (i.e. in gastric juice)

Front 335

What is the partition coefficient a measurement of?

Back 335

Lipophilicity (is more important to diffusion rate than non-ionized fraction when comparing thiopental and pentobarbital)

Front 336

What structures can a drug bind before binding its active receptor (i.e. to remain in the drug reservoir)?

Back 336

Soluble proteins in blood, protein in tissue, fat deposits - the sequestration of drugs in these reservoirs prolongs its action (keeps it from being degraded or excreted)

Front 337

What factors can influence a drug’s binding capacity and what effects can this have on the patient?

Back 337

Two drugs can compete for the same binding site
certain diseases can influence a drug's binding capacity (e.g. hypoalbuminemia)
if the drugs binding capacity is decreased, plasma levels will increase causing possible toxicity of the drug

Front 338

What are some examples of binding proteins that will bind basic drugs?

Back 338

albumin (also binds acidic compounds), α1-acid glycoprotein, lipoproteins

Front 339

What other processes function to balance out a sudden increase in free drug levels when the drug has been displaced from its binding protein by a competitor?

Back 339

increased metabolism and excretion

Front 340

Which diseases reduce albumin binding?

Back 340

hypoalbuminemia, hyperbilirubinemia, uremia

Front 341

During which diseases is α1-acid glycoprotein increased and what effect does this have?

Back 341

cancer, arthritis, Chron's disease
causes an increase in the binding of basic drugs and thus higher doses are needed to exert the same therapeutic effects

Front 342

For what sites of infection are antibodies effective?

Back 342

Extracellular sites (interstitial spaces, blood, lymph, epithelial cells), but NOT for intracellular spaces (cytoplasm, vesicles)

Front 343

By what DIRECT mechanisms can pathogens cause damage and what are some examples of diseases that result from each mechanism?

Back 343

exotoxin production (secretions form pathogen): boil, food posioning, cholera, tetanus
Endotoxin (toxin is intrinsic part of pathogen): gram-negative sepsis, meningitis, pneumonia
Direct cytopathic effect (directly kill the cell): lots of viral infections

Front 344

By what INDIRECT mechanisms can pathogens cause damage and what are some examples of diseases that result from each mechanism?

Back 344

Immune complexes: kidney damage
Anti-host antibody: rheumatic fever
Cell-mediated immunity: tuberculosis

Front 345

By what mechanisms do macrophages destroy pathogens?

Back 345

acidification, toxic oxygen derived products, toxic nitrogen oxides, antimicrobial peptides, enzymes (lysozymes, acid hydrolases), competitors (Vit B12 protein and lactoferrin for Fe)

Front 346

Which T effector cells respond to parasites?

Back 346

CD4 TH2 cells - they are important for switching to IgE production

Front 347

What is the purpose of the CD4 regulatory cells?

Back 347

They suppress T-cell response to prevent auto-immune disease

Front 348

What is the primary antigen-presenting cell used in the acquired immune response?

Back 348

dendritic cell (it is ubiquitous throughout the body)

Front 349

What do TH17 cells do?

Back 349

they activate fibroblasts and epithelial cells to bring in neutrophils

Front 350

What is the difference between a toxin and a toxoid?

Back 350

a toxoid is the inactive form of the toxin which can be used as a vaccine

Front 351

Which Ig isotypes are best at activating the complement system?

Back 351

IgM and IgG3

Front 352

What is meant by “original antigenic sin”?

Back 352

after an initial antigenic response, the immune system will only respond to previously presented epitopes during a second exposure, even though the organism causing the second infection may have different epitopes that those found on the original organism - this concept has been found to exist in response to influenza, malaria, and HIV

Front 353

What concept of drug metabolism does flurazepam exemplify?

Back 353

Drugs which are both active and have an active metabolite – also, the half-life of the drug and the metabolite must be taken into consideration (for flurazepam T1/2 = 2-3 hrs, and its metabolite desalkylflurazepam has a T1/2 of 30-100 hrs)

Front 354

What is the end-result from a CYP450 drug metabolism?

Back 354

Oxidation of the parent drug

Front 355

In which case can Phase II metabolism occur without prior Phase I metabolism?

Back 355

If the parent compound already contains a functional group that can be directly conjugated

Front 356

What type of reaction is involved in Phase II metabolism?

Back 356

Biosynthetic metabolism (i.e. an endogenous substrate conjugates with the Phase I metabolite)

Front 357

What are the characteristics associated with Phase I metabolism?

Back 357

Usually oxidation that inactivates the parent compound by unmasking a functional group which makes it more polar; if the metabolite is polar enough, the metabolite will be excreted, otherwise it will undergo Phase II metabolism – instead of oxidation, the parent compound can also undergo reduction or hydrolysis in Phase I metabolism

Front 358

What are the various aspects of “first-pass” metabolism?

Back 358

Liver metabolism before entering general circulation; Intestinal metabolism (chlorpromazine, cyclosporine); Gastric acid (PPIs: omeprazole,esomeprazole); Digestive enzymes (insulin)

Front 359

What is the main organ of drug metabolism?

Back 359

Liver (also lungs, kidney, intestine, placenta in decreasing order)

Front 360

What is the usual end-result of drug metabolism by the body?

Back 360

Usually less pharmacologically active, more polar, more water soluble, more readily excreted

Front 361

What are drugs called that are activated by metabolism and what is an example?

Back 361

Pro-drugs: codeine  morphine (also cyclophosphamide, carbamazepine, proton pump inhibitors)

Front 362

What are polarized drugs more readily excreted?

Back 362

Non-ionized drugs can diffuse across cell membranes to be reabsorbed in the blood stream; however, if it is ionized, this diffusion will not be possible and the drug will be excreted

Front 363

What P450 isoform is responsible for the metabolism of ethanol and acetaminophen?

Back 363

CYP2E1

Front 364

Which drugs are considered inhibitors of CYP2A6 and CYP2B6?

Back 364

Tranylcypramine, methoxysalen

Front 365

Which drugs are considered inhibitors of CYP1A1 and CYP1A2?

Back 365

Fluoxetine, cimetidine, ciprofloxacin

Front 366

What effect will a low sulfate diet, along with acetaminophen intake have on the patient?

Back 366

Acetaminophen will not be metabolized as rapidly, leading to toxic levels of acetaminophen which can cause liver failure

Front 367

By what mechanism does irreversible enzyme inhibition take place and how can this process be resolved?

Back 367

An inhibitor is metabolized to a form that irreversible binds to and inactivates the enzyme (e.g. erythromycin and 3A4); can only be resolved by synthesizing new enzyme

Front 368

By what two mechanisms can competitive enzyme inhibition occur?

Back 368

Two drugs bind to the same active site on an enzyme (e.g. macrolide antibiotic and statin on 3A4); One drug that functions as a substrate and another that inhibits the enzyme (codeine and quinidine on 2D6)

Front 369

What enzymes are responsible for Phase II metabolism, where in the cell are they found, and what can complicate their functioning?

Back 369

Transferases; can be microsomal or cytosolic – the transferases use endogenous substances (e.g. sulfate) for their reaction mechanisms, so a lack of these substances in diet can result in problems with drug metabolism

Front 370

What is the most predominant P450 isoform, and what is the importance of its closely related isoforms?

Back 370

CYP3A4 (accounts for 50% of all drug oxidations) – CYP3A5 has a similar specificity but is not expressed in all individuals (determined by genetics); CYP3A7 is also similar but is only expressed in the fetus

Front 371

Which drugs, with narrow therapeutic indices, are metabolized by CYP2C9?

Back 371

Phenytoin, warfarin (also metabolizes NSAIDs) – responsible for 20% of all drug oxidations

Front 372

Which P450 isoform comprises only about 5% of all liver isoforms, but actually accounts for around 30% of all drug oxidations?

Back 372

CYP2D6 (responsible for codeine  morphine metabolism)

Front 373

Which drugs are considered inhibitors of CYP3A4?

Back 373

Cimetidine, erythromycin, ketoconazole, grapefruit juice, HIV antivirals

Front 374

Which drugs are considered inducers of CYP2D6?

Back 374

Dexamethasone, rifampin

Front 375

Which drugs are considered inducers of CYP2C9 and other 2Cs?

Back 375

Phenobarbital, dexamethasone, rifampin

Front 376

Which drugs are considered inducers of CYP2A6 and CYP2B6?

Back 376

Phenobarbital, dexamethasone

Front 377

Which drugs are considered inducers of CYP1A1 and CYP1A2?

Back 377

Smoking, char-grilled meat, omeprazole

Front 378

What clinical problems can arise from enzyme induction?

Back 378

Therapeutic failure when active drug concentration is lowered by enhanced metabolism; Increased drug effects when the metabolite is the active form (i.e. with pro-drugs)

Front 379

What factors are able to induce (i.e. increase) enzyme metabolism and by what mechanisms can this occur?

Back 379

Prolonged exposure to certain drugs, air pollutants, cigarette smoke, ingested materials – can occur by increased synthesis of new enzyme (e.g. dexamethasone and rifampin induction of 3A4) or by decreased proteolytic degradation of enzyme (e.g. ethanol-mediated induction of 2E1)

Front 380

Which drugs are considered inhibitors of CYP2C9?

Back 380

Fluoxetine, fluconazole, zafirlukast,

Front 381

Which drugs are considered inhibitors of CYP2D6?

Back 381

Fluoxetine, cimetidine, paroxetine, quinidine!

Front 382

Which drugs are considered inhibitors of CYP2C19?

