Pathology Exam 2

Front 1

Hypersensitivity Intro

Back 1

-Hypersensitivity is a immune response to FOREIGN antigens that had a adverse outcome
-It can be a exaggerated response or a response to a harmless agent

Front 2

Classification of Hypersensitivity Disease

Back 2

-The first 3 are classified as immediate or antibody mediated and the fourth is delayed type or cell mediated
Type 1 - Anaphylaxis or Immediate Hypersensitivity -Antigen leads to MHC II activation of CD4+ TH2 and production of IgE which bind mast cells. Known as allergies
Type 2 - Antibody-mediated or immune cytotoxic reaction - Antibody binds to fixed tissue/cell surface antigens and cause phagocytosis and inflammation
Type 3 - Immune complex-mediated - Antibody bind to antigen and form complexes that deposit in vascular beds to cause inflammation secondary to complement activation
Type 4 - T-cell mediated - T-cells cause injury via direct killing or release of cytokines

Front 3

Type 1 Introduction

Back 3

-Immediate Type or Anaphylactic: Ag contacts Ab bound to Fc receptor on mast or basophil cell.
-Can be targeted to a organ like the nose (rhinitis), eye (conjuncivitis), or the skin (dermitis)
-Can be systemic and cause anaphylactis like a penicillin shot

Front 4

Type 1 Terminology

Back 4

Atopy: A disease associated with the production of IgE and includes 10-15% of the population

Reaginic Antibody - Antibodies responsible for the allergic response

Allergen - Antigen that induce allergic responses

Front 5

Type 1 Pathogenesis

Back 5

1st exposure: Sensitization. When exposed to a antigen the TH2 cell activates a B-cell and in certain individuals the B-cell will switch from IgM to IgE. These people are known as atopic. The IgM (and IgG1) are known as homocytotropic since they bind their host's cells (mast/basophil). These antibodies will bind the Fce receptor (CD23). The process of binding mast cells and basophils by homocytotrophic antibodies is known as sensitization

Front 6

Type 1 Pathogenesis

Back 6

2nd exposure: When the antigen binds IgE on the mast/basophil the IgE will crosslink (takes 2 of them) and become activated and degranulate and release mediators
-In non-atopic individuals the IgE density is very low so this reaction does not occur
-The mast cell mediators include vasoactive amines/lipids which cause immediate problems and cytokines which cause the late phase reaction since they have to be translated first

Front 7

Type 1 Mediators

Back 7

Mediators:
Granule
1. Histamine - Vascular permeability, vasodilation, bronchospasm, and mucus secretion
2. Eosinophil chemotactic factor (ECF-A): Attracks eosinophils to the site
3.Proteases/Hydrolase: Cause tissue damage
4. Neutral Protease - Cleave complement/kinin components and amplify the immune response

Lipid Derived
1. Leukotrienes (SRS-A) - Vasoactive and spasmogenic
2. Platelet Activating Factor: Platelet aggregation, release of histamine, bronchospasm
3. Prostaglandins - Bronchospasm and mucus secretion

Cytokines - Involved in the late response important for the more chronic diseases like asthma

Other: Proteoglycan (heparin) - Package and store mediators

Front 8

Type 1 Results

Back 8

1. Vasodilation and increased vascular permeability
2. Increased mucus production
3. Bronchoconstriction of smooth muscle (bronchospasm)
4. Activation of sensory nerve ending leading to itchiness

Histology: Dilated BV, edema, and lots of eosinophils - very little neutrophils or macrophages!

Front 9

Clinical Examples of Local Anaphylaxis

Back 9

-the local anaphylaxis may have similar biochemical mechanisms but the pathology location depends on where the antigen binds and the type of antigen

A. Atopic Dermatitis: Characterized by hives, urticaria, angioedema. Urticaria is raised itchy either red surrounded by white or vice versa. You get it on the dermis or subcutaneous tissue. Angioedema is similar but usually affects deeper dermis/subQ fat/submucosal tissue commonly on the face, lips and tongue. The erythematous and edematous swelling usually subsides after 24 hours but can reoccur a few times
Histology: Edema with a few eosinophils

Front 10

Allergic Rhinitis and Conjunctivitis

Back 10

-Another example of local anaphylaxis
-aka hay fever
-Most common allergic disease
-Get BV dilation, edema, nerve irritation
-Symptoms include congestion, sneezing, pruritus (elevated skin), rhinorrhea, and lacrimation
-Can be due to seasonal allergies like pollen or perennial like dust mites or animal dander
-Chronic can lead to nasal polyps or otitis media
-Histology will show lots of eosinophils in the secretions

Front 11

Allergic Gastroenteritis

Back 11

-Usually due to a ingested food
-Causes perioral erythema and swelling of the lips, tongue, and pharynx. Can include nausea and vomiting

Front 12

Asthma

Back 12

-2 types, intrinsic and extrinsic, with bronchial asthma as both extrinsic and the most common form
Symptoms: Reversible airway obstruction leadings to wheezy dyspnea except with exercise asthma or chronic non-productive asthma
Morphology: Overdistended lungs, occlusion of bronchioles with mucus plugs, hypertrophy of bronchail wall muscle
Histology:
1. Increased goblet cells producing a thicker mucus layer with eosinophils found in it
2. Lamina Propria expanded and includes dilated BV and round cells
3. Basement membrane thicker
4. Increased bronchial smooth muscle
5. Increased glandular tissue

Front 13

More Type 1

Back 13

-Immune system preprogrammed to overproduce IgE in response to certain antigens
-eosinophil role is not certain, may break down histamine and keep the reaction local. Also, they may bind Ag with their Fc receptor and get rid of it
-once mast cells are sensitized, they are sensitized throughout the body

Front 14

Anaphylactic Shock

Back 14

-Systemic type 1 hypersensitivity due to parenteral intro of an allergen (bee sting or penicillin injection)
-Patient can go into shock within 1 hour
-Patient can bring in air but due to airway restriction they cannot exhale which requires smooth muscle relaxing
-Of those who die 70% die from respiratory distress and 30% from cardiovascular dysfunction

Front 15

Clinical Features

Back 15

1. Respiratory Tract
2. GI
3. Skin
4. Cardiovascular

Hint 15

1. Smooth muscle contraction leading to bronchospasm and increased vascular leakage leading to laryngeal edema. Histology looks normal but septi may be broken and filled with fluid. Laryngeal edema presents as hoarseness
2. Increased peristalsis leads to cramps, vomit, and diarrhea
3. Increased vascular leakage leads to urticaria and angio-edema, as well as lacrimation and runny nose.
4. Vasodilation and increased vascular leakage lead to hypotension which leads to shock

Front 16

Prevention

Back 16

1. Good medical history cause 50% of atopic individuals have a family history
2. Avoid parenteral drug administration
3. Warn patient of possible symptoms
4. Desensitization therapy with suballergic doses of Ag and generating blocking antibodies

Front 17

Treatment

Back 17

ABC - adrenaline, benadryl, and corticosteroids
Epinephrine - Given SubQ it will lead to vasoconstriction (alpha-1) and bronchodilation (beta-2). Additionally, by acting on mast cell receptors and activating adenylate cyclase to convert ATP to cAMP, degranulation and mediator synthesis will be blocked.
-Theophylline which blocks cAMP conversion to 5-AMP by PDE will have a similar effect

2. Anti-Histamines (Benadryl) - These work by competing at the active site which is no good in acute phase since the histamine had already bound the receptor.

3. Steroids - Can prevent mediator release which is not helpful in the acute phase when the mediators have already been released

Front 18

Protective Effect of Anaphylaxis

Back 18

-May help with immunity to parasitic disease
-Worm in the GI tract will be eliminated once anaphylaxis causes massive diarrhea
-Also the eosinophils may attack the worm by using antibody-dependent cellular cytotoxicity via IgE

Front 19

Type II Hypersensitivity

Back 19

Immune Cytotoxic Reaction or Ab Dependent Cytotoxic Reaction
-Caused by IgG or IgM antibodies that react with antigen that HAS TO BE cell or tissue bound
-Cell destroyed by 3 mechanisms
1) Activation of complement leading to the membrane attack complex and cell lysis
2) Opsonization by either complement C3b coating or Mac/PMN phagocytosis via their Fc receptor
3) Antibody-Dependent Cell-Mediated Cytotoxicity ADCC via NK cells or monocytes where enzymes are released to induce the target cell to undergo apoptosis. Even the receptors on the ADCC are Fc for IgG and IgM

Front 20

Targets of Type II

Back 20

-If the target is a RBC they are phagocytized since they have no nucleus to undergo apoptosis. This is anemia
-If the target is platelets then the result is thrombocytopenia and there is no apoptosis
-If the target is PMN then you get agranulocytosis
-If the target is GBM then you get glomerulonephritis

Front 21

Common Antigens

Back 21

-Exogenous moieties that become bound to cell or tissue such as drugs (haptens) which are absorbed and expressed on the cell surface
-Mismatched blood transfusion
-D-antibodies in the maternal blood

Front 22

Mismatch Blood Transfusion

Back 22

-Someone with A blood has the A-antigen on their RBC and B-antibodies circulating in their blood.
-A and B are carbohydrates which directly activate B-cells to produce IgM
-What happens is a individual with type A blood is accidentially transfused with type B blood leading to antibody attack of the type B RBC
-This ends up with RBC being lysed, phagocytosized, and a complement cascade initiated leading to acute kidney failure, vascular collapse, and DIC (random blood clots)
-The majority of failures are due to uncontrolled bleeding due to DIC or renal failure

Front 23

Immunohemolyrix Anemias

Back 23

-antibodies recognize antigens on RBC leading to anemia

1) Warm Type - Caused by IgG which are active at 37 degrees. Most cases are idiopathic while some are associated with immune disease
-The result is opsonization of RBC by autoantibodies which leads to erythrophagocytosis in the spleen and other places
-Drugs like a-methyldopa induce autoantibodies directs against RBC antigens like Rh. Additionally, penicillin can act as a hapten and induce a response by binding the RBC membrane proteins

Front 24

Immunohemolytic Anemia - Cold Type

Back 24

-Caused by low-affinity IgM (IgM9) which only bind RBC at temps below 30 degrees and are found on distal body parts
-Since the later steps of complement occur poorly at this temperature most cells will bind IgM and then C3b but stop at this point without lysis.
-When these cells travel to warmer temperatures the IgM is released by the C3b allows for phagocytosis, he3nce the hemolysis in this case is extravascular
-Frequently cold agglutinin (increase blood viscosity) develop like in recovery from pneumonia caused by Mycoplasma and Mono
-Besides anemia, Raynaud phenomenon is often seen as a result of the addlutination of RBC in capillaries of exposed body parts

Front 25

Erythroblastosis Fetalis

Back 25

-The RBC can be coated with a glycoprotein D-antigen known as the Rhesus factor
-Glycoprotein as a antigen can lead to IgG (traverses the placenta) or IgM
-If mother Rh- and baby Rh+ then the mother will make antibodies against Rh. The first child is usually not harmed
-If the second child is Rh+ then the antibodies against Rh attack the child and lead to several problems
-Complement leads to RBC damage, increased billirubin (jaundice and kernicturus brain damage due to billirubin)
-Fetus can also get anemia leading to heart failure, enlarged liver/speen, and hydrops fetalis (swelling all over)
-The main problem is the D-antigen glycoprotein nature which produces IgG. For blood types, since they are carbohydrates, no IgG is produced and an A-type Mom can give birth to B-type children

Front 26

Autoimmune Thrombocytopenia Purpura

Back 26

-Clinical you see low platelet count and megakaryocytes in the BM
-Patients present with cutaneous signs like petechiae, purpura, and mucosal bleeding
-The major risk is spantaneous bleeding into the vital organs

Front 27

Type 3 Hypersensitivity

Back 27

Immune Complex Mediated Hypersensitivity
-Ab (IgG or IgM) combines with SOLUBLE antigen resulting in immune complexes deposited in vessel or EC space
-Injury caused by result of complement activation to the complexes leading to PMN infiltration. Other outcomes is platelet aggregation and activation of hageman factor
-Where complement occurs the blood vessel or other structure (glomeruli) is destroyed

Front 28

Type 3 Precipitation

Back 28

-3 possible scenarios for soluble antibody and antigen
-In the first scenario there is way more antibody than antigen, the second the ratio is equal, and in the third antigen outweighs antibody number
-In the second scenario large lattice complexes btw antibody-antigen form which are quickly eliminated by the immune system
-In the other two, especially the third scenario, small soluble complexes form which activate complement, attrack neutrophils, but the neutrophils have trouble with them
-These small soluble complexes tend to accumulate in areas of bifurcation and fenestration like the lungs, kidney, and skin
-The antigen needs to be multivalent since monovalent won't form a good enough immune complex

Front 29

Stages of Type 3 Hypersensitivity

Back 29

1) Ag-Ab complex builds up at endothelial cells
2) Complement is initiated leading to C3a and C5a
3) C3a and C5a cause vascular changes like dilation and increased permeability
4) Immune complexes get in between the endothelial cells and are trapped by the basement membrane. Still activating complement
5) Neutrophils delivered to the sites of vascular activation.
6) Neutrophils want to phagocytize but have a difficult time doing this. In the process they release lysosomal enzymes which destroy the blood vessel
7) Result is vasculitis or destruction of the blood vessel

If this occurs in the kidneys you get destroyed glomeruli known as glomerulonephritis. Get blood, protein, and cellular casts in the urine.

Front 30

Serum Sickness

Back 30

-Prototype of systemic immune complex disease
-Used to be a bigger problem when sick individuals were treated with xenogenic "anti-serum" that contained neutralizing antibodies for a particular antigen
-This is still a problem today with serum treatments for snake bites
1. Anti-serum delivered and while it starts with a high concentration, that will decrease once it spreads throughout the body
2. As the antigen decline you'll begin to see the formation of immune complexes on day 7
3. As the antigen continues to decline due to halflife elimination, the number of Ab will outweigh the Ag and this is the most dangerous time for serum sickness

Front 31

Serum Sickness Clinical Manifestations

Back 31

-Clinical signs start 8-14 day after serum treatment
-Starts with fever, malaise, arthraligias, arthritis, nausea, vomitting, and glomeruloneprhtiis, vasculitis, and lymphadenopathy
-As the complexes localize to areas like the kidney, joints, skin, heart, and small vessels, the vascular lesions take on the form of acute necrotizing vasculitis and glomeruli become hypercellular.
-Immune complexes can lead to aggregation of platelets and activation of Hageman factor initiate clotting which contributes to tissue injury by producing local ischemia

Front 32

Serum Sickness Histology

Back 32

-Blood vessels are indistinguishable and destroyed
-immune complex is a micro thrombus
-Glomeruli will appear punctate and irregular on immunofluorescence. Get this pattern with a Ig stain or C3b stain

Front 33

Poststreptococcal Glomerulonephritis

Back 33

Antigen: Streptococcal antigen type 12, 4, and 1 group alpha-B hemolytic. the streptococcal cell wall antigen is planted in the glomerular basement membrane
Pathogenesis: Takes 1-4 weeks following infection leading to hypercellularity of the glomerulus and nephritis
Clinical Symptoms/Signs: hematuria, red cell casts, proteinuria, mild hypertension, oliguria (low urine output), malaise, fever

Front 34

Arthus Reaction

Back 34

-Following injection of antigen the immune complex forms with antibodies that have DIFFUSED outside the capillaries
-You get complement activation and release of inflammatory mediators near the site of injection
-Patients can get vessel damage (vasculitis) as well as platelet accumulation and vessel occlusion

Book:
Tissue necrosis from aucte immune complex vasculitis. Antibodies against the antigen are already in circulation. Due to initial antibody excess, immune complexes are formed as the antigen diffuses into the vascular wall. Peak 4-10 hours after injection

Front 35

Type 3 in the Lung

Back 35

-End up with destroyed alveoli septa and hypercellularity leading to a thickening
-The immunofluorescence shows a irregular and punctate pattern
Causing agents...
1) Farmer Lung - Micropolyspora Faeni
2) Pigeon Breeder Lung - Pigeon droppings
3) Humidifyer Penumonitis - Thermophilic Actinomycetes
4) Mushroom Picker Lungs - M. Faeni
5) Detergent Workers Lung - Bacillus Subtilus

Front 36

Type Antigen:Disease Relationship

Back 36

1. Drug, hormones, foreign serum
2. Microbe
3. Inhaled Antigen
4. Autoantigen
5. Oral Antigen

Hint 36

1. Serum sickness
2. Post-streptococcal glomerulonephritis, syphillis, bacterial endocarditis
3. Hypersensitivity penumonitis
4. Systemic lupus erythematosus (SLE)
5. Periodontal disease

Front 37

Causes of Death

Back 37

-In high-income countries we are better equipped to handle organisms that cause GI and respiratory disease
-However, in low-income countries the leading cause of death still includes lower respiratory infections, malaria, and diarrheal disease

Front 38

Host Defense

Back 38

1) Skin - Epithelium is a mechanical barrier. Its dryness and low pH (5) are not conductive to bacterial growth, and since it desquamates and sheds, bacteria are removed before reaching the dermis

Respiratory: For the holes in our body we have several defenses. At first the hair and mucosa filter out larger particles, then mucociliary escalator gets rid of finer things in the trachea. If anything makes it to the alveoli we have the alveoli macrophages to eliminate them

3. GI - Protected by low pH, mucus layer, lytic pancreatic enzymes (defensins prevent bacterial replication), bile detergents, and secretion of IgA antibodies. Additionally, vomiting gets rid of dangerous microbes. Finally, our stomach is already colonized by helpful bacteria that make it harder for others to form a colony

Front 39

Host Defense 2

Back 39

4. Genito-Urinary - Remains sterile with a low pH and secretion of sIgA. Additionally, it is colonized by lactobacilli that outcompete other bacteria

5. Mouth - Protected by the oral mucosa that turnsover quickly and antibacterial/antivirus products from our salivary glands

Front 40

Infectious Agent Mechanism of Disease

Back 40

1) Enter host and cause death directly

2) Initiate a inflammatory response that does the killing

3) Release toxins that kill the host or act as enzymes to degrade tissue or damage blood vessels causing necrosis

Front 41

Inflammatory Response to Infection

Back 41

1) Pyogenic bacteria lead to suppurative inflammation forming an abscess

2) For a non-digestable organism like M. Tuberculosis we defend ourselves with granulomatous inflammation

3. Hepatitis B causes chronic inflammastion and scaring

4. Cytopathic virus get into the cell and kills it like HSV whereas cytoproliferative like HPV uses the cells replication mechanism to replicate itself. These have sparse inflammatory cells.

5. Bacteria like anthrax (bacillus anthracis) causes necrotizing inflammation

Front 42

Mechanisms of Bacterial Virulence

Back 42

-Bacteria need to either attach to a cell, invade it, or deliver toxins to use
-Virulence genes are found grouped together in clusters called pathogenicity islands
-Some bacteria do not express virulence genes until they are needed. Gram+ S. aureus secretes autoinducer peptides as its concentration increases so it is able to overcome host defense and move on to another site

Front 43

Mechanism of Bacterial Virulence

Back 43

1) Adherence - Adhesins bind the host and allow the bacteria to get in. The fibrillae on S. Pyogenes is composed of a lipoteichoic acid which binds fibornectin and buccal epithelial cells and the M. protein prevent phagocytosis. Bacteria also use pili (Gram-) which are specific on the AA on the tip and determine binding specificity. N.Gonorrhoeae express a P pilus which binds uroepithelial cells to cause UTI

Endotoxin - Gram- bacteriause LPS recognized by TLR-4 to activate macrophages

Exotoxin - AB toxins of anthrax are secreted with B getting the toxin into the cell and then A breaking off and wreaking havoc. Superantigens on strep/staph cause a massive immune response

Front 44

Virulence of Intracellular Bacteria

Back 44

-Intracellular bacteria infect with epithelial cells, macrophages, or both. By growing inside an organism they are able to evade host immune system and move to other locations like the M. tuberculosis does inside the M-phage from the lungs to other sites
-Bacteria can coat themselves with C3b causing phagocytosis to get inside (TB)
-G- bacteria use a secretion system from their surface to enter epithelial cells.