Back 382

Fluoxetine, cimetidine, PPIs (omeprazole)

Front 383

Which drugs are considered inhibitors of CYP3A4?

Back 383

Cimetidine, erythromycin, ketoconazole, grapefruit juice, HIV antivirals

Front 384

Which drugs are considered inducers of CYP2D6?

Back 384

Dexamethasone, rifampin

Front 385

Which drugs are considered inducers of CYP2C9 and other 2Cs?

Back 385

Phenobarbital, dexamethasone, rifampin

Front 386

Which drugs are considered inducers of CYP2A6 and CYP2B6?

Back 386

Phenobarbital, dexamethasone

Front 387

Which drugs are considered inducers of CYP1A1 and CYP1A2?

Back 387

Smoking, char-grilled meat, omeprazole

Front 388

What clinical problems can arise from enzyme induction?

Back 388

Therapeutic failure when active drug concentration is lowered by enhanced metabolism; Increased drug effects when the metabolite is the active form (i.e. with pro-drugs)

Front 389

What factors are able to induce (i.e. increase) enzyme metabolism and by what mechanisms can this occur?

Back 389

Prolonged exposure to certain drugs, air pollutants, cigarette smoke, ingested materials – can occur by increased synthesis of new enzyme (e.g. dexamethasone and rifampin induction of 3A4) or by decreased proteolytic degradation of enzyme (e.g. ethanol-mediated induction of 2E1)

Front 390

Which drugs are considered inhibitors of CYP2C9?

Back 390

Fluoxetine, fluconazole, zafirlukast,

Front 391

Which drugs are considered inhibitors of CYP2D6?

Back 391

Fluoxetine, cimetidine, paroxetine, quinidine!

Front 392

Which drugs are considered inhibitors of CYP2C19?

Back 392

Fluoxetine, cimetidine, PPIs (omeprazole)

Front 393

How does age affect drug metabolism?

Back 393

Maturation of full function occurs slowly after birth; Decline in drug metabolism occurs with aging, especially affecting the elderly (this affects mainly Phase I metabolism!)

Front 394

What causes “alcohol flush”?

Back 394

A mutant allele causing a deficiency in alcohol dehydrogenase – common in Asian populations

Front 395

Which conjugating enzyme is commonly polymorphic and how does this influence those affected?

Back 395

NAT (N-acetyltransferase): acetylates isoniazid, procainamide, caffeine; people with less active enzyme will be slow acetylators and take longer to metabolize the aforementioned drugs

Front 396

What can a deficiency of CYP2C19 lead to?

Back 396

An enhanced therapeutic effect of omeprazole (reducing ulcers), possibly leading to toxicity

Front 397

Which P450 isoform is a good example of polymorphism occurring in populations?

Back 397

CYP2D6 (5-10% of European Caucasians are poor metabolizers as are 1-2% of Southeast Asians)

Front 398

During which phases of pregnancy does induction of metabolism occur?

Back 398

Second and third trimesters

Front 399

Which drugs are thought to be affected somewhat by gender differences?

Back 399

Ethanol, propranolol, benzodiazepines, estrogens, salicylates

Front 400

Which drugs are considered inducers of CYP3A4?

Back 400

Glucocorticoids, rifampin, phenobarbital, St. John’s wort!, carbamazepine, phenytoin, pioglitazone

Front 401

What types of disease will have a large effect on drug metabolism?

Back 401

Liver disease: hepatitis, alcoholic liver, biliary cirrhosis, hepatocarcinoma, fatty liver, altered liver perfusion secondary to cardiac disease

Front 402

Which Ig isotype is best at opsonization and sensitization for killing by NK cells?

Back 402

IgG – whereas IgE is best at sensitization of mast cells

Front 403

What is meant by somatic hypermutation regarding Ig exposure to antigen?

Back 403

Actively proliferating B cells experience a large amount of point mutations in their hypervariable regions (1/103 bp vs. 1/108 for normal somatic genes)

Front 404

What Ig isotype does IL-5 augment the production of?

Back 404

IgA

Front 405

When IL-4 is secreted from T-helper cells, which Ig isotypes will be produced by the B cells?

Back 405

IgG1 and IgE (also inhibition of IgG2a and IgG3)

Front 406

Which Ig isotype can easily diffuse into extravascular sites?

Back 406

IgG

Front 407

Why do IgM and IgA have trouble crossing the placenta?

Back 407

IgM is very large and IgA forms a dimer – IgG is best at crossing the placenta

Front 408

What Ig isotype is needed for protection of mucosal surfaces and what characteristic makes it function so well?

Back 408

IgA (dimer): can easily transport across epithelium

Front 409

What are the different phases of the primary acquired immune response?

Back 409

Lag phase (~1 week); Log Phase; Plateau phase; Decline

Front 410

What is found on the 5’ side flanking each Ig isotype coding domain, and what is the function of this sequence?

Back 410

A switch site (all switch sites have the same sequence) – switch recombinase links together two switch sites and loops out the connecting piece of DNA; this is how B cells can change Ig isotype in response to CD40L binding to CD40

Front 411

What is the difference in the quality of the immune response when comparing primary and anamnestic (secondary) response?

Back 411

Primary: IgM; Secondary: IgG, IgA, IgE

Front 412

Once B cells have differentiated into plasma cells, where do they travel to and what do they secrete?

Back 412

Travel to the bone marrow where they secrete massive amounts of antibody (3,000-30,000/sec)

Front 413

How do TI-2 antigens cause activation of B cell in contrast to TI-1 antigens?

Back 413

They cause extensive cross-linking of antigen receptors (since TI2 antigens are highly polymeric structures – e.g. bacterial cell wall polysaccharides and polymeric proteins like flagellin);
whereas TI1 antigens use the CD14 receptor

Front 414

What is the receptor on B cells that responds to LPS and what effect does this type of activation have at low concentrations?

Back 414

CD14 (via LBP) – at low concentrations, this signal decreases the threshold for B cell activation by another antigen on the bacterial surface

Front 415

What substance (in high concentrations), made by Gram-negative bacteria, functions as a polyclonal activator of all B cells?

Back 415

Lipopolysaccharide (LPS) = example of a TI1 antigen

Front 416

What is the key difference between T-dependent B cell activation and T-independent B cell activation?

Back 416

T-dependent B cell activation is normally used when the antigen is a protein whereas T-independent B cell activation is in response to carbohydrates (constituents of bacterial cell walls)

Front 417

How do plasma cells make the switch from secreting membrane Ig to secreting antibody?

Back 417

By differential RNA processing of the primary transcript so that the hydrophobic amino acids that normally insert in the membrane are spliced out

Front 418

What functions have plasma cells lost in comparison to B cells?

Back 418

No surface Ig, no surface MHC-II, no growth, no somatic hypermutation, no isotype switching; only high-rate Ig production

Front 419

What does somatic hypermutation of the hypervariable region of Ig lead to?

Back 419

Affinity maturation of the antibody response – i.e. mutations in the antibody variable region will lead to an increase in the affinity of the antibody for the antigen (since those mutations with lower affinity will die by apoptosis and those with higher affinity will proliferate more vigorously)

Front 420

Which enzyme, found in B cells, is responsible for creating the mutations that cause affinity maturation and by what mechanisms does it achieve this?

Back 420

Activation-induced cytidine deaminase (AID) – AID is an RNA editing enzyme which changes cytosine to uracil; it can also change single-stranded DNA, but ends up changing cytosine to adenine, thus changing a CG pair to an AT pair; (note, AID is also involved in isotype switching)

Front 421

Why are point mutations only seen in the hypervariable regions and not in any of the structural regions?

Back 421

Mutations in the structural regions will lead to a defective Ig and thus apoptosis

Front 422

How does the B cell response to TI activation differ from that of TD activation?

Back 422

Differentiation is limited to only IgM secreting plasma cells; there is no somatic hypermutation and no affinity maturation of the response; also, no memory cells are produced

Front 423

What is meant by Antibody Dependent Cellular Cytotoxicity (ADCC)?

Back 423

Cells with Fc receptors (e.g. NK cells, macrophages) recognize antibody bound to antigen  cross-linking of Fc receptors activates the cell and the antigen is destroyed;
The same process occurs with opsonization where antibody-bound antigen is recognized by Fc receptors on macrophages, thus facilitating phagocytosis of that antigen

Front 424

What must happen before the Fc receptor will bind antibody?

Back 424

The antibody must bind antigen in order to induce a conformational change so that the Fc receptor can accept it – the one exception is FcεRI, which will bind antibody without antigen bound to it (mostly associated with mast cells and allergens)

Front 425

What deficiency is found in patients with Hyper IgM Syndrome, what are the two causes, and what pathology is characteristic in these patients?

Back 425

Isotype switching is not possible – in Type 1, T cells do not produce CD40L, whereas in Type 2 there is a deficiency of the enzyme AID; both types do not have primary follicles or germinal centers in their lymph nodes

Front 426

During the first year or two of life, which Ig isotypes are found at low levels?

Back 426

IgG and IgA – they do not reach mature levels for the first several years; this normal process used to be diagnosed as perinatal immunodeficiency

Front 427

What is the primary cell transformed in follicular lymphoma?

Back 427

The B-1 B cell (as opposed to the much more common B-2 B cells)

Front 428

How does the B cell response to TI antigen differ in infants?

Back 428

There is no response to TI2 antigen and a limited polysaccharide response

Front 429

When happens after C1/C1q has bound the antigen-antibody complex?

Back 429

The serine esterase C1r activates is neighbor, serine esterase C1s

Front 430

After the initial C3bBb is bound to the pathogen surface, what enzyme cooperates with it and with what end-result?