Front 45

Syphillis Intro

Back 45

-Reemergences on a 10yr cycle include now with >50 million affected worldwide
-Occupational hazard for dentist
-Transmitted through mucosal to mucosal, dry skin won't work
-Prevalence of infection is 50-100 times higher in the US than other industrialized countries

Front 46

Syphillis Organism

Back 46

-Gram negative spirochete called Treponema pallidum
-Man is the only natural host
-Most contracted during sex, but can also be passed in utero or through contact with a mucosal lesion (dental hazard)
-Syphillis does not produce toxins or cause direct cell lysis. Then why is it so dangerous? Because it cannot be phagocytized and tissue damage is due to a host immune response

Front 47

Primary Syphillis

Back 47

-Major finding is a chancre (shenker)
-This is a singular, highly contagious lesion that is a raised ulcer with a hard/indurated rolled border
-It takes 2-3 weeks after infection for it to show up at the site of infection because this is the time it takes for plasma cells to come in
-The actual damage is done by lymphocyte induced periarteritis (inflammation of the vasculature) leading to endarteritis (swollen endothelial cells) causing vascular damage and ischemia to the surrounding tissue (endarteritis obliterans) and leading to ulcers. The rolled border is the body trying to wall it off
-There is not pain because the nerve vessels are obliterated
-THe chancre is filled with syphillis which can spread using lymph nodes to non-genital sites, most frequently being the oral cavity
-The chancre has lots of T/B lymphocytes with macrophages and giant cells

Front 48

Primary Syphillis Outcome

Back 48

-2-6 weeks after chancre appearance the lesion will disappear
-50% of patients progress to secondary phase and 50% get rid of it completely with no treatment

Front 49

Secondary Syphillis

Back 49

-Spirochetes multiply at distal sites that were colonized during primary infection
-So this is a systemic spread leading to malaise, fever, lymphadenopathy
-2-3 months after chancre heal the patient gets multiple highly infectious macular papular rashes (primary has a single lesion, secondary has multiple)
-The macular/papular rash can occur on their hands and feet
-1/3 of the patients also present with mucous patches. No rolled border but a gray-white non wipable appearence
-The patient can also form papular lesions resembling viral papillomas known as condylomata lata. These occur in moist areas like anogenital and are elevated lesions
-Several immunocompromised patients can have a explosive and wide spread form known as lues maligna

Front 50

Secondary Syphillis Histopathology

Back 50

-The patients histology is characterized by vasculitis, most likely due to deposits of syphillis Ag and immune Ag
-The circulating complexes can lead to arthritis or glomerulonephritis
-The vasculitis is usually accompanied by proliferative endarteritis

Front 51

Outcome of Secondary Syphillis

Back 51

-The manifestations of secondary syphillis usually last just weeks but can reoccur a number of times
-After the stop coming back most patients develop immunity
-30% go on to tertiary syphillis

Front 52

Tertiary Syphillis

Back 52

-Syphillis stays dormant for several years and can arise in 30% of people
-Commonly see cardiovascular, neuro, and benign teriary syphillis (Gumma - anywhere in the body)
-No spirochetes detectable
-Still periarteritis (vessel still intact with RBC and lymphocytes), leading to endarteritis (vessel indistinguishable from surrounding tissue), leading endarteritis obliterans

Front 53

Neurosyphillis

Back 53

-10% of tertiary syphillis cases
-Defined as periarteritis in the neural tissue. The final name and symptoms depend on where the destruction occurs
1) Meningovascular - anterior spinal artery affected leading to paraplegia
2) General paresis - Cerebral cortex, meninges, and cerebral arteries affected leading to atrophy of the frontal and temporal lobes and dilation of the ventricles. Mental and physical problems like dementia and hallucinations. Spirochetes often found in the lesion
3) Tabes Dorsalis - Affects the spinal cord leading to dorsal root atrophy and demyselinzation. This leads to paresis (partial loss of voluntary movement), trouble walking
4) Primary Optic Nerve Atrophy - Affects the optic nerve leading to blindness

Front 54

Cardiosyphillis

Back 54

-May take up to 40 years to develop
-End up with endarteritis obliterans of the vaso vasora of the aorta leading to replacement of the muscular wall with rigid collagen
-Wall loose elasticity and this can lead to aneurysms, coronary insuffiency, and MI

Front 55

Benign Tertiary Syphillis

Back 55

-Development of gummas in various organs
-The gummas are solitary, indurated granulomatous ulcerations
-Contain few T. pallidum and are not contagious
-Exhibit a central area of coagulative necrosis surrounded by lymphocytes, epitheloid cells, and giant cells
-Intraoral lesions are usually on the palate and tongue (interstitial glossitis)
-Atrophy of the doral tongue papilla leads to leutic glossitis

Front 56

Congenital Syphillis

Back 56

-2/3 of infected women will transmit T. pallidum across to the placenta
-If the women is in 1st/2nd syphilis with lots of bacteria then the fetus usually dies in utero. Smaller numbers cause early and late congenital syphillis
Early Congenital Syphillis - Appears w/i 2 years of birth and the lesions are similar to those in secondary syphillis. Child is teeming with organisms which will eventually move on to teriary syphillis
Late Congenital Syphillis - Develops after 2 years of birth and the lesions are similar to those in teriary syphillis (gummatous necrosis)
-Peg-shaped incisors (Hutchinson's incisors)
-Dome-shaped molars (Mulberry Molars)
-Hutchinson Triad - interstitial keratitis (corneal inflammation), deafness, and Hutchinson's incisors

Front 57

Diagnosis and Treatment of Syphillis

Back 57

-dark field microscopy isn't used much anymore
-two main serological test
1) Low sensitivity - Use rapid plasma reagin (RPR) and venereal disease research laboratory (VDRL). These are non-specific in that they only tell you if you have a active infection and will be positive during primary and secondary syphillis
2. High Sensitivity - Fluorescent treponemal antibody absorption (FTA-ABS) and T. Pallidum hemaglutination assays (TPHA) will be positive anytime after syphillis contraction since they tell you if you have formed antibodies to the bacteria. However, they do not tell you if the infection if active
-Treat primary and secondary syphillis with penicillin

Front 58

Diptheria

Back 58

-Caused by G+ rod bacteria Corynebacterium Diptheria
-Passes between people via aerosols or skin shedding
-Works via a A-B exotoxin. The B gets it in and the A fragment stops protein synthesis via EF2 ADP-ribosylating and a single toxin can kill a cell
-Controlled by immunization which is formalin-fixed toxin. Does not stop colonization but prevents lethal effects
-Also have a anti-toxin that stops the effect of the toxin
-Even if someone is immunized they can still be asymptomatic carriers

Front 59

Diptheria Sign and Symptoms

Back 59

-fever, headache, malaise, anorexia, sore throat, vomiting
-the life-threatening syndrome is the formation of a white-yellow membrane the becomes adherent and gray and eventually black/green and necrotic.
-It can compromise the airway, lead to bull neck, myocarditis, and paralysis through neurologic involvement

Front 60

Diagnosis and Treatment

Back 60

1) If non-clinical diagnosis - Take culture from nasal mucosa and under DPT membrane and look for microbe. Need 3 negative cultures to prove it has been removed
2) If clinical diagnosis - Still take a specimen but start them immediately on antitoxin and antibiotics (penicillin)

Front 61

Streptococcal Infections

Back 61

-G+ pyogenic cocci that leads to suppurative infection depending on the strain
-Grow in pairs or chains
-B-hemolytic (complete lysis) via M-protein
S. mutans - caries
S. pneumoniae - lung and meninges
-treatment with penicillin
-different strains lead to tonsillitis/pharyngitis, scarlet fever, impetigo, and erysipelas

Front 62

Streptococcal Virulence

Back 62

1) Rapid Multiplication
2) M-Protein - molecule on the cell membrane resists phagocytosis via inhibiting activation of alternate complement
-type-specific antibodies to M-protein can give you long lasting immunity
3) Lipoteichoic Acid (LTA) - Cell wall component that allows adherence to mucus membranes
-Once attached, it will proliferate and invade the tissue
4) C5A Peptidase - Cleaves complement C5a and hence destroys chemotactic signals

Front 63

Streptococcal Virulence

Back 63

1) Extracellular products
-Hemolytic toxins streptolysin O and S
-Toxic to PMN and platelets
-Strep S is nonantigenic and produced in the presence of serum. It is a polypeptide that is lytic for RBC and WBC
-Strep O is a immunogenic single-chain protein that induces a quick antibody response which are good indicators of a recent infection

2) Pyrogenic Exotoxins - Three exotoxins A, B, and C. Are superantigens and cause T-cells to proliferate. Cause fever and scarlet rash, as well as endotoxic shock

3) Nucleases - A, B, C, and D deoxyribonucleases assist in the liquefaction of pus and help to generate substrate for growth

4) Other Enzymes - 2 streptokinases which form a complex with plasminogen activator and helps convert plasminogen to plasmin thus digesting fibrin.
-It also has a hyaluronidase that helps digest connective tissue

Front 64

Tonsillitis and Pharyngitis

Back 64

-25% caused by group A, B-hemolytic streptococci
-most common bacterial spread in humans (human to human)

Signs and Symptoms: sore throat, fever, dysphagia, tonsillar hyperplasia, palatal petechiae, lymphadenopathy, white strawberry tongue. DONT usually see rhinitis, laryngitis, and bronchitiis

Suppurative Complications: abscess, otitis media, sinuitis, necrotizing fascitis, bacteremia, meningitis

Non-Suppurative Complications - acute rheumatic fever, acute glomerulonephritis, toxic shock syndrome

Front 65

TP Diagnosis and Treatment

Back 65

-Diagnose with a throat culture or rapid antigen detection test
-Certain clinical features (sort throat + ulcers and diarrhea) suggest a virus and testing should be discouraged
-Treat with antibiotics like penicillin

Front 66

Scarlet Fever

Back 66

-Group A, B-hemolytic causing a systemic infection in children 3-12
-Small amount of people with strep throat move on to this
-pyrogenic, Erythrogenic, exotoxin that attacks blood vessels and produces a skin rash that starts at the neck/chest and spreads

Front 67

Clinical Symptoms

Back 67

Day 0 - looks like tonsillitis and pharyngitis
Day 2 - white strawberry tongue , fever, facial erythema, body rash with sunburn + goose pimples
Day 4 - red strawberry tongue (tongue desquamates), circum-oral pallor, and transverse streaks called pastia's line

Result: rash clears in a week but skin desquamation continues for 2 months
-with strawberry tongue the fungiform papilla are red and protruding

Front 68

Scarlet Fever Diagnosis and Treatment

Back 68

Diagnosis: Characteristic rash, strawberry tongue, throat culture positive for S. pyogenes

Front 69

Impetigo

Back 69

-Superficial skin infection due to either S. pyogenes or Staphylococcus aureus
-Occur in young children
-pruritis and lymphadenopathy can be seen
two presentations
1) Nonbullous impetigo - short lived fragile vesicle erupts and is replaced by thick adherent amber crust
2) Bullous impetigo - Lasting bullous lesion that forms a thin honey colored crust when they erupt

Front 70

Impetigo Additional Detail

Back 70

-associated with overcrowded living conditions, poor skin hygiene, and minor trauma
-Spreads via direct contact (human or environmental) and houseflies
-DIFF strain than tonsillitis
Nonbullous lesion - Go from macules to papules and then vesicles. Form pustules and are itchy
Bullous Lesion - More associated with S. aureus. Form bulla that become purulent over time

Front 71

Impetigo Diagnosis and Treatment

Back 71

Diagnosis: Look at clinical signs or take skin culture

Treatment: Topical antibiotics if the lesion is small and systemic if it is larger. Corticosteroids will only reduce the crust, not clear the red/raw lesions