Back 430

Properdin (factor P) binds to and stabilizes C3bBb which continues to act as a C3 convertase causing multiple C3b to bind to the pathogen surface

Front 431

What is the mechanism by which the alternative pathway results in the binding of C3b to the pathogen surface?

Back 431

C3 is hydrolyzed forming iC3  the enzyme B binds to iC3  enzyme D cleaves B into Bb and Ba where Bb remains attached to iC3 and Ba floats away  another C3 binds to the newly formed iC3Bb and is cleaved into C3a and C3bBb bound to the pathogen surface

Front 432

What does C4b2a cleave and what happens to its products?

Back 432

It binds to and cleaves C3 into C3a and C3b  C3b subsequently binds to the microbial surface

Front 433

What is the function of C2a?

Back 433

C2a binds to the surface C4b forming C4b2a, the classical C3 convertase

Front 434

Besides cleaving C4, what other effect does C1s have?

Back 434

It cleaves C2 into C2a and C2b, where C2a is the larger component

Front 435

What does C1s exert its effect on and what are the two possible outcomes?

Back 435

C1s cleaves C4a off of C4, leaving behind the C4b part which now contains an exposed thioester bond  nucleophilic attack on the thioester bond by H2O creates soluble C4b, whereas nucleophilic attack by R-OH or R-NH2 results in C4b binding to the pathogen surface

Front 436

What three pathways are associated with complement activation and what is the common end-result of all three?

Back 436

Classical pathway: antibody-antigen binding; Lectin pathway: mannose-binding lectin binds to surface pathogen; Alternative pathway: pathogen surface creates local environment conducive to complement activation – all three pathways lead to complement activation and covalent binding of C3b to surface component of the pathogen

Front 437

How does C1 binding differ when comparing its interaction with IgM vs. IgG?

Back 437

C1 binds to a single antigen-bound IgM pentamer whereas it requires two or more antigen-bound IgG to bind C1q

Front 438

What are the early acting components of the classical pathway and which component has the largest plasma concentration?

Back 438

C1q,r,s; C2; C3; C4 – C3 has the largest plasma concentration

Front 439

What are the ligands of the CR1 receptor, and what is the receptor’s function?

Back 439

C3b, C4b; CR1 promotes C3b and C4b decay, stimulates phagocytosis, and is involved in erythrocyte transport of immune complexes

Front 440

When a C5 convertase cleaves C5, what happens to the formed C5b fragment?

Back 440

C5b joins with C6 and C7 and inserts itself in the bacterial cell membrane  C8 then joints followed by a large number of C9s which form a pore in the bacterial cell wall

Front 441

How do the C3 convertases in the classical, lectin, and alternative pathways become C5 convertases?

Back 441

By binding an additional C3b (thus becoming C4bC2aC3b for the classical and lectin, and C3bBbPC3b for the alternative)

Front 442

How do erythrocytes aid in the destruction of certain immune complexes?

Back 442

Antigen-antibody complexes form in circulation  C3b becomes activates and binds to the complex  C3b then binds to the CR1 receptor on erythrocytes --> in the spleen and liver the immune complex is handed over to phagocytic cells that destroy it

Front 443

What is the mechanism by which bacteria are engulfed by neutrophils?

Back 443

Antibody binds to the pathogen and activates complement --> C3b binds to pathogen --> engulfment of pathogens is now mediated by Fc receptors and complement binding

Front 444

Which receptor is found on Kupffer cells and functions in bacterial opsonization?

Back 444

CRIg – binds to C3b and iC3b

Front 445

Where are the CR3 and CR4 receptors found, what is the ligand, and what is their function?

Back 445

Found on macrophages, monocytes, PMNs; their ligand is iC3b and they stimulate phagocytosis

Front 446

What receptor on the macrophage surface binds to C3b and what happens next?

Back 446

CR1 binding causes opsonization of the pathogen

Front 447

In the lectin pathway, which segment associated with the MBL/ficolins cleaves C2 and C4 and which part of these molecules is the active part?

Back 447

MASP-2; cleaves C2 and C4 so that C2a and C4b can form C4b2a, which is the C3 convertase

Front 448

What does the MBL/ficolins attach to on the bacterial cell surface?

Back 448

Repeating carbohydrate molecules

Front 449

What are C3a, C4a, and C5a known as and what is their function?

Back 449

Anaphylatoxins – they act on blood vessels to increase vascular permeability allowing for extravasculation of antibodies and complement as well as leading to increased migration of macrophages , neutrophils, and lymphocytes

Front 450

Where in the body is the bulk of complement created, and what is special about the biosynthesis of C1, C7, factor D and especially factor P?

Back 450

90% is synthesized in the liver – C1: intestinal epithelium, macrophages, monocytes; C7: bone marrow granulocytes, dendritic cells; factor D: adipose tissue; factor P: dendritic cells ONLY

Front 451

Deficiency of which complement is the most commonly occurring (though still rare)?

Back 451

C1INH, MLB, C2

Front 452

What is the function of CD59 and how does it accomplish this?

Back 452

It prevents pore formation by inhibiting the membrane attack complex at the C8 to C9 stage

Front 453

What molecule can inactivate C5 convertase and what subsequent cleavage occurs?

Back 453

CR1 and H both have the capability to displace C3b from C5 convertase, changing the C5 into a C3 convertase; this is followed by factor I coming in to cleave the C3b on the C3 convertase, completely silencing the enzyme activity

Front 454

What three molecules have the capacity to displace C2a from the C4b2a complexes and how do they function?

Back 454

DAF, C4BP, CR1 – after displacing C2a, factor I is drawn in which is a protease that cleave C4b (into inactive C4c and C4d) and prevents it from rebinding C2a

Front 455

What is the molecule that can control complement activation by covalently binding to C1r and C1s, and in what disease does the patient have reduced levels of this compound?

Back 455

C1INH (C1 inhibitor) – reduced levels are found in people with hereditary angioneurotic edema (HANE); they will have bouts of skin, gut, and airway edema triggered by stress

Front 456

What are the ligands of the CR1 receptor, and what is the receptor’s function?

Back 456

C3b, C4b; CR1 promotes C3b and C4b decay, stimulates phagocytosis, and is involved in erythrocyte transport of immune complexes

Front 457

When a C5 convertase cleaves C5, what happens to the formed C5b fragment?

Back 457

C5b joins with C6 and C7 and inserts itself in the bacterial cell membrane  C8 then joints followed by a large number of C9s which form a pore in the bacterial cell wall

Front 458

How do the C3 convertases in the classical, lectin, and alternative pathways become C5 convertases?

Back 458

By binding an additional C3b (thus becoming C4bC2aC3b for the classical and lectin, and C3bBbPC3b for the alternative)

Front 459

How do erythrocytes aid in the destruction of certain immune complexes?

Back 459

Antigen-antibody complexes form in circulation  C3b becomes activates and binds to the complex  C3b then binds to the CR1 receptor on erythrocytes --> in the spleen and liver the immune complex is handed over to phagocytic cells that destroy it

Front 460

What is the mechanism by which bacteria are engulfed by neutrophils?

Back 460

Antibody binds to the pathogen and activates complement --> C3b binds to pathogen --> engulfment of pathogens is now mediated by Fc receptors and complement binding

Front 461

Which receptor is found on Kupffer cells and functions in bacterial opsonization?

Back 461

CRIg – binds to C3b and iC3b

Front 462

Where are the CR3 and CR4 receptors found, what is the ligand, and what is their function?

Back 462

Found on macrophages, monocytes, PMNs; their ligand is iC3b and they stimulate phagocytosis

Front 463

What receptor on the macrophage surface binds to C3b and what happens next?

Back 463

CR1 binding causes opsonization of the pathogen

Front 464

In the lectin pathway, which segment associated with the MBL/ficolins cleaves C2 and C4 and which part of these molecules is the active part?

Back 464

MASP-2; cleaves C2 and C4 so that C2a and C4b can form C4b2a, which is the C3 convertase

Front 465

What does the MBL/ficolins attach to on the bacterial cell surface?

Back 465

Repeating carbohydrate molecules

Front 466

What types of physiological interactions are seen in ADRs and what are examples of them?

Back 466

Absorption: opioid analgesics --> altered gastric motility and drug absorption; Protein binding: tolbutamide lowers blood sugar, but in combination with dicumarol (which displaces tolbutamide from albumin) can cause hypoglycemia; Renal excretion: probenicid and penicillin; Inhibition of metabolism: acetaminophen in glutathione-depleted chronic alcoholics; Induction of metabolism: barbiturates; Interactions at the site of action: opioids and CNS depressants

Front 467

How does the categorization of NSAIDs differ between 1st & 2nd trimesters and the 3rd trimester?

Back 467

During 1st & 2nd it is a Category B drug whereas during the 3rd trimester it becomes Category D due to its effects on the premature closing of the ductus arteriosus

Front 468

What distinguishes Category D from Category X drugs?

Back 468

Both have positive evidence of risk of fetal harm, but with Category D drugs the benefits to the pregnant mother may outweigh the risks to the fetus (e.g. lithium, phenytoin), whereas Category X drugs should never be used in pregnant women (e.g. statins, isotretinoin, thalidomide)

Front 469

What defines pregnancy Category C drugs?

Back 469

There are no adequate, well-controlled studies in pregnant women and either animal studies have shown adverse effects or none have been conducted

Front 470

How are pregnancy Category A and Category B drugs defined, respectively?

Back 470

Category A: safe; Category B: either no harmful effects in animals but no human studies done OR adverse effects in animals but none found in well-controlled human studies (acetaminophen, penicillin, oxycodone)

Front 471

What is the most dangerous time for the fetus to be exposed to drugs?

Back 471

18-55 days after conception; earlier exposure usually causes death; later exposure produces minor malformations/retardation/functional deficits

Front 472

What changes in pregnant women alter drug levels?

Back 472

Increased plasma volume, GFR, CO (decreases drug levels); Increased body fat (increased Vd for fat-soluble drugs); Decreased albumin levels (increase free drug/increased renal excretion); Delayed gastric emptying (increases absorption in stomach/delays absorption from intestine); Increased gastric pH (decreased absorption of acid-requiring drugs); Estrogen/progesterone (modulate hepatic enzyme activity)

Front 473

What is the difference between Type A and Type B ADR?

Back 473

Type A: extension of the primary effect or an additional known pharmacological effects;
Type B: unusual or unexpected reactions (idiosyncratic) or immune-mediated reactions

Front 474

What results when a patient is given IV heparin and antihistamine?

Back 474

The acid and base will form an inactive salt (another example of a chemical interaction is tetracycline chelation by metal containing antacids like Maalox)

Front 475

What percent of hospitalizations is due to ADRs and what percent of these is preventable?

Back 475

3-5% (300,000); inpatients have ~30% chance of an ADR – 85% of ADRs are preventable

Front 476

Why are opioids used in high doses during pregnancy considered Category D?

Back 476

If used close to term, they can cause addiction by the fetus and depress respiration

Front 477

How does infection/inflammation influence glomerular filtration?

Back 477

Increases due to increased pore size (may allow protein-bound drugs to pass through)

Front 478

What are colesevalam and activated charcoal examples of?

Back 478

Drugs that are used to keep substances from being absorbed in the intestine – colesevalam for cholesterol and activated charcoal for a variety of toxins

Front 479

What are some examples of drugs that are excreted through anion and cation transporters, respectively?

Back 479

Anion transport: furosemide, penicillin G (must be given along with probenecid to block the transporter in order to offset excessive transport); Cation transport: cimetidine, neostigmine, morphine

Front 480

How does active tubular secretion come about and for which drugs is this an important method of excretion?

Back 480

Through the use of cation and anion transporters – important in drugs that are highly protein-bound and don’t filter through the glomerulus

Front 481

What happens to aspirin when the urine is alkalinized?

Back 481

Since aspirin is a weak acid, it will become ionized in alkalinized urine, making it more readily excreted (important in aspirin overdose)

Front 482

How does acidification and alkalinization of the urine affect drugs that are weak bases and weak acids, respectively, in regard to tubular reabsorption?

Back 482

Acidification: promotes reabsorption of weak acids and decreases reabsorption of weak bases; Alkalinization: promotes reabsorption of weak bases and decreases reabsorption of weak acids

Front 483

What drug characteristics allow for greater back diffusion (i.e. tubular reabsorption)?

Back 483

Non-ionized, lipophilic drugs

Front 484

What are the principle organs of excretion?

Back 484

Kidney(!), intestine, biliary system, lungs – also sweat, saliva, milk, hair

Front 485

What drug characteristics lower their glomerular filtration?

Back 485

Large size, charge (especially anions), globular shape , reduced protein-binding

Front 486

What are the three processes that determine the concentration of substances in the urine?

Back 486

Glomerular filtration, active secretion, tubular reabsorption

Front 487

Why is the half-life of ezetimibe substantially longer that expected?

Back 487

After being glucuronidated and excreted by the liver, it is hydrolyzed by the intestinal flora back to its original form and subsequently reabsorbed in the intestine to once again exert its effects

Front 488

What are some examples of drugs that can be found in breast milk?

Back 488

Caffeine, nicotine, ethanol, aspirin, barbiturates, morphine, ACE inhibitors

Front 489

How does the pH of milk differ from that of plasma and how does it affect drug excretion?

Back 489

Milk pH: 6.5 vs. plasma pH: 7.4; weak bases will be more ionized in milk and get trapped

Front 490

What is the general rule of thumb regarding drug safety in pregnant women?

Back 490

If the drug is safe to use in a neonate, it is safe to be taken by the lactating woman

Front 491

What is the clinical significance of drugs being excreted through sweat?

Back 491

They can sometimes cause dermatitis or other skin reactions

Front 492

What happens to drugs secreted in saliva?

Back 492

They are swallowed and thus reabsorbed

Front 493

What determines whether a drug can be excreted via the lungs?

Back 493

Whether it is volatile (e.g. N2O, alcohol, acetone, garlic)

Front 494

By what mechanisms does biliary excretion occur and what is an example of a drug that uses this system?

Back 494

Anion and cation transporters – cardiac glycosides are excreted this way

Front 495

What is meant by enterohepatic recycling and what drugs use this system?

Back 495

Drugs that are excreted by the liver into the bile are often reabsorbed in the intestine and thus not excreted from the body – examples are Vit. D3, Vit. B12, folic acid, estrogen

Front 496

How does the dose-response curve shift when a nonequilibrium competitive antagonist is added to a particular agonist?

Back 496

The curve shifts to the right AND the maximum response is decreased (because the total available receptors is reduced) – these effects cause the slope of the curve to be decreased

Front 497

What mechanism is responsible for a cell’s basal level of functioning?

Back 497

Without the presence of agonists or antagonists, a cell receptor is in equilibrium between its active and inactive form; the time it spends in the active form is responsible for its basal functioning

Front 498

What effects do inverse agonists have, how do they achieve this effect, and what are some examples of receptors for which inverse agonists have been described?

Back 498

They reduce basal functioning of the cell (i.e. they have negative efficacy) by binding to the inactive form of the receptor with higher affinity – found for 5-HT, opioid, β-adrenoceptor, benzodiazepine

Front 499

How does the dose-response curve of functional antagonism compare to that of noncompetitive antagonism?

Back 499

The are identical (nonspecific, not surmountable)

Front 500

What are the characteristics of functional antagonism?

Back 500

Two agonists that initiate signaling via independent and opposite cellular pathways will cause functional antagonism (e.g. simultaneous sympathetic and parasympathetic innervation)

Front 501

How does the dose-response curve shift when a noncompetitive antagonist is added to a particular agonist?

Back 501

The curve shifts to the right AND the maximum response is decreased; in contrast to competitive antagonism the effects are NOT specific and will affect many agonists (because it doesn’t function at the level of the receptor, but rather on a particular step in a signaling pathway)

Front 502

W hat are the hallmarks of nonequilibrium competitive antagonism?

Back 502

Specific, irreversible, competitive, not surmountable (i.e. it reduces maximum response)

Front 503

What are the two types of antagonisms and what are examples of each?

Back 503

Chemical: protamine/heparin or dimercaprol chelation; Pharmacological: most common type, many examples possible

Front 504

What are the hallmarks of equilibrium competitive antagonism?

Back 504

Specific (for a particular agonist), reversible, competitive, surmountable (i.e. it has no effect on maximum response)

Front 505

How does the dose-response curve shift when an equilibrium competitive antagonist is added to a particular agonist?

Back 505

A parallel shift to the right (i.e. a greater dose of agonist is required to get the same level of response, but the shape of the curve does not change)

Front 506

To what form of the receptor does a (neutral) antagonist bind?

Back 506

Both the active (R*) and inactive (R) forms – neutral simply means that is has an efficacy of 0 and does not change basal functioning of the cell

Front 507

What results when you add an inverse agonist to an agonist?

Back 507

The inverse agonist will reduce the response generated by the agonist

Front 508

What calculation is used to calculate half-life?

Back 508

[t1/2 = 0.693/ke] where ke is the elimination rate constant calculated by [rate of elimination/amount in body] or by looking at the slope of the plasma concentration vs. time log curve

Front 509

When using the 2 compartment model of pharmacokinetics, what two phases can be seen on the drug plasma concentration vs. time graph?

Back 509

Distribution phase and elimination phase

Front 510

What is the relationship between clearance and half-life?

Back 510

It is an inverse relationship (i.e. if you increase the half-life of a drug you will decrease its clearance)

Front 511

What is the term that describes the volume of plasma from which drug is removed per unit time and how is it calculated?

Back 511

Clearance – [Renal clearance = total amount in urine/AUC] and [systemic clearance = dose/UAC] or [systemic clearance = Vd x ke]

Front 512

How does ascites affect volume of distribution?

Back 512

It increases the total extracellular fluid volume

Front 513

How is it possible for certain drugs to have a very large volume of distribution (e.g. amiodarone)?

Back 513

If the drug gets selectively taken up by a tissue or binds to a binding protein, it can appear to have a much greater volume of distribution when compared to their plasma volume

Front 514

What is meant by volume of distribution and how is it calculated?

Back 514

Volume of fluid in which the drug appears to be dissolved – [Vd = total amount of drug absorbed/drug in plasma at t=0]

Front 515

What does the pharmacokinetic parameter AUC (area under the curve) mean?

Back 515

It is calculated from a drug plasma concentration vs. time curve; it gives an indication of drug exposure, clearance, bioavailability, etc.

Front 516

What physiological factors affect half-life?

Back 516

CYP inhibition/induction, renal/hepatic impairment

Front 517

How many half-lives does it take to eliminate >95% of dose?

Back 517

Between 4 and 5

Front 518

What factors determine the absorption rate constant, Ka?

Back 518

Chemical and physical properties of the drug formulation; the presence of food (ingesting food along with a drug delays the action of that drug because it delays the amount of time it takes for the drug to get to the intestine and it dilutes the drug)

Front 519

What is a loading dose and how is it calculated?