Front 72

Erysipelas

Back 72

-Superficial skin infection associated with lymphatic involvement caused by the same group A Streptococci
-Also known as St. Anthony's Fire
-Can be confused with facial cellulitis due to a dental infection

Front 73

Erysipelas Clinical Features

Back 73

-Effects the young and old
-See butterfly lesions on the cheeks, nose, and eyelids
-The butterlfy lesions are red, sweollen, indurated, and painful
-Patients can exhibit systemic problems like fever, sore throat, and lymphadenopathy

Front 74

Diagnosis and Treatment

Back 74

Diagnosis: Characteristic clinical signs as well as cultures from the lesion and throat

Treatment: Penicillin or erythromycin. Right after treatment the lesion enlarges due to bacterial lysis but it will usually resolve after 48 hours

After treatment the erysipelas can reoccur

Front 75

Cat Scratch Fever

Back 75

-Due to contact with cats with fleas in the fall or winter
-Get papule or vesicle, swollen lymph nodes in armpit (most common)
-Systemic effect like fever, malaise, headache
-Caused by B. henselae

Front 76

Streptococcal Complications

Back 76

Acute rheumatic fever, glomerulonephritis, and toxic shock syndrome

1) Acute rheumatic fever
-Latent period of 2-3 weeks after pharyngitis
-Followed by arthritis, carditis, chorea, and erythema marginatum
-May be due to the exotoxin or cross reactvitiy between the strep antigen and heart tissue

Front 77

Streptococcal Complications

Back 77

2) Glomerulonephritis
-Specific nephritogenic strains (type 12 and 49)
-Due to immune complex deposition within the glomerulus

3) Toxic Shock Syndrome
-Shock and organ failure
-Caused by type 1 and 3 M-protein
-The pathogenesis is due to streptococcal pyrogenic exotoxins A-C and streptococcal super antigen

Front 78

Hepatitis B Introduction

Back 78

-A very prevalent disease worldwide with many more infected than HIV
-Most common cause of cirrhosis and liver cancer
-Present in all body fluids except stool and so hardy that it can remain in blood for up to 6 months and drying/extreme temp won't kill
-Also persist because it has many routes of infection like vertical transmission, needles, fluids like blood transfusion or semen
-A occupational contact for dentist
-Even with all these routes, 30% of people infected have no known etiologic agent

Front 79

Hepatitis B Genes

Back 79

HBcAg (c antigen) - nucleocapsid core protein. Someone c+ has had or has actively replicating HBV and this is a good diagnostic tool

HBeAg - polypeptide transcript

HBsAg "s" antigen - Envelope glycoprotein. One of the first expressed genes and a good marker. Now everyone with the vaccine is "s" positive so it's not a great diagnostic tool

HBx - From the X region.

Front 80

Pathogenesis

Back 80

-Probably due to the CD8+ T-cell response to infected hepatocytes

1. HBV enters hepatocyte through a receptor
2. Virus self replicates and makes proteins
3. The "s" antigen is presented at the hepatocyte surface as a MHC I complex
4. CD8+ T cells respond to this antigen presentation causing hepatocyte apoptosis via Fas-FasL and TNF-TNFR binding
5. At the same time CD8+ cells release IFN that initiate a complex immune response

Front 81

Breakdown of Infection Types

Back 81

Three main forms of hepatits, acute, chronic, and fulminant
After infection
1. 60-65% of people get SUB-CLINICAL symptoms, all of who recover
2. 20-25% go on to ACUTE HEPATITE, most of quick recover but 1% go on to FULMINANT HEPATITIS (liver destruction beyond repair) and death
3. 5-10% are HEALTHY CARRIERS
4. 4% move on to CHRONIC PERSISTANT of which 70-90% of these people RECOVER and 10-33% go on to CHRONIC ACTIVE
5. 20-50% of CHRONIC ACTIVE move on to CIRRHOSIS, HEPATOCELLULAR CARCINOMA, and DEATH

Front 82

Acute Hepatitis

Back 82

-Defined as virus causing necrosis and inflammation of the liver. Defined in 4 stages
1) Incubation Period - time between viral entry and the first symptoms
2) Prodromal/Pre-Icteric - Begin to see symptoms.
3. Icteric - Begin to see jaundice due to cholestasis or blockage of bile flow (billirubin is released through bile). Children are often anicertic and get no jaundice. Bile flow blocked by ballooning of hepatocytes and these histology stain brown
4. Convalescence - Recovery

Additional - Inflammation in the portal tract is fought by Kuppfer Cells. Hepatocytes undergo ballooning degeneration and enlarge

Front 83

Serum Markers in Acute Hepatitis

Back 83

HBsAg - First serum marker and disappears during recovery period, indicating full recovery from acute hepatitis. After "s" antigen disappears, the "s" antibody appears which gives life long immunity

2. HBcAg - The antigen appears after "s" but does not clear the virus or protect against infection. Remains elevated for life and is a good indicator of past infection

3. HBeAg - Appears near clinical disease and correlates with maximum viral replication and infectivity. "e" antibody appears after antigen removal and while it stays in the blood antigen-antibody complexes can form causing glomeruloneprhritis, arteritiis, and arthritis

Two causes of cell death in acute hepatitis, one is cytolysis where the necrotic cell appears to have dropped out. The other is apoptosis

Front 84

Fulminant Hepatitis

Back 84

-Massive hepatic necrosis causing liver failure in 2-3 weeks
-Major complication is cerebral edema which is the leading cause of death - 25-90% of the people
-The liver shrinks and the the reticulin framework and capsule collapse
-Necrotic areas are muddy red with blotchy bile staining
-At first there is little inflammation but then a massive influx of inflammatory cells come in
Suggested causes?: Direct cytopathic effect of virulent strain or massive immune response (cytokine release or ag:ab complex)

Front 85

Chronic Hepatitis

Back 85

Begins as acute hepatitis but the inflammation and necrosis does not resolve for 6 months
-Of all the risk factors, age is the most important one. The younger you are the more likely you are to progress to chronic hepatitis
-Two morphologies of chronic hepatitis are chronic persistent and chronic active

Front 86

Chronic Persistent Hepatitis

Back 86

-Mild form of chronic hepatitis with inflammatory infiltration limited to the portal tracts
-Most patients do not progress to more severe disease
-Histological you'll see scattered liver cells with large granular cytoplasm containing lots of "s" antigen, and these are ground glass hepatocytes

Front 87

Chronic Active Hepatitis

Back 87

-necrotizing inflammatory disease that can progress to cirrhosis and liver cancer
-Portal tracts filled with lymphocytes leading to one of the hallmarks of this called piecemeal necrosis. Get a irregular appearence of the portal zone because inflammation surrounds groups of hepatocytes on the portal tract borders
-Also get bridging fibrosis which is repair that disrupts liver function by branching out and destroying the central vein and parenchyma
-At the end you get dense collagenous septa, and destroy the lobular architecture by dividing the liver into nodules, this appearences is cirrhosis

Front 88

Hepatocellular Carcinoma

Back 88

-Chronic carriers 200x more likely to develop it than the unaffected
-20% of people with cirrhosis develop it
-Once symptoms develop they are at the terminal stage
-Sinc development of HCC is typically seen 30-50 years after getting the infection, it usually occurs to people who get infected when their young

Front 89

Mechanism of HCC

Back 89

1) Integration of HBV DNA into oncogene (activate) or tumor suppressor gene (deactivate)
2)Inflammation leading to free radicals that damage host DNA
3) Accelerated proliferation with less time for DNA repair

Front 90

HCC Prevention

Back 90

-Most important tool is the vaccine

Diagnosis: Use liver function test, PCR, or enzyme immunoassay

Treatment: Immune modulators, anti-virals

Prevention: Vaccine with HBsAg and anti HBsAg immunoglobulin preparation (HBIG) given after birth

Dental Implications
1) Easy to spread to patients and staff
2) If someone is suspected of carrying it do not do dental work on them
3) These patients bleed a lot mroe so you do a preoperative prothrombin time (PTT)

Front 91

Human Papillomavirus

Back 91

-most common STD virus
-SPread via any kind of contact or vertical transmission
-Cannot study in non-human models
-Causes cervical cancer in women
-Undergoes cytoproliferative response where infected cells divide leading to HPV lesions
-Three major groups of lesions caused by HPV: cutaneous warts, epidermodysplasia verruciformis, and mucosal HPV infections

Front 92

HPV Life Cycle.

Back 92

HPV is a non-enveloped icosahedral virus with circular dnDNA
1) HPV infects squamous epithelial cells, usually the basal cells. They can become latent at this point, or...
2) As the basal cells differentiate, more HPV genes are expressed.
3) As HPV DNA is maintained episomal plasmid more proteins are expressed leading to cell growth and wart formation (veruca vulgaris or condyloma accuminatum if on the vagina) which is usually handled by the immune system
4) In some people HPV integrates into the DNA and can lead to a tumor by inactivating p53 and Rb. HPV E6 ubiquitinates p53 and HPV E7 binds to Rb allowing entry into the cell cycle

Front 93

Cutaneous Warts

Back 93

-Only appear via active warts and on keratinized squamous epithelium
-Classified by appearence
1) Verruca Vulgaris or common wart
2) Deep hyperkeratotic palmoplantar wart or myrmecia
3) Superficial mosaic type palmoplantar wart
4) Verruce plana or flat wart
-acetc acid can be used to diagnose warts on the cervix

Front 94

Epidermodysplasia Verruciformis

Back 94

-rare, life-long disease
-probably autosomal recessive
-Infected people get widespread warts and a high probability of these going to malignancy
-Malignancy usually occurs in sunexposed and traumatized areas

Front 95

Mucosal HPV Lesions

Back 95

-HPV lesions in the genital tract, oral cavity, conjunctiva, and respiratory tract
-COndylomata acuminata (genital warts) are the most common genitor tumor but it is usually benign
-laryngeal papilloma is a rare condition that although a benign tumor it has to be removed regularly to prevent respiratory tract blockage

Front 96

Cervical Cancer

Back 96

-HPV 16 and 18 infections are associated with (cervical) carcinogenic progression
-A high percentage of cancers are due to HPV
-PAP smears and early detection can lead to successful treatment
-HPV DNA can be detected in 95% of cervical cancer and 50% of cervical cancer have HPV16

Front 97

Linking HPV to Cervical Cancer

Back 97

1) HPV DNA is detected in 95% of cervical cancers
2) Certain HPV like 16/18 are associated with cervical cancer
3) HPV E6/E7 can disrupt the cell cycle and cell death pathways leading to tumor development
4) HPV DNA is usually integrated in the genome when the tumor is malignant, and for other HPV lesions it is usually episomal
5) HPV-16 cancer have been associated with chromosome abnormalities like 3p deletions and 3q amplifications
6) Vaccines directed against papillomarvirus can prevent precancerous disorders