Back 519

Amount of drug given to a patient to reach steady state level faster than it would normally take (i.e. ~5 half-lives) – it is calculated as [LD = Css x Vd]

Front 520

How long does it take to achieve steady state on multiple drug dosing and how is the concentration at steady state (Css) calculated?

Back 520

It takes ~5 half-lives to achieve steady state – Css is calculated by either [Css = (F x DoseRate)/Clearance] or [Css = (F x Dose)/(Clearance x T)]

Front 521

How does the zero-order elimination graph differ from first-order elimination and how does zero-order elimination occur?

Back 521

In zero-order elimination a constant amount is eliminated per unit time, whereas in first-order elimination a constant fraction is eliminated per unit time; zero-order elimination most commonly occurs because of saturation of their elimination process (i.e. the drug’s degrading enzyme is constantly saturated) – examples of zero-order drugs are ethanol and phenytoin

Front 522

What factors affect bioavailability and how does bioavailability affect Cmax and Tmax

Back 522

Pre-systemic degradation, export transporters in the small intestine, drug formulation – bioavailability directly influences Cmax, but has no effect on Tmax

Front 523

What is meant by bioavailability and how is it calculated?

Back 523

It is the fraction of orally administered drug which is absorbed into the plasma – [F = AUCoral/AUCiv]

Front 524

How does a higher value of Ka affect Cmax and Tmax?

Back 524

If increases Cmax and decreases Tmax (more absorbed in a less time)

Front 525

What are examples, concerning the 2 compartment model of pharmacokinetics, of rapid and slowly excreting compartments?

Back 525

Rapid compartment: Brain, muscles, maybe visceral; Slow: fat, skeleton, maybe visceral

Front 526

What factors affect Cmax and Tmax, respectively?

Back 526

Cmax: Ke, Ka, F; Tmax: Ke, Ka

Front 527

How does oral administration of a drug compare, pharmacokinetically, to IV administration?

Back 527

Oral administration has an added absorption phase, which limits the maximum possible plasma concentration of the drug (Cmax) occurring a given time (Tmax)

Front 528

By what mechanisms do various extended release drug formulas function?

Back 528

Multiple layer tablets (zolpidem); Microparticle pH-dependent release (carvedilol); Dual polymer matrix (oxycontin); Osmotic extended release system (concerta)

Front 529

What compound is responsible for the release of IκB-α inhibitor protein from NF-κB, and what two effects can NF-κB have in the nucleus?

Back 529

IKK phosphorylates IκB-α inhibitor protein which is subsequently degraded; free NF-κB moves to the nucleus where it either binds with HAT to perform histone acetylation, or functions alone to increase transcription of κB elements

Front 530

Where is TNF-α secreted and what are its effects?

Back 530

Secreted by monocytes, macrophages; can kill tumor cells, induce production of pro-inflammatory cytokines, stimulate WBC adhesion/activation, cause fever, stimulate bone reabsorption/cartilage degradation

Front 531

What are the effects of the leukotrienes LTC4, D4, E4, and LTB4?

Back 531

LTC4, D4, E4: bronchoconstriction, increased vascular permeability; LTB4: chemoattraction, adhesion/activation of leukocytes, pain sensitization

Front 532

What is the function of PGE1, PGE2, PGF2a, PGI2 (prostacyclin), TXA2?

Back 532

PGE1: maintenance of patent ductus arteriosus; PGE2: vasodilation, gastric cytoprotection, pain sensitization, fever, uterine contraction/initiation of labor; PGF2α: vasoconstriction, uveoscleral drainage, contraction of uterine/GI/bronchial smooth muscle; PGI2 (prostacyclin): vasodilation, gastric cytoprotection, pain sensitization, fever, uterine relaxation (!), prevents platelet aggregation, limits action of TXA2; TXA2: stimulation of platelet aggregation

Front 533

What characterizes eicosanoids?

Back 533

Short half-life, released at site of action

Front 534

What is the difference between the COX-1 and COX-2 isoforms?

Back 534

COX-1: constitutively expressed, “housekeeping” functions, responsible for acute prostaglandin production following inflammatory stimuli, gastric cytoprotection, platelet aggregation; COX-2: inducible by inflammatory stimuli, responsible for sustained acute prostaglandin production following inflammatory stimuli

Front 535

By what mechanism does synthesis of eicosanoids (prostaglandins/leukotrienes) occur?

Back 535

Phospholipids are metabolized to arachidonic acid by PLA2 (generates PAF as a side-product) --> Arachidonic acid is then metabolized by either cyclooxygenase (COX-1, COX-2) to prostaglandins OR by lipoxygenase to leukotrienes

Front 536

What is NF-κB and what is it involved in?

Back 536

A family of transcription factors involved in inflammation, immunity, and many other processes

Front 537

What stimuli cause NF-κB activation?

Back 537

Antigen binding to T cell receptors; Pro-inflammatory cytokines (TNF-α, IL-1); Oxidative stress; Co-stimulatory activation signals; Bacterial LPS

Front 538

What form of NF-κB is normally found in the cell and how is this maintained?

Back 538

Inactive form is found in the cytoplasm; it is bound to IκB-α inhibitor protein; once the inhibitor protein releases NF-κB, it becomes activated and moves into the nucleus

Front 539

What is the general therapeutic use of glucocorticoids and what are some examples of commonly used glucocorticoid drugs?

Back 539

Used as immunosuppressants and anti-inflammatory drugs – examples include dexamethasone, methylprednisolone, prednisone, prednisolone; most glucocorticoids end on –sone or –lone

Front 540

How can glucocorticoid use lead to an adrenal crisis and what are the symptoms associated with this?

Back 540

Abrupt discontinuation of glucocorticoids or a stressful event can cause a deficiency in plasma glucocorticoid – this can lead to weakness, fainting, hypotension, cardiovascular collapse, and death

Front 541

By what mechanism do high-dose, long-term adverse effects of glucocorticoid use occur?

Back 541

Suppression of the hypothalamic-pituitary axis (HPA) which causes inhibition of corticotropin-releasing factor (CRF) in the hypothalamus, and inhibition of ACTH in the pituitary

Front 542

What are the short-term adverse effects of PO or IV glucocorticoid use?

Back 542

CNS stimulation, appetite stimulation, nausea/vomiting, slightly increased risk of infection

Front 543

What are the chronic hematological effects of glucocorticoids?

Back 543

Decrease in primary antibody response; decrease in production of established antibody

Front 544

What are the acute hematological effects of glucocorticoids?

Back 544

Increase in circulating neutrophils; decrease in circulating lymphocytes/monocytes/basophils/ eosinophils (they become sequestered in lymphoid tissues)

Front 545

What are the molecular effects generated by glucocorticoids?

Back 545

After passing through the cell membrane and binding to their cytosolic receptors, they inhibit histone acetylation/increase histone deacetylation (in order to decrease transcription of inflammatory genes), and bind to DNA promotors (in order to cause transcription of anti-inflammatory genes, or cause repression of certain genes leading to adverse side-effects)

Front 546

What are the two receptors for TNF-α and how do they differ in cell-surface vs. soluble forms?

Back 546

p55/p75; cell surface p55/p75 initiates inflammatory responses; soluble p55 initiates inflammatory responses; soluble p75 antagonizes inflammatory responses – overall effect is initiation of inflammatory response

Front 547

What are the two most important biological oxidants that mediate the inflammatory response?

Back 547

Superoxide (made by NADPH oxidase/detoxified by SOD) and nitric oxide (made by NOS/detoxified by oxyHb) – in inflammatory states NAPDH oxidase and iNOS are increased

Front 548

What is special about the IL-1 surface receptors?

Back 548

They have an endogenous receptor antagonist (IL-1ra) that competes for binding to IL-1 receptors, thus balancing the inflammatory response

Front 549

What pathological problems are associated with high-dose, long-term use of glucocorticoids?

Back 549

Increased risk of infection; masked signs of infection; osteoporosis; decreased bone growth in children; hypokalemia, sodium and fluid retention, hypertension (all due to mineralocorticoid activity); hyperglycermia, diabetes (since glucocorticoids decrease glucose utilization and increase gluconeogenesis); impaired wound healing; wasting of skeletal muscles; glaucoma, cataracts; redistribution of fat to face and back; dermatological changes (acne, skin atrophy, striae, growth of fine hair)

Front 550

Glucocorticoids interact with what P450 isozyme?

Back 550

They are inducers of CYP3A4

Front 551

What molecule causes vasodilation in response to H1 receptor mediated activation?

Back 551

Endothelial derived relaxing factor: NO

Front 552

Where are H4 receptors located and what are they associated with?

Back 552

Found in the GI tract and the CNS; they are associated with eosinophils and neutrophils causing shape changes, chemotaxis, and upregulation of adhesion molecules

Front 553

What is the H3 receptor mediated response?

Back 553

A decrease in Ca++ influx into the neuronal cells, modulating neurotransmitter release (the H3 receptor is presynaptic)

Front 554

What changes are seen in response to activation of the H2 receptor and what are the associated physiological effects?

Back 554

Gastric acid secretion: increased gastric acidity/irritation; Vasodilation of vascular smooth muscle: decreased blood pressure leading to increased rate and contractility of the heart (also due, in a minor part, to direct effects on the heart)

Front 555

How does activation of the H1 receptor cause pruritus/cough reflex, nasal/bronchiole mucus, and wakefulness, respectively?