Front 98

Diagnosis and Treatment of HPV

Back 98

-No serologic markers of HPV
-HPV detected by papanicolaou cytologic test (pap smear) and DNA hybridization techniques
-A lesion is removed by electrocauterization, cryosurgery, laser vaporization, and surgery
-Oral mucosa HPV lesions are similar to those in the genitalia

Front 99

EBV and Mono Intro

Back 99

-Epstein-Barr virus is most associated with mononucleosis
-Once infected you are a host for life
-Occurs through saliva contamination, like kissing or toys
-In developing nations most kids have it by age four
-In developed countries only half of the college students have it and so it becomes universal in college
-it is a self-limiting lymphoproliferative disease leading to fever, lymphadenopathy, hepatosplengomegaly, and atypical activated t-lymphocytes

Front 100

EBV Pathogenesis

Back 100

-EBV glycoprotein binds B-cell complement C3d protein and attacks the B-cell
-It will mostly integrate in the genome and become latent, and in a minority of cells it will be lytic
-Because it is passed through saliva, it usually affects the tonsils first
-The destruction comes through CD8+ T-cell and NK cell proliferation in lymph tissue as your body mounts the response
--You can make a diagnosis based off a blood smear due to the presence of atypical lymphocytes with enlarged cytoplasm, clear vaculoations, oval/indented nuclei, and cytoplasmic azurophilic granules

Front 101

EBV Clinical Manifestation

Back 101

-Get massive lymph node enlargement
-The enlarged spleen can lead to rupture
-Liver function is usually affected due to lymphocyte proliferation in portal areas and parenchymal necrosis
-Get CNS edema

Front 102

EBV Clinical Manifestations

Back 102

Infant/Toddler - Usually asymptomatic
Children/Adults
1) 2 week prodromal phase with the t-cells begin to mount a attack. Get fever, malaise, and weight loss
2) Symptomatic phase - Sore throat (enlarge tonsils have yellow exudate), lymphadenopathy, hepatosplenomegaly, necrotizing ulcerative gingigivitis (NUG), and necrotizing mucositis

Front 103

EBV Diagnosis and Treatment

Back 103

Diagnosis:
-Clinical presentation
Tests: All very specific but still in increasing order of specifiicity
1. blood smear with atypical lymphocytes
2. Positive heterophile antibody reaction (monospot test). Detects B-cell produced antibody that agglutanates animal RBC
3.Specific antibodies for EBV

Treatment:
-Palliative therapy including NSAIDS and non-aspirin anti-pyretics
-avoid contact spots so no spleen rupture
-Can use steroids if the airway obstruction becomes life threatening but must be careful because diminishing the immune response too much allows the virus to cause greater problems like encephalitis and myocarditis

Front 104

Funal Histoplasmosis

Back 104

-Most common systemic fungal infection in the US and caused by H. capsulatum
-Inhalation of fungal spores leads to lung and systemic disease
-Grows in 2 phases; haploid unicellular which occurs at body temp. and multicellular hyphal which grows in its natural environment

Front 105

Histoplasmosis Clinical Features

Back 105

-Usually asymptomatic because once ingested alveolar macrophages attack the organism followed by T-cell and antibody mediated responses
-more serious complication can be due to spore quantity, immune status, and strain varietal
1) Acute Histoplasmosis - Pulmonary infection usually due to high spore quantity. Fever, headache, and flu symptoms for 2 weeks
2) Chronic - Usually occur in immunocompromised or elderly. Have fever, weight loss, hemoptysis, and similar to TB
3) Disseminated - Very rare and leads to extrapulmonary spread. Can lead to solitary painful ulcerations in the oral mucosa that are usually firm

Front 106

Histopathology

Back 106

-Collection of macrophages and giant cells organized into a granuloma
-Can see the fungus with a PAS or Grocott-Gomori methenamine silver strain. May also see in H&E, but difficult

Front 107

Diagnosis and Treatment of H. Capsulatum

Back 107

Diagnosis: Histopathological observation using the techniques above or serologic methods using antibodies to the fungal antigens

Treatment:
Acute: No treatment needed
Chronic: Anti-fungal agents like amphotericin B or the "azoles" are good in non-immunocompromised patients. If not treated chronic could lead to pulmonary disease
Disseminated - Mortality is very possible, but much like chronic you can try amphotericin B or the "azoles", however in this case the azoles lead to slower recovery and more chance of relapse

Front 108

Candidiasis

Back 108

-most common oral fungal infection, especially the yeast-like C. albicans
-Part of the normal flora but people can develop problems if they are immunocompromised, if their oral mucosal environment changes, or if the strain is especially virulent
-Being HIV infected is the biggest risk factor, but other thigns that change the oral environment can be risk factors too like antibioticis, steroids, chemo drugs, dentures, and decrease salivary flow

Front 109

Candidiasis Additional

Back 109

-It is a dimorphic fungus, switching between the yeast and hyphal stage
-The hyphal stage is more invasive

Front 110

Clinical Manifestations

Back 110

-the many different clinical manifestations can occur individually or in combination
1) Pseudomembranous Candidiasis (oral thrush) - Creamy white removeable plauqes that can be wiped off leading to a burning sensation and foul taste
-The plaque contain the yeast and dead epithelial cells
-Common in kids with under developed immune system and also people on broad spectrum antibiotics

Front 111

Clinical Manifestations

Back 111

2) Erythematous Candidiasis - Flat red patches anywhere on the oral mucosa. Several different presentations.
-Central, chronic, and denture are all chronic, largely asymptomatic
a) Acute Atrophic Candidiasis (antibiotic sore mouth) - Feel like scalded by a hot beverage and end up losing filliform papillae leading to a bald tongue
b) Central Papillary Atrophy - Symmetric loss of filliform papillae from the MIDLINE of the DORSAL tongue.
c) Chronic Multifocal Candidiasis - Multiple red sites similar to central papillary atrophy. Called kissing lesions cause happen on palate between tongue and corresponding palate, as well as the junction of the palates and the angle of the mouth
d) Denture Stomatitis - Erythema and petechiae localized to denture. Often the fungus is not even on the mucus so it's not a true infection, but positive culture on the denture which needs to be cleaned
e) Angular Cheilitis - Redness and fissuring of the angles of the mouth that occurs frequently in older immunosuppressed patients. Saliva pools in these areas can cause fungus growth. Occur frequently with chronic multifocial candidiasis. Can occur in combo with other agents like S. aureus

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Clinical Manifestations

Back 112

3) Hyperplastic Candidiasis - White patch on tongue/mucosa that CANNOT be removed by scraping
-Distinguish it from leukoplakia via hyphae appears on histo and resolution after antifungal therapy

Front 113

Candidiasis Diagnosis and Treatment

Back 113

Diagnosis: Based on clinical appearance. Also use a Sabouraud Agar slant positive culture or the presence of hyphae (or pseudohyphae) on a PAS. Will also see microabscesses, thickened para keratin, and elongated ridges on the histology

Treatment:
-Antifungal agents like nystatin or the azoles
-If the lesion does not respond to antifungals then do a biopsy

Front 114

Actinomycosis

Back 114

-Most common strains of actinomycosis is A. israelii or A. viscosis
-They are filamentous, G+ bacteria
-Become virulent when they enter into subQ tissue usually from caries, tooth extraction, or trauma

-organisms of most classes like bacteria, protozoa, and viruses can become opportunistic infections
-Actinomycosis, although rare, is difficult to diagnose and delayed treatment can lead to long term treatment needed
-Most of the time it occurs in the oral cavity because it is part of the normal oral flora
-Usually see it in the tooth cervicofacial region

Front 115

Actinomycosis

Back 115

Clinical:
-painless, indurated masses with sinus tracts that drain pus (seminar w/acute and chronic in one)
-Associated with fibrosis with a central abscess. Suppurative inflammation is closer to the organism
-Do not follow facial planes or involve lymph nodes or BV but form sinus tracts where you see the pus and acute inflammation

Histology: Actino is surrounded by PMN which are furhter surrounded by granulation tissue and fibrosis.
-The organism within the abscess form club-shaped filament forming a rosette pattern
-Sometimes you can get sulfur granules from the sinus tract, strongly indicate of this organism

Front 116

Actinomycosis Diagnosis and Treatment

Back 116

Diagnosis:
-Positivie culture (tough because of all the other bacteria present which overgrow it)
-Sulfur granules w/indirect fluorescence(can rarely be Botryomycosis)

Treatment:
-Antibiotics with abscess drainage and surgical removal of the sinus tracts
-Need high dose antibiotics because of the fibrosis. Up to a year if it is deep

Front 117

Men 2B

Back 117

-Multiple endocrine neoplasia 2B is a genetic disorder that affects the oral cavity
-Characterized by neuromas on the tongue/lips, pheochromocytoma, and medullary thyroid cancer. Also get marfanoid or long face

Front 118

Mendelian Genetics

Back 118

-Most diseases do not follow simple mendelian genetics
-includes autosomal dominant/recessive, x-linked, and single gene mutations like missense (single AA swap), nonsense (early stop codon), and frameshift problems

Front 119

Autosomal Recessive

Back 119

-both parents unaffected carrier so 25% chance of getting it and this is equal between sexes
-It's usually a metabolic disorder due to enzyme function because having one of the protein allows you to metabolize normally, but missing both copies puts you in trouble
-Consanguineous mating (imbred) increases the incidence
-A proband is a diamond on a hereditary chart indicating that this is the patient they're charting for
-Usuall the problem is that a falty enzyme means there isn't enough product made, the intermediate that isn't metabolized is dangerous (PKU), or w/o that enzyme the metabolite goes down another pathway which causes trouble

Front 120

Phenylketonuria

Back 120

-example of a autosomal recessive trait
-Patients are deficient in the liver enzyme phenylalanine hydroxylase which converts phenylalanine to tyrosine
-W/o this conversion F is converted down another pathway by transaminase to phenylpyruvate which builds up and causes mental retardation and seizures
-Additionally, without F you don't get tyrosine so these patients usually have fair skin and suffer from eczema
-Newborns are usually screened and their diets monitored. As they get older they can incorporate more F into their diet

Front 121

Autosomal Dominant

Back 121

-One parent is effected and so the child has a 50% chance of getting it
-Changes of getting it is equal between sexes
-This disease usually affects a child in every generation unless it is a new mutation or when the parent carrying the gene is unaffected (nonpenetrance) or mildly affected (variable expressivity)
-If both parents have the disease then it's likely that passing along boths faulty genes leads to a still born so the chance of being a carrier are 2/3 and of being unaffected is 1/3
-Autosomal dominant diseases are usually more complex and involve a greater array of genes.

Front 122

Types of Autosomal Dominant Disorders

Back 122

1) Porphyria (what kind George III had) - Part of the heme metabolism. Under stress these cannot produce enough heme and they can suffer dimentia and madness.
2. Familial Hypercholesterolemia (Complex metabolic pathway) - Problem with the LDL receptor leading to high cholesterol depending on the # of genes affected. These patients can have heart attacks by the time they turn 3. Osteogenesis Imperfe
4. Achondroplasia (Gain of Function)- FGFR-3 problem where it is constitutively on and the epiphysial growth plate closes too quickly
5. Marfan Syndrome - Fibrillin problem
6. Retinoblastoma - Rb deletion
7. Adenopolyposis Coli - Colon cancer (APC)

Front 123

Osteogenesis Imperfecta

Back 123

-autosomal dominant
-Change the AA sequence of collagen type 1 so it cannot be tightly packed leading to brittle bones that fracture frequently

Front 124

Dentinogenesis Imperfecta I

Back 124

-occurs in people with OI
-Get normal enamel but defective dentin
-The teeth are translucent and discolored, usually brown
-The teeth are weaker and come out or break more easily

Front 125

Dentinogenesis Imperfecta II

Back 125

-Dentinogenesis imperfecta w/o OI
-Problem with dentin protein DSPP
-Get bulbous teeth that are still translucent and brown
-Due to dentin problem you have very little including narrow roots and oliterated/absent canals/pulp

Front 126

Achondroplasia

Back 126

-Due to a missense mutation to FGF-3 so that it is active all the time and the growth plates close early
-FGF-3 is the most common mutated gene and this is the most common way for someone to have reduced stature
-Due to this cartilege defect they have normal intelligence but have shortened limbs, trident hand (all fingers the same length), prominent brow, maxillary hypoplasia leading to anterior overbite
-They are also bowlegged

Front 127

Marfan Syndrome

Back 127

-Loss of function mutation in either fibrillin 1 or 2
-End up tall and thin, with a narrow face, and the digits are extended
-Dental things are a narrow/high palate leading to crowded teeth
-Their lenses are off center leading to myopia (nearsightedness)
-The have loose and flexible joints and can get scoliosis
-The biggest problem for them is decreased elasticity of lung tissue and BV since it is made out of connective tissue. They can easily get aortic dissection and die

Front 128

X-Linked

Back 128

-men are hemizygous because they either have it or don't, no middle group
Scenario 1: Affected Mom (two bad copies of X)
-all boys have it, all girls are carriers
Scenario 2: Affected father
-No boys have it, all girls are carriers
Scenario 3: affected mother
-Half of the boys have it/half don;t
-Half of the girls are carriers, half aren't

Front 129

Hemophilia

Back 129

-On the hereditary chart someone x-linked carrier has a dot in the cirlce (female obviously)
-These people lack a clotting factor which is a problem during dental surgery

Front 130

X-Linked Expressivity in Females

Back 130

-Very complicated because early in development with less than 100 cells a "X" in each cell is turned off, this is lyonization
-Therefore, whether the female is affected depends on how much of the enzyme is needed or where it is turned off. Turning off a detox enzyme in the liver is basically like not having the enzyme at all
-An example of this is the fur coat in cocalico cats leading to mozaicism. In the cells where the X was on, they get one pattern, and when it was off they get another
-Another thing to remember is that if the mutated gene is fatal, then all the X's that keep it on will die. Therefore, even in a carrier only the normal genes will survive and so the child will show no signs of having the disorder in their germ cells. An example of this is ornithine transcarbamylase

Front 131

Amelogenesis Imperfecta 1E

Back 131

-X-linked disease probably affecting amelogenin leading to a defect in enamel matrix deposition (hypoplastic)
-In men there are no carriers so they show thin hard enamel resulting in microdontia and yellow-brown teeth
-In women due to lyonization they have a moaic pattern

Front 132

Mitochondrial Inheritance

Back 132

-Non-mendelian genetics
-Known as matrilineal inheritence since we only get it from our mother
-Since the mitochondria have their own DNA, and the egg contains all the mitochondria, it depends on the mother
-Additionally, within the ovum there may be a collection of Mt with different stages of mutations, so the severity depends on the number of bad Mt inherited (heteroplasmy)
-Additionally, even if a brother and sister are affected, only the sister will pass it on since the children will get her Mt and nothing from the brother
-An example is Leber Hereditary Optic Neuropathy where patients have loss of the optic nerve and blindness

Front 133

Genomic Imprinting

Back 133

-Where the genotype and phenotype don't always match
-Even though you inherit an allele from each parent, sometimes the gene from one parent can be turned off in all cells, this is called imprinting
-In paternal imprinting all the father's genes in the sperm are silenced and this is passed to all the child's cells
-It is a epigenetic process
-Most typical examples is Prader-Willi Syndrome and Angelman, but also seen in Huntington, Neurofibromatosis, and Myotonic Dystrophy

Front 134

Prader-Willi Syndrome

Back 134

-Child inherits a deletion on chromosome 15 from the father (usually), or possibly uniparental disomy or 2 C15 from the mother, or a problem with imprinting
-The child is hypotonia, obese, small hands, retarded, and has hypogonadism
-Basically a few genes on C15 are absent

Front 135

Angelman Syndrome

Back 135

-Have a deletion on chromosome 15 that is inherited from the mother
-Causes are similar, mother imprinting, getting 2 of Dad's #15, imprinting defect, or inheriting a mutated UBE3A gene (where 15 is deleted in the other causes)
-The children have ataxis gait, inappropriate laughter, severe mental retardation, and seizures
-They are known as happy puppys and a pleasure to be around

Front 136

Genetic Heterogeneity (Genocopy)

Back 136

-People with the same disease (phenotype) have different genes that are mutated (genotype)
-Could be because the gene products have similar function, are along the same metabolic pathway, or perform similar functions in the cell
-Example is Alzheimers and Breast Cancer

Front 137

Variable Expressivity (allelic variation)

Back 137

-People have the same mutated gene but show different phenotypes
-This can because the mutations are to different sites in the allele, due to modifying genes, or due to environmental factors
-Example of this is neurofibromatosis
Modifyer genes: For example, people with sickle cell anemia are affected by another gene that makes hemoglobin F. The hemoglobin F amount made varies between people, so if someone with sickle cell made a lot of hemoglobin F then they wouldn't exhibit the symptoms as much
Environment: A disease that hinders excretion of nitrogen would be less severe in someone who didn't eat as much protein since nitrogen comes from amino acids
Different Mutations: In the rat MEN gene one mutation leads to MEN2A causing MTC and pheochromoctyoma. Another mutation leads to MEN2B which leads to neuromas. A third mutation leads to familial medullary thryoid carcinoma.

Front 138

Penetrance

Back 138

-Percent of patients (heterozygotes) who shown the genetic mutation phenotype dividied by the number of patients with the genetic mutation
-Usually associated with autosomal dominant disorders
-Patient can have the diseased gene but not show the phenotype for a ton of factors like environment or modifyiner
-For example, with colon cancer you need multiple mutations, so just because you have one doesn't mean you'll show the phenotype

Front 139

Heterozygous Advantage

Back 139

-A autosomal recessive disease continues to spread because having one bad copy gives you an advantage (doesn't affect reproduction) whereas having both copies hinders you
-For example, people with one copy of the sick gene cannot get malaria
-People with one copy of the cystic fibrosis gene cannot get TB

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Founder Effect

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-If small groups of people inter-relate then a mutation that should be eliminated continues to thrive in high numbers
-Because the Ashkinazi jews intermarried, Tay Sachs continued to thrive
-Same with the American Indians who were geologically isolated

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Trinucleotide Repeat Disease

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-For some reason a group of three nucleotides will begin to repeat
-At a young age when the repeat number is small this may not make a different in the protein, however, as you age the number increases and the chance of having the disease increases
-These continue because people usually reach the reproductive age before they take affect
-This occurs in Huntington's, Fragile X syndrome, and Kennedy Disease

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Multifactoral Inheritance

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-Diseases are known to have a genetic component because more incidences occur within a family, but no one single gene can be the culprit. Most likely it is a combination of genes that leads to the disease
-Study these with twims, with identical are more likely to both have it then fraternal
-Example are cleft lip, neural tube defects, diabetes, schizophrenia, and CHD

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Cleft Lip/Palate

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-Common cranialfacial malformation
-The more and closer relatives that have it, the higher the chance that a patient will be born with it
-Genes shown to increase the chance if mutated include RARa, TGFB3, Folic Acid metabolism. Folate and B6 decrease cleft lip
-Also, malnitrition or having an alcohol mother seem to increase the chance of contracting it

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Chromosomal Abnormalities

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-p = small arm (on top of karyotype)
-q = long arm
G-band = stain that tells us where the chromosome is missing a piece. The more genes defective the more the stain and the more you can see it on a microscope
Three types of human chromosomes
1) Metacentric - centromere in the middle
2) Submetacentric - centromere closer to one end
3) Acrocentric - centromere close to the end of one arm. The short arm has a unique structure with a mass of satellite DNA connected by narrow stalks
Karyotype: Stained picture of metaphase chromosomes
-Old karyotype was called spectral and told us whether we had the wrong number or very large defects
-Newer karyotype is called SKY where each chromosome has its own color and you can distinguish smaller defects

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Structural Chromosomal Abnormalities

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-include deletions, translocations (swap between chromosomes - can cause protein or dividing problem), isochromosomes (instead of having a P and Q, you have 2 Ps), inversions (can tell with a G-stain), and ring chromosomes (chromosomes lose their telomers and form a ring. This is usually seen in cancer because the ring chromosome makes it easier to amplify
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Williams Syndrome

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-Example of microdeletion where there is a loss of material but it is not always seen cytogenetically
-Have a deletion in chromosome 7q11.2 (chromosome 7, arm Q, 11.23 is the distance from the centromere) so they lose elastin (responsible for aorta problem) and LIM-kinase 1 (poor visuospatial development)
-These people have low IQ but are outgoing and excel at verbal and music areas
-Wide mouth, starburst iris, broad forehead, thick curly hair, and narrowing of the aorta right above the aortic valve (SVAS)
-orally they have widely spaced small teeth and suffer from enamel hypoplasia making them at a increased risk of caries

-Known as elfin-face syndrome
-A common test is the D of Y test. Make a D out of a bunch of Y's and they won't see the D