Back 555

Pruritus/cough: activates selected sensory nerves; Nasal/bronchiole mucus: increased glandular secretions; Wakefulness: modulation of CNS functions

Front 556

What effect does activation the H1 receptor have on post-capillary venules?

Back 556

Contraction of the endothelium, creating gaps between cells which leads to edema

Front 557

What are the different effects due to the activation of the H1 receptor regarding vascular endothelium and non-vascular smooth muscle?

Back 557

Vascular endothelium: indirectly causes vasodilation; Non-vascular smooth muscle: directly causes vasoconstriction

Front 558

What is meant by the statement that histamine is an autocoid?

Back 558

It is a substance produced as a local hormone within the tissue in which it acts

Front 559

What do histamine receptors have in common and how do they differ?

Back 559

The four subtypes are all derived from the G protein-coupled superfamily, so they all function via intracellular signal transduction pathways; however, the end-result of receptor activation differs for each subtype

Front 560

What are factors that trigger the release of histamine?

Back 560

Noxious stimuli: cold/heat, bacterial toxins/insect bites, cellular injury; Pathophysiological reactions to an allergen; Therapeutic agents: morphine-like narcotics, curare-like neuromuscular blocking agents

Front 561

What side-effects are associated with H1 receptor antagonist’s interaction with muscarinic and monoaminergic receptors, respectively?

Back 561

Muscarinic: sedation (sometimes CNS excitation in children), dry mouth, blurred vision, tachycardia, urinary retention, suppression of Parkinsonian symptoms, reduction of nausea/vomiting/motion sickness/vestibular disturbances; Monoaminergic: anti-anxiety

Front 562

Which Cimetidine drug interactions are particularly worrisome?

Back 562

Interactions with Warfarin (small therapeutic index), Phenytoin (zero-order kinetics)

Front 563

What drug interactions are associated with H2 receptor antagonists?

Back 563

Ranitidine inhibits the glucuronidation of acetaminophen; Drugs that require an acidic environment for absorption (ketoconazole, itraconazole) will be less absorbed; Cimetidine inhibits CYP1A2/CYP2C19 as well as CYP2D6/CYP3A4 (weakly), altering their metabolism

Front 564

What is the most important therapeutic action of H2 receptor antagonists and what are some examples of them?

Back 564

They inhibit the secretion of gastric acid stimulated by histamine, gastrin, cholinometics, and vagal stimulation; Examples include Cimetidine (Tagamet), Ranitidine (Zantac), Famotidine (Pepcid), Nizatidine (Axid)

Front 565

How does the duration of action differ when comparing first and second generation H1 receptor antagonists?

Back 565

Second generation H1 receptor antagonists have a much longer duration of action (~24 hours vs. 4-8 hours for first generation drugs)

Front 566

What are examples of second generation H1 receptor antagonist drugs and what symptoms can they treat?

Back 566

Cetirizine (Zyrtec); Fexofenadine (Allegra); Loratadine (Claritin): appetite stimulant; Desloratadine (Clarinex): is the active metabolite of Loratadine

Front 567

What are examples of first generation H1 receptor antagonist drugs and what symptoms can they treat?

Back 567

Dimenhydrinate (Dramamine): motion sickness; Diphenhydramine (Benadryl): motion sickness, insomnia; Hydroxyzine (Vistaril, Atarax): anxiety, psychosis-induced tension; Meclizine (Antivert): vertigo, motion sickness; Promethazine (Phenergan): nausea, vomiting

Front 568

\What are examples of drugs that inhibit release of mast cell granules, and what are some functional antagonists of the products released from mast cells?

Back 568

Release inhibitors: cromolyn sodium, nedocromil; Functional antagonists: isoproterenol, theophylline, epinephrine

Front 569

What is the difference between first generation and second generation H1 receptor antagonists?

Back 569

First generation: not very selective for histamine receptor, enter CNS; Second generation: more selective for histamine receptor (meaning fewer side-effects associated with sedation/anti-emetic/anti-cholinergic), less lipophilic (do not enter CNS as readily)

Front 570

What happens initially at the onset of inflammation to the vasculature?

Back 570

Vasoconstriction of arterioles (seconds) followed by vasodilation of arterioles and subsequently the capillaries (due to histamine and NO)

Front 571

How do selectins bind their ligands and what is an example of a disease in which this binding is deficient?

Back 571

They bind using low affinity calcium-dependent binding; Leukocyte Adhesion Deficiency-2 (LAD-2) is an example of deficient selectin binding in humans

Front 572

What are the three selectins used in adhesion and where is each found?

Back 572

E-selectin (aka CD62E, ELAM-1): found on activated endothelial cells; P-selectin (aka CD62P, GMP140, PADGEM): found in platelet alpha granules and endothelial Weibel-Palade bodies;
L-selectin (aka CD62L, LAM-1): found on leukocytes

Front 573

How is margination defined?

Back 573

Movement from the central lumen to the luminal periphery

Front 574

What substances are responsible for angiogenesis seen in inflammation?

Back 574

VEGF, histamine, substance P

Front 575

How do leukocytes mediate endothelial injury?

Back 575

Via toxic oxygen species and proteolytic enzymes during margination and activation

Front 576

Which substances are responsible for the endothelial gaps in venules (as part of the immediate transient response)?

Back 576

Histamine, bradykinin, leukotrienes, substance P

Front 577

What are some examples of agents that cause inflammation?

Back 577

Microbial infections, physical agents, chemicals, necrotic tissue, immunological reactions

Front 578

What is the difference between exudate and transudate?

Back 578

Exudate (e.g. pus): high protein, specific gravity > 1.02, cellular debris; Transudate: low protein, specific gravity < 1.02, ultrafiltrate of blood

Front 579

What are the cardinal signs of inflammation?

Back 579

Heat (calor), redness (rubor), edema (tumor), pain (dolor), loss of functio (function laesa)

Front 580

What is meant by diapedesis and what is responsible for this process?

Back 580

Migration of leukocytes through the endothelium (also known as transmigration); stimulated by chemokines (e.g. PECAM-1, CD31) in venules – this process is aided by collegenases which help cells move through the basement membrane

Front 581

What molecules are involved in the process of opsonization?

Back 581

IgG Fc:FcR (activates complement cascade); C3b:CR1-3 (or via alternative pathway); Collectins:C1q

Front 582

What responses are seen due to leukocyte activation and what signals are responsible for this activation

Back 582

Production of arachidonic acid metabolites; degranulation and secretion of lysosomal enzymes; activation of oxidative burst; secretion of cytokines; modulation of leukocyte adhesion molecules – these functional responses are due to increased cytosolic calcium, and activation of protein kinase C & phospholipase A2

Front 583

By what mechanism does chemotaxis occur?

Back 583

Increased cytosolic calcium and activation of GTPases/kinases causes polymerization of actin within the cell --> actin and myosin generate contractions in pseudopodia in response to actin-regulating proteins (filamin, gelsolin, profilin, calmodulin) --> these contractions pull the cell closer to the source of the chemotactic agent

Front 584

What chemical agents are responsible for chemotaxis?

Back 584

Exogenous causes: bacterial products; Endogenous causes: C5a, Leukotriene B4, IL-8

Front 585

What is the difference between LAD type 1 and type 2?

Back 585

Type 1: defect in biosynthesis of β2 chains; Type 2: absence of Sialyl LewisX (ligand for E-selectin) – both deficiencies present with recurrent bacterial infections

Front 586

Which molecules are the first to arrive in normal transmigration, and how does this differ in viral infections and hypersensitivity reactions, respectively?

Back 586

Normally: neutrophils (6-24 hours); Viral infections: lymphocytes; hypersensitivity reactions: eosinophils – also, in pseudomonas infection neutrophils are delayed (2-4 days)

Front 587

What is the purpose of integrins, what are the two classes of integrins, and what is the function of each class?

Back 587

Promote cell-cell or cell-matrix interactions; Beta1-containing integrins (e.g. CD49a, CD29, VLA) are found on leukocytes for attachment to the endothelium; β2-containing integrins (e.g. CD11a-c, CD18, LFA-1) are responsible for leukocyte adhesion to other cells

Front 588

What compounds are responsible for the redistribution and induction of adhesion molecules, respectively?

Back 588

Redistribution: histamine, thrombin, PAF; Induction: IL-1, TNF

Front 589

What are mucin-like glycoproteins composed of, what is their ligand, and where are these adhesion molecules found?

Back 589

Composed of heparan sulfate; bind to leukocyte adhesion molecule CD44; found in the extracellular matrix and on cell surfaces

Front 590

What is meant by diapedesis and what is responsible for this process?

Back 590

Migration of leukocytes through the endothelium (also known as transmigration); stimulated by chemokines (e.g. PECAM-1, CD31) in venules – this process is aided by collegenases which help cells move through the basement membrane

Front 591

What molecules are involved in the process of opsonization?

Back 591

IgG Fc:FcR (activates complement cascade); C3b:CR1-3 (or via alternative pathway); Collectins:C1q

Front 592

What responses are seen due to leukocyte activation and what signals are responsible for this activation

Back 592

Production of arachidonic acid metabolites; degranulation and secretion of lysosomal enzymes; activation of oxidative burst; secretion of cytokines; modulation of leukocyte adhesion molecules – these functional responses are due to increased cytosolic calcium, and activation of protein kinase C & phospholipase A2

Front 593

By what mechanism does chemotaxis occur?

Back 593

Increased cytosolic calcium and activation of GTPases/kinases causes polymerization of actin within the cell --> actin and myosin generate contractions in pseudopodia in response to actin-regulating proteins (filamin, gelsolin, profilin, calmodulin) --> these contractions pull the cell closer to the source of the chemotactic agent

Front 594

What chemical agents are responsible for chemotaxis?