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Translocation

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1) Balanced - Exchange between chromosomes ia reciprocal and no lost genetic material
-Most of these people have no noticable abnormality but it is a problem with their offspring
-If 2 acrocentric genes are fused then this is the Robertsonian Translocartion (abnormal chromosome number in offspring). Robertsonian is a subset of balanced
-Sometimes if a gene is interupted they can show the features of a autosomal dominant single gene disorder
Unbalanced - Exchange of material is not reciprocal and under a microscope the patient appears to have monosomic or trisomic chromosomal segments (known as aneuploidy)
-Extra chromosomes are common for 21, 18, 13 (trisomy), and X. These are the only trisomy where you have 3 full copies and the patient lives past birth
-Loss of chromosomes is common in turner's syndrome

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Down Syndrome

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-Trisomy 21
95% of cases there is an extra chromosome, in 5% it is a Robertsonian translocation
-Leading cause of mental retardation
-Patients have epicanthic folds and a flat facial profile
-They exhibit the simian crease (pathognomic)
-40% have cardiac malformation
-They have a increased risk of early senility, leukemia, and alzheimer's disease
-The incidence increases with the maternal age during conception

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Abnormal Sex Chromosome Number

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-Having extra X's are OK because you inactivate the extra ones
-45 genes with a missing X to 49 genes with extra X are viable
-45X = turner syndrome: No secondary sex characteristics like breast. Webbed neck, low posterior hairline, wide nipples, growth retardation, and aortic and kidney malformation, high arched palate
-Multiple X and a Y is Klinefelter Syndrome: Like having extra estrogen, patients have hypogonadism, testicular atrophy, gynecomastia, sterility, and mild mental impairment
-Multiple Y is normal
-Multiple X with no Y is normal

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Wearing Down Terms

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Attrition - Wear/tear on occlusal/incisal surfaces leading to a shiny surface
Abrasion - Wear/tear on lingual/buccal surfaces usually due to habitual trauma
-Both attrition and abrasion cause secondary dentin formation
Erosion - Affect lingual surface mostly and due to anything from acid reflux to bulemia

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Fusion

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-When early in development the teeth fuse together
-Need to count all teeth in arch because only fusion if one tooth is missing. If all the teeth are there but it looks like fusion then it is germination

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Microdontia

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-Small tooth in the mouth, usually a maxillary lateral incisor (peg laterals)
-Typically a manifestation of a genetic disease like down syndrome

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Dens Invaginatus

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-Tooth within a tooth
-Usually occur to a tooth with a prominent cingulum like the incisors
-Prone to decay because they are difficult to clean

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Mesiodens

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-Same as supernumerary but called mesiodens if it is between the central incisors
-May or may not erupt

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Taurodontism

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-Molar tooth with a long neck

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Concrescence

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-Fusion of the roots occurs during development but there remains two crowns
-This makes extractions very difficult

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Dilaceration

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-Root is misshapen and diverges
-Can be due to trauma during development

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Hypercementosis

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-Increased cementum production seen as a large radiopacity

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Enamel Hypoplasia

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-Reduction in enamel production leading to small pits on the tooth surface
-Can be due to many genetic diseases and also viral infection like chicken pox and measles
-Everything from fusion to enamel hypoplasia occur during development and won't suddenly occur to a patient on the 2nd visit for example

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Tooth Number Genetic Disorders

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Hypodontia - Reduced tooth number
Oligodontia - Have only a few teeth
Anodontia - Absense of teeth
Hyperdontia - Increased number of teeth

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Ectodermal Dysplasia

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-Commonly X-linked defect it leads to problems in ectodermal and neuroectodermal structures including enamel leading to hypodontia and microdontia

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Cleidocranial Dysplasia

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-Missing clavicles and supernumberary teeth

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Amelogenesis Imperfecta

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-Can be X-linked as well as autosomal recessive/dominant
-Can present itself in a variety of ways
Hypoplastic AI - defect in enamel production
Hypomaturation AI - Enamel production fine but the defect is in the enamel maturation
Hypocalcified - Normal enamel production but there is a defect in calcfication

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Dentin Dysplasia

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Type 1: Defect in the radicular dentin so the teeth are sometimes called "rootless".The pulps are often obliterated and these teeth are prone to infection, especially the deciduous teeth

Type 2: Defect in coronal dentin due to DSPP mutation. The phenotype would probably be identical to dentin dysplasia
-Where gene is mutated dictated what mutation it is

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Hypophosphatasia

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-A metabolic and systemic bone disease due to a deficiency in ALP
-There is a shortage of cementum leading to enlarged pulps and teeth spontaneously falling out
-During testing you would see increased urinary phosphoethanolamine
-oral complications may be the first indication
-Fall out because nothing for sharpey fibers to attach to and all teeth have mobility
-early the disease is shwon the worse the prognosis
-Diagnosis: clinical presentation (teeth fall out) and radiogrtaphs (large pulp chambers)

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Abnormalities in Tooth Color

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-These are intrinsic meaning that they were gotten during tooth development and cant be cleaned at the dentist
Acquired: Tetracycline or fluorosis
Developmental: Hyperbilirubinemia
Genetic: Porphyria and hyperbilirubinemia (increase bilirubin so the kid born jaundice will have green teeth until levels return to normal)
-anything added to teeth make them weaker

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Regional Odontodysplasia

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-Not a genetic disease, due to a local problem near developing teeth that strangles the blood supply
-It is usually localized so only a few teeth unilateral are affected
-The teeth have enlarged pulp chambers so it can be confused with DI, but DI is general and this is localized
-Additionally, the enamel is thin, and it is hard to distinguish the small amount of hard tissue. Due to this, the teeth appear broken down and they are nicknamed "ghost teeth"

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Pulp and Jaw Pathology

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-Like other pathology it is divided into acute and chronic inflammation
-The tooth protects itself against vias via the non permeable dentin, the formation of new dentin, and a inflammatory response
-Pulpal exudate cannot escape so there is a build up in pressure leading to poor drainage and necrosis

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Caries

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-Most common cause of pulp disease
-Products of bacteria metabolism like organic acids and proteolytic enzymes cause destruction
-The metabolites are also able to reach the pulp and cause a inflammatory reaction

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Dental Sclerosis

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-A progress by which the dentin respond to stress and reduce their permeability in a attempt to protect the pulp
-As irritating substances diffuse through the tubules, odontoblast will fill the tubules with caries crystals (apatite crystals) in the case of bacteria, or continue the formation of peritubular dentin in the case of tooth abrasion
-Dentinal sclerosis occurs at the periphery of most caries lesions

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Reparative Dentin

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-Dentin formed during development is primary dentin
-After the tooth comes into occlusion the rate of dentin deposition is slowed, and this new dentin is physiological secondary dentin. It grows at a slow rate and reduces the size of the pulp chamber
-Reparative dentin is a defense mechanism against the loss of enamel, dentin, or cementum. In response to stress (unusual wear or bacterial) it forms at the base of the tubules ONLY in the area of the tooth being irritated. So physiologic secondary dentin has a clear demarcation whereas teriatry is not uniform
-RD is usually less tubular and calcified than other dentin. The quality of the pulp at the time of repair affects the quality of RD
-If the pulp is so bad that RB is laid down haphazardly, then areas of soft tissue can become embedded in the matrix, this is the swiss-cheese pattern
-The area of dentin between primary and RD are thickened, filled with dentin, and very impermeable

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Response of OB to Injury

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1) Bacteria encroach on the DEJ
2) Odontoblast (still in the tubules) increase collagen production followed by a phase where they either die or shrink to become more cuboidal or flat
3) As the primary odontoblast die dead tracts are formed
4) The primary odontoblast that have died are replaced by fibroblast that migrate from the cell-rich pulp zone, become replacement odontoblast, and lay down RD over the dead tract

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Progression of Caries

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-Can progress at different rate with periods of inactivitiy
-The rate of progression affects the type of pulpal inflammation.
-Pulpal inflammation evoked by carious legions because slow grade and as a chronic inflammatory response. If the bacteria is removed then the connective tissue formed in response to inflammation will return the pulp to a healthy state
-As the bacteria come near the pulp a acute inflammatory response will occur with BV dilation and neutrophils invasion
-As pus forms the osmotic pressure of the area increases and this can impinge on nerves leading to pain. Draining the pus can lead to relief

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Classification of Pulp Pathology

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-acute and chronic
-subtotal (affecting one part of the pulp) and generalized (affecting all the pulp)
-infected (bacteria in pulp) vs. sterile (bacteria still in dentin/enamel)
-Reversible and irreversible. Can be reversible for years, but once the inflammation is too severe and removal of bacteria won't save, then it is irreversible
-pulp necrosis

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Reversibe vs. Irreversible Pulpitis

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Reversible Pulpitis - Bacteria have no infiltrated the pulp
-You get a short, localized pain, upon cold stimuli
-The EPT testing current is low
-Clinical symptoms are minimal
-You treat the pulpitis by removing the irritation (bacteria)

Irreversible Pulpitis - The bacteria have infiltrated the pulp
-Hot things cause a unlocalized and long lasting pain
-The EPT current a high/no response
-Patients experience lots of pain that only subsides after the tooth is pulled or following a root canal

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Pulp Necrosis

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-Since the pulp is housed in mineral there is no where for edema to go. Furthermore, the pulp does not have collateral circulation as all must enter through the apical foramen
-Therefore, inflammation leads to high intrapulpal pressure which can alter blood flow
-One way the pulp can die is through pyogenic bacteria, via things like endotoxins
-Another way is through the immune response which release toxic products in addition to collagen from fibroblast causing pulp fibrosis. This leads to hetroylysis followed by suppuration, abscess formation, and is liquefactive necrosis
-Coagulative necrosis occursd if the blood supply is cut off
-Gangrenous necrosis can also occur when there is widespread pulp necrosis in additional to bacterial growth
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Spread of Inflammation from The Pulp

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-The pulpal connective tissue is connected to the PDL so this facilitates the spread of disease between the two
-The type of inflammation in the periapical tissue depends on the bacteria's virulence and the host defense system. If the defense system is cell-mediated then you get a periapical granuloma. If the bacteria are pyogenic then you were an abscess
-Even if you start out with granuloma formation, if the host defense weakens or the bacteria virulence increase, you can switch to a acute, suppurative response called acute exacerbation

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Periapical Abscess

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-A direct extension of suppurative pulpitis
-Due to the pus being formed in the confined space you get a positive percussion test and sensitizity upon palpation
-The EPT is negative since the pulp is necrotic
-Clinical symptoms include the typical acute ones like pain and swelling, in addition to tooth elevation due to the pus formation apically
-Histopathology shows lots of PMN and liquefactive necrosis
-The treatment is drainage followed by antibiotics and then extraction or root therapy
-On the radiograph you'll typically see no change in bone intiially (no radiolucency), and after a week you'll begin to see bone loss in a pattern known as "moth eaten"
-Once the abscess reaches a drainage point, the presure within the abscess goes away and the lesion enters the chronic stage