Back 594

Exogenous causes: bacterial products; Endogenous causes: C5a, Leukotriene B4, IL-8

Front 595

What is the difference between LAD type 1 and type 2?

Back 595

Type 1: defect in biosynthesis of β2 chains; Type 2: absence of Sialyl LewisX (ligand for E-selectin) – both deficiencies present with recurrent bacterial infections

Front 596

Which molecules are the first to arrive in normal transmigration, and how does this differ in viral infections and hypersensitivity reactions, respectively?

Back 596

Normally: neutrophils (6-24 hours); Viral infections: lymphocytes; hypersensitivity reactions: eosinophils – also, in pseudomonas infection neutrophils are delayed (2-4 days)

Front 597

What is the purpose of integrins, what are the two classes of integrins, and what is the function of each class?

Back 597

Promote cell-cell or cell-matrix interactions; Beta1-containing integrins (e.g. CD49a, CD29, VLA) are found on leukocytes for attachment to the endothelium; β2-containing integrins (e.g. CD11a-c, CD18, LFA-1) are responsible for leukocyte adhesion to other cells

Front 598

What compounds are responsible for the redistribution and induction of adhesion molecules, respectively?

Back 598

Redistribution: histamine, thrombin, PAF; Induction: IL-1, TNF

Front 599

What are mucin-like glycoproteins composed of, what is their ligand, and where are these adhesion molecules found?

Back 599

Composed of heparan sulfate; bind to leukocyte adhesion molecule CD44; found in the extracellular matrix and on cell surfaces

Front 600

What is defective in chronic granulomatous disease?

Back 600

Microbicidal activity

Front 601

What are the two pathways of arachidonic acid metabolites and what are some of the metabolites that become activated as an end-result?

Back 601

Cyclooxygenase: TXA2 (platelet aggregation/vasoconstriction), PGI2 (vasodilation/aggregation inhibition), PGD2 (vasodilation/edema potentiation), PGE2 (pain/fever); Lipoxygenase pathway: LTB4 (chemotaxis/aggregation of neutrophils), LTC4/LTD4/LTE4 (vasoconstriction/ bronchospasm/increased permeability), LXA4 (vasodilation) – TX means thromboxane, PG means prostaglandin, LT means leukotriene, LX means lipoxin

Front 602

What effects does C5a have?

Back 602

It causes release of inflammatory mediators via the lipoxygenase pathway of arachidonic acid metabolism, and causes increased adhesion/chemotaxis of leukocytes

Front 603

What two plasma proteases function as chemical mediators and what are their characteristics?

Back 603

Hageman factor: activated by collagen, basement membrane, or activated platelets (requires the co-factor HMWK); Kinin-kallikrein system: makes bradykinin which functions like histamine and causes pain; Thrombin: enhances leukocyte adhesion, generates fibrinopeptides which increase vascular permeability and is chemotactic for leukocytes, converts fibrinogen to fibrin clot

Front 604

Besides transmitting pain signals, what other effects does substance P have?

Back 604

Regulation of vessel tone and modulation of vascular permeability

Front 605

Where is serotonin found and what are its effects?

Back 605

It is found in platelet dense bodies and has effects similar to that of histamine – it is released in response to platelet aggregation

Front 606

Where is histamine found and what is its release stimulated by?

Back 606

Found in mast cell granules, basophils, platelets; Release stimulated by physical injury, immune reactions, anaphylatoxins, substance P, IL-1, IL-8 – histamine causes arteriolar dilation and increased vascular permeability

Front 607

What effects do major basic protein and defensins have on pathogens, respectively?

Back 607

Major basic protein: secreted from eosinophils for parasite toxicity; Defensins: form holes in microbial membrane

Front 608

What pathology is seen in both Chediak-Higashi syndrome and Diabetes Mellitus?

Back 608

Defective phagocytosis

Front 609

What is neutropenia commonly caused by?

Back 609

Chemotherapy in cancer treatment

Front 610

What side-effects are associated with H1 receptor antagonist’s interaction with muscarinic and monoaminergic receptors, respectively?

Back 610

Muscarinic: sedation (sometimes CNS excitation in children), dry mouth, blurred vision, tachycardia, urinary retention, suppression of Parkinsonian symptoms, reduction of nausea/vomiting/motion sickness/vestibular disturbances; Monoaminergic: anti-anxiety

Front 611

Which Cimetidine drug interactions are particularly worrisome?

Back 611

Interactions with Warfarin (small therapeutic index), Phenytoin (zero-order kinetics)

Front 612

What drug interactions are associated with H2 receptor antagonists?

Back 612

Ranitidine inhibits the glucuronidation of acetaminophen; Drugs that require an acidic environment for absorption (ketoconazole, itraconazole) will be less absorbed; Cimetidine inhibits CYP1A2/CYP2C19 as well as CYP2D6/CYP3A4 (weakly), altering their metabolism

Front 613

What is the most important therapeutic action of H2 receptor antagonists and what are some examples of them?

Back 613

They inhibit the secretion of gastric acid stimulated by histamine, gastrin, cholinometics, and vagal stimulation; Examples include Cimetidine (Tagamet), Ranitidine (Zantac), Famotidine (Pepcid), Nizatidine (Axid)

Front 614

How does the duration of action differ when comparing first and second generation H1 receptor antagonists?

Back 614

Second generation H1 receptor antagonists have a much longer duration of action (~24 hours vs. 4-8 hours for first generation drugs)

Front 615

What are examples of second generation H1 receptor antagonist drugs and what symptoms can they treat?

Back 615

Cetirizine (Zyrtec); Fexofenadine (Allegra); Loratadine (Claritin): appetite stimulant; Desloratadine (Clarinex): is the active metabolite of Loratadine

Front 616

What are examples of first generation H1 receptor antagonist drugs and what symptoms can they treat?

Back 616

Dimenhydrinate (Dramamine): motion sickness; Diphenhydramine (Benadryl): motion sickness, insomnia; Hydroxyzine (Vistaril, Atarax): anxiety, psychosis-induced tension; Meclizine (Antivert): vertigo, motion sickness; Promethazine (Phenergan): nausea, vomiting

Front 617

\What are examples of drugs that inhibit release of mast cell granules, and what are some functional antagonists of the products released from mast cells?

Back 617

Release inhibitors: cromolyn sodium, nedocromil; Functional antagonists: isoproterenol, theophylline, epinephrine

Front 618

What is the difference between first generation and second generation H1 receptor antagonists?

Back 618

First generation: not very selective for histamine receptor, enter CNS; Second generation: more selective for histamine receptor (meaning fewer side-effects associated with sedation/anti-emetic/anti-cholinergic), less lipophilic (do not enter CNS as readily)

Front 619

What does release of platelet-activating factor result in?

Back 619

Platelet aggregation/degranulation, bronchoconstriction; vasodilation/increased permeability; leukocyte adhesion/chemotaxis/degranulation/oxidative burst; stimulates synthesis of eicosanoids

Front 620

What are some common causes of chronic inflammation?

Back 620

Viral infections, persistent microbial infections, prolonged exposure to toxic agents (e.g. silica, lipids), autoimmune diseases (e.g. rheumatoid arthritis, DM-1)

Front 621

Why are viral infections capable of causing chronic inflammation?

Back 621

They require lymphocytes and monocytes to resolve the infection

Front 622

How is tissue repair accomplished in chronic inflammation?

Back 622

Via angiogenesis and fibrosis

Front 623

What is a key feature of acute inflammation progressing to chronic inflammation?

Back 623

Neutrophils are replaced by macrophages, lymphocytes, and plasma cells

Front 624

How does the outcome of acute inflammation differ from that of chronic inflammation?

Back 624

Acute inflammation causes limited injury with minimal tissue damage, damaged tissue is capable of regeneration, and histologic/functional normalcy can be restored – scarring or fibrosis can occur with acute inflammation

Front 625

Which cytokines regulate lymphocyte function, innate immunity, and macrophage activation, respectively?

Back 625

Lymphocyte function: IL-2 (stimulates), TGF-β (inhibits); Innate immunity: TNF, IL-1; Macrophage activation: IFN-γ, IL-12

Front 626

What functions do the lipoxins have?

Back 626

Endogenous regulators of leukotrienes; inhibit neutrophil chemotaxis/adhesion; stimulate monocytes adhesion

Front 627

What substance specifically inhibits phospholipase A2 (PLA2)?

Back 627

Glucocorticoids

Front 628

How do aspirin and NSAIDS reduce inflammation?

Back 628

They inhibit COX-1 and COX-2 (although the lipoxygenase pathway is not inhibited); overuse can predispose to gastric ulceration

Front 629

What types of activation signals do macrophages respond to, and which substances induce the formation of giant cells?

Back 629

Normal activation signals: IFN-γ, endotoxin, acute inflammatory mediators, fibronectin; Giant cells: IL-4, IFN-γ

Front 630

How is the protective index calculated?

Back 630

PI = ED50 for toxicity/ED50 for therapeutic effect – the greater the number, the safer the drug

Front 631

What effects can a substance that causes potentiation of a drug have?

Back 631

It can either shift the dose-response curve to the left, or increase the maximum response of the drug

Front 632

What do efficacy and intrinsic activity mean and what determines them?

Back 632

The maximum response that a given drug can produce – depends on the chemical structure of a drug

Front 633

What determines the potency of a drug?

Back 633

The log dose of a drug at its ED50 – this only works when comparing two drugs which produce similar effects

Front 634

How does EC50 differ from ED50?

Back 634

EC50 is only applied to in vitro settings where the concentration of a drug is fixed

Front 635

What is meant by biological variability?

Back 635

No two subjects have the same dose-response curve, meaning that the value of the ED50 is characteristic for each subject

Front 636

What is the difference between a quantal dose-response curve and a graded dose-response curve?

Back 636

In a quantal dose-response curve, every subject is given one dose to see whether or not there is an effect (“all-or-none” response); in a graded dose-response curve every subject is given a number of doses to see what the graded response is with each increasing dose – the quantal dose-response curve gives MEDIAN ED50, whereas the graded response curve gives MEAN ED50

Front 637

What is meant by the ED50?

Back 637

The median effective dose that produces a desirable effect in 50% of the population

Front 638

What determines the safety of a certain drug and what measure is used to describe this?

Back 638

The difference between the ED50 and LD50 – this calculated by the therapeutic index (LD50/ED50); the greater the therapeutic index, the safer the drug (TI >10 is desirable)

Front 639

How does LD50 differ from ED50?

Back 639

The LD50 is the dose for a particular drug that is lethal in 50% of the population

Front 640

What does tachyphylaxis refer to, what does it depend on, and by what mechanisms can it occur?

Back 640

A rapidly-occurring decrease in the response to a drug after repetitive administration – depends on the dose and interval of administration; can occur because a required intermediate is “used up”, receptors are internalized, or signal transduction becomes uncoupled

Front 641

How do the values of α and e determine, respectively, whether a drug is an agonist or antagonist?

Back 641

If α=1 the drug is a full agonist; if 0<α<1 the drug is a partial agonist; if α=0 the drug is an antagonist – if e>0 the drug is an agonist (there is no limit for e); if e=0 the drug is an antagonist

Front 642

What parameters determine the ED50?

Back 642

Intrinsic activity (α) or efficacy (e); and the dissociation constant (KA where [KA=k2/k1])

Front 643

What concept determines the difference between intrinsic activity and efficacy?

Back 643

The term intrinsic activity is used when the maximum response occurs when all receptors are occupied; Efficacy is used when the maximum response can occur when there are still spare receptors which are not occupied

Front 644

What is the difference between an agonist and an antagonist?

Back 644

Agonists resemble an endogenous substance which binds to a receptor and initiates a response (i.e. stimulation of the receptor); Antagonists also resemble an endogenous substance and bind to a receptor, but they do not trigger a response (rather, they block receptor responses to agonists)

Front 645

What are the two types of interactions that a drug can have with a receptor?

Back 645

Binding may alter the activity of a channel or an enzyme; Binding may initiate a biological response

Front 646

What is the distinction between tolerance and tachyphylaxis?

Back 646

Tolerance requires a physiological rearrangement in the body that occurs over a long period of time (i.e. days)

Front 647

What is the concept called that states that the sum of two particular drugs is greater than their individual effect?

Back 647

Synergism

Front 648

In Type III hypersensitivity reactions, what is the immune reactant, the antigen, and the effector mechanism?

Back 648

Immune reactant: IgG; Antigen: soluble antigen; Effector: complement, phagocytes

Front 649

What are the spasmogens released from mast cells and what is their effect?

Back 649

Histamine, PGD2, LTC4, LTD4 --> all cause bronchial smooth muscle contraction, mucosal edema, and mucus secretion

Front 650

What happens to the armed mast cells on second exposure to bee venom?

Back 650

They release spasmogens, activators, and chemoattractants – histamine peaks first, then leukotrienes appear (longer acting)

Front 651

What happens to the IgE secreted by a plasma cell in response to bee venom?

Back 651

The IgE binds to FcεR1 on a mast cell; this binding extends the half-life of the IgE from 2-3 days to >30 days (it inhibits signaling pathways that lead to apoptosis

Front 652

What is the mechanism by which bee venom activates the immune system?

Back 652

After entering the body, the venom is taken up by an APC and the peptide sequence presented --> a CD4 T Cell interacts with the APC and secretes IL-4 --> IL-4 activates a TH2 cell in combination with its interaction with the APC --> the TH2 cell secretes more IL-4 and activates a B cell --> the B cell differentiates into a plasma cell which secretes IgE
8.

Front 653

What are some examples of Type I, II, III, and IV hypersensitivity reactions?

Back 653

Type I: allergic rhinitis, asthma, systemic anaphylaxis; Type II: drug allergies, chronic urticaria; Type III: serum sickness, arthus reaction; Type IV: contact dermatitis, chronic asthma, chronic allergic rhinitis, contact dermatitis

Front 654

In Type IV hypersensitivity reactions, what is the immune reactant, the antigen, and the effector mechanism?

Back 654

Immune reactant #1: TH1; Antigen #1: soluble antigen; Effector #1: macrophage activation; Immune reactant #2: TH2; Antigen #2: soluble antigen; Effector #1: eosinophils activation; Immune reactant #3: CTL; Antigen #3: cell-associated antigen; Effector #3: cytotoxicity

Front 655

What are the 4 types of hypersensitivity reactions according to Gell and Coombs?

Back 655

Type I: IgE-mediated (2-30 min); Type II: Antibody-mediated (5-8 hours); Type III: Immune-complex (2-8 hours); Type IV: cell-mediated (24-72 hours)

Front 656

In Type II hypersensitivity reactions, what is the immune reactant, the antigen, and the effector mechanism?

Back 656

Immune reactant: IgG; Antigen #1: cell/matrix associated antigen; Effector #1: complement, FcR+ cells; Antigen #2: cell-surface receptor; Effector #2: antibody alerts signaling

Front 657

In Type I hypersensitivity reactions, what is the immune reactant, the antigen, and the effector mechanism?

Back 657

Immune reactant: IgE; Antigen: soluble antigen; Effector: mast-cell activation

Front 658

What enzymes and toxic proteins are released from eosinophils and what are their effects?

Back 658

Eosinophil peroxidase: toxic via catalyzing halogenation, triggers histamine release from mast cells; Eosinophil collagenase: remodels connective tissue matrix; Matrix metalloproteinase-9: matrix protein degradation; Major basic protein: toxic to parasites, triggers histamine release; Eosinophil cationic protein: toxic to parasites, neurotoxin

Front 659

How does immune complex formation occur in Type III hypersensitivity reactions?

Back 659

A constant presence of antigen leads to a massive production of antibody --> with enough antibody around, a soluble immune complex will form to which complement (C1qrs) can bind --> this activates the classical pathway of complement activation --> production of anaphylatoxins (C3a, C4a, C5a) leads to inflammation and tissue destruction

Front 660

How can hemolytic disease of the newborn be prevented clinically?

Back 660

The mother receives anti-Rh antibodies immediately after childbirth has occurred --> the anti-Rh antibodies bind to the FcγRIIB-1 receptor on naïve B cells --> binding activates immunoreceptor tyrosine-based inhibitor motifs (ITIMs) which prevent the formation of Rh antibodies; Anti-Rh antibody must be given with each pregnancy because memory B cells do not respond to it

Front 661

In what scenario do problems with Rh factor cause hemolytic disease of the newborn?

Back 661

If the mother is Rh- and the fetus Rh+, the fetus will expose the mother to Rh antibody, usually at birth; the mother will produce IgG antibodies in response, which, in subsequent pregnancies with an Rh+ fetus, cross the placenta and cause destruction of fetal RBCs (not via the complement system, but via macrophage phagocytosis)

Front 662

By what pathway does a blood transfusion hypersensitivity reaction occur?

Back 662

IgM antibody in the patient reacts with antigen on the transfused blood cells --> classical complement pathway is activated --> lysis of donor cells and agglutination; the patient will also produce large amounts of IgG in response to the blood antigen --> this leads to phagocytosis of blood cells by the liver and spleen --> circulatory shock and kidney necrosis

Front 663

What type of hypersensitivity reactions are blood transfusions categorized as?

Back 663

Type II – IgG

Front 664

What route of action is needed to cause systemic anaphylaxis?

Back 664

Intravenous (either directly or following massive absorption) – can be caused by drugs, serum, venom, peanuts

Front 665

What are the activators released from mast cells and what is their effect?

Back 665

Histamine: vasodilation, vascular permeability; Platelet activating factor (PAF): microthrombi; Tryptase: activates C3; Kininogenase: activates kinins --> vasodilation, edema

Front 666

What aspect of anaphylaxis can be fatal?

Back 666

Hypovolemic shock – due to vasodilation and edema

Front 667

What are the chemoattractants released from mast cells and what is their effect?

Back 667

IL-3, IL-5, CXCL8, CCL3, TNF-α --> attract neutrophils, eosinophils, basophils; LTB4, PAF --> attract basophils

Front 668

How can Type III hypersensitivity reactions cause joint, kidney, and vascular disease?

Back 668

Deposition of immune complexes in these areas activates the complement system which leads to localized tissue destruction

Front 669

By what mechanism do Type IV hypersensitivity reactions occur?

Back 669

A T-helper cell interacts with an APCs --> activation of the T-helper cell causes it to secrete cytokines (IL-3, TNF-α), chemokines (RANTES), and cytotoxins (TNF-β) --> they cause vasodilation leading to leaky vessels and swelling

Front 670

What syndromes can result from Type IV hypersensitivity reactions and what antigens are associated with each?

Back 670

Delayed-type hypersensitivity: due to proteins (insect venom, mycobacterial proteins); Contact hypersensitivity: due to haptens (poison ivy) or small metal ions (nickel, chromate); Gluten-sensitive enteropathy (Celiac disease): due to gliadin