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Phoenix Abscess

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-When the bacteria change within a existing granuloma leading to a radiolucency resembling a granuloma

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Flare Up

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After endodontic treatment you can form suppuration and pain at the root apex
-This is because the trauma associated with the BMI in addition to pushing the bacteria into the chronic inflammatory tissue at the root apex leads to this

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Parulis (gum boil)

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-A small sessile nodule on the mucosa adjacent to the tooth with the abscess
-Its location depends on the abscess's location and it signifies the presence of a sinus tract leading to the abscess
-The parulis is pus surrounded by chronic inflammatory tissue
-The parulis will rupture allowing pus to escape followed by repeated cycles of swelling and rupturing

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Periapical Granuloma

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-not a true granuloma because epitheloid cells are missing
-it is a accumulation of chronic inflammatory cells due to persistance of bacteria, toxic products, or a necrotic pulp
-It begins to enlarge in a circular pattern leading to a radiolucency
-You usually find lots of macrophages, fibroblast, and collagen, and granulation tissue
-The clinical symptoms are usually absent (asymptomatic) and so there is no response to percussion, palpation, or the EPT
-It is treated via root canal and extraction
-75% of all periapical abscesses are due to periapical granulomas

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Periapical Cyst

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-Epithelium-lined cavity filled with fluid
-This one is inflammatory in origin
-The walls are made of fibrous connective tissue with the lumen lined by epithelium
-The cavity can develop in 3 ways
1) A periapical granuloma undergoes central tissue breakdown producing a cavity
2) Chronic inflammation leads to proliferation of epithelial cells. The ones in the middle are cut off from nutrients forming a cavity. The necrotic cell by products changes the osmotic gradient to bring in fluid
3) Natural inclination of epithelium to line the connective tissue after a periapical lesion tissue breakdown
-The cyst fluid is often brown due to RBC breakdown and release of pigment
-There are often cholesterol crystals which have a golden color
-Lots of albumin is found and this is a diagnostic test to distinguish a cyst from other periapical radiolucencies
-HARD to distinguish a cyst from a periapical granuloma radiographically because both are well-demarcated radiolucencies

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Osteomyelitis

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-Organism typical for odontogenic infection reaches the bone marrow and causes inflammation
-Uncommon in healthy normal patients
-Inflammation starts in the marrow space, spreads to cancellous bone, and then along the blood vessels and into the periosteum. The bone cells (osteocytes) become necrotic due to nourishment cut off. This turns it into bone devoid of osteocytes known as a sequestrum
-Osteoclasts will try to resorb the sequestrum and in other cases the bone will exfoliate itself in a process known as sequestration
-OM has a male predilection and favors the mandible over the maxilla

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OM Factors

Back 185

-It can be caused by chronic systemic disease as well as a immunocompromised patient
-Bone hypovascularity can be excellerated by radiation therapy, osteopetrosis, paget's disease, and florid cemento-osseous dysplasia
-Tobacco, alcohol, and drugs can make it worse

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OM Diagnosis and Treatment

Back 186

Histology: PMN and liquefactive necrosis in the BM. Accumulation of lymphocytes at the periphery
Radiology: Initially there is no radiologic evidence of OM, when destruction gets big enough there will be a radiolucency. Over time reactive hyperplasia of bone will produce a peripheral zone of sclerosis which is more radiolucent than normal bone adjacent to the lesion
Clinical: Severe pain, swelling malaise, and a elevated WBC count. Poisitive to percussion and mobile
Treatment:If the immune status is compromised then it is difficult to treat. Otherwise you can give high-dose, long-term antibiotics

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Chronic OM

Back 187

-Progresses from un-or-under-treated acute OM
-chronic OM may occur without a clinically detectable acute phase
-Radiographically the bone looks moth eaten
-Treatment is tougher because the necrosis is sheilded by fibrous tissue and the blood supply is limited
-If high-dose, long-term IV antibiotics don't work then surgical resection down the good bone is the only other way to do it

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Focal Sclerosing OM (Condensing Osteitis)

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-Due to chronic inflammation from bacteria around or in the tooth, cytokines lead to hyperplasia of the bone around the canal
-Usually see it in younger people in the mandible around the first molar
-Radiographically it appears as a radiopaque area near the root apex
-A negative pulpal test only solifies your case for condensing osteitis
-You can treat it with extraction or do endo therapy on the affect tooth and usually the bone will remodel and have a normal radiographic appearence

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Immunopathology Introduction

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-Study of immunological diseases due to cellular or molecular aberrations or from a encounter with foreign material under certain conditions that creates
-Broken into hyperreactivity, autoimmune, immunodeficiency, transplant rejection, and immunoproliferative disorders

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Innate vs. Adaptive Immunity

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Innate - In place before organisms enter our body. The same reaction every time regardless of the agent
-Involves PMN, mast cells, and macrophages
-Involves PAMP being recognized by TLR

Adaptive - Takes time to develop the first time because antigen being presented must make its way to the lymph node where the B and T cells are. Relies on the innate system APC
Cells: lymphocytes and macrophages
Receptors: Lymphocyte encountering a specific antigen

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Features of the Immune Response

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1. Specificity/Diversity - Immune system can distinguish different complexes that differ by the slightest amount. This is due to the millions of lymphocytes that have specific antigen receptors due to genetic recombination during development. Every antigen has its own lymphocyte that will develop memory

2. Adaptive - This part of the immune system is acquired over the life span. Not built in inherently but as we are exposed to various antigens we'll build up a memory so that when they reoccur the response is quicker (true of IgG but not IgM). During the second attack the adaptive response is quicker and the Ab are better at binding and killing

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Features of the Immune Response

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3. Memory - Reason why we give vaccines. A antigen exposure is imprinted on our immune system elading to high and more specific and quicker Ab titers during the second exposure

4. Differentiation - Immune is able to distinguish between self and non-self. When we're exposed to a foreign Ab there is immune activation leading to clonal expansion. When we're exposed to a self antigen the response is tolerance (anergy or deletion). This is controlled during thymus T-cell differentiation as well as inactivation of mature self reactive B and T cells

5. Dichotomy of the response - Adaptive response broken down into humoral immunity (b-cell) and cell-mediated immunity (t-cell). These are very intertwined though, for example B cells are activated through T-cells

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Antibodies (Immunoglobulins)

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-4 peptides chain, 2 heavy and 2 light
-All connections made via disulfide bonds
-Each peptide has a variable and constant region, the variable region is where it binds the antigen and the constant region is where distinguishes different classes of Ab
-The Fc also gives it the function

1) IgG - Majority of serum and e.c. Ig. It is transferred to the fetus though the placenta. It is responsible for complement and it can bind to macrophages leading to opsonization and ADCC. Able to agglutinate and bind 2 antigens at once

2. IgM -In the serum and is the original Ab on B-cells until class switching. It is a great agglutinator and forms a pentamer with 5 IgM binding via their Fc region. Also involved in complement

3. IgA - Secreted across epithelia including breast milk. Very common in mucosa like saliva and tears. There are two forms, a monomer in the serum and a dimer in the mucosa where there are 4 antigen binding sites connected via the Fc region

4. IgE - Low serum levels, mostly bound to mast cells and basophils and involved in allergies and fighting parasites

5. IgD -Very low in serum and serves as a antigen in some b-cells

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Antibody Function

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5 main functions
1. Opsonization leading to phagocytosis
2. Toxin neutralization
3. In combindation with complement it helps in cell lysis
4. Agglutination/aggregation of antigen
5. Viral neutralizaqtion

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Antibody Diversity

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-Each antibody is made from 4 genes of which we have several copies of that splice together to create one specific Ab
-The Fc region is made by the C gene and the Fv is made by the D, V, and J gene
-Not only do different D, V, and J come together to make the variable region, but when they combine there can be insertions, deletions, and other changes to add an additional layer of specificity

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Complement

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-Blood proteins that regulate inflammation, lead to opsonization, or participate directly with cell lysis (both foreign and self)
-Complement can happen spontaneously (alternative pathway) or occur through Ag-Ab binding
-Mediator: act as a chemotactic agent or help in vasodilation/vascular permeability
-C3a/C5a involved in mast cell degranulation
-Cga and C6a work as chemokines

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Activation of Complement

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-The key to complement is the proteolytic cascade leading to C3 cleavage into C3a and C3b
1) Classical Pathway
a) IgG binds Ag leading to a conformational change in the Fc region allowing it to bind C1
b) C1 binds C4
c) The C1/C4 complex binds C2
d) The C1/C4/C2 complex is known as C3 convertase and cleaves C3 into Ca and Cb
e) C3b binds the C1/C4/C2 complex and this is known as C5 convertase
f)C5 is cleaved into C5a and C5b

2) Alternative Pathway - Not Ab mediated
1) Proteins called factor B, D, and P bind the bacterial surface
2) The PBD complex binds C3b either through random degredation of C3 or through the classical pathway

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Role of the Complement Cascade Components

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C3a - anaphylatoxin which binds to mast cells leading to granule release. Also involved in lysosomal enzyme release
C3b - opsonization and regular B-cell function
C5a - anaphlyatoxin, chemotaxis, lysosomal enzyme release
C1/C4 - Bind antibody on virus leading to cell lysis via their downstream activation of C8/C9. Form a hydrophilic transmembrane channel and the cell burst

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Cytokines

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-soluble protein which mediate the effector function of immune cells and allows for cells involved in the immune response to "talk" to one other and amplify the response
-A interleukin is a cytokine produced by one leukocyte which targets another leukocyte. Usually numbered in order IL-X however some are not sure as TNF and IFN
-cytokines are needed to mount a normal host response and an excess can lead to a pathological response. They are used as inflammatory modifiers and can be used as such in therapeutics
-Cytokines can come from many different cells but mainly from macrophages and lymphocytes in the immune response
-The cytokines T-cells release are needed in growth and differentiation of immune cells like macrophages
-the function of cytokines can be both pleiotrophic (one doing many) and redundant (many doing the same thing)

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Cytokine Functions

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1) Help with natural immunity - These cytokines are produced by endothelial cells, macrophages, and non-lymphocytes to trigger acute inflammation. TNF, IL-1, IL-6, IL-12, IFN

2) Regulate Lymphocytes - These are made from CD4+ Th cells and regulate other T-cells. Include IL-2, IL-4, IL-10

3) Activate Effector Cells - Made by T-cells and stimulate other cells which go to work on the pathogen. IFN stimulates macrophages, IL5 stimulates eosinophils, and TNF stimulates neutrophils

4) Hematopoietic Factors - Produced by bone marrow stromal cells and stimulate differentiation of all leukocytes and blood cells. Includes IL3, IL7, IL11, and CSF

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B and T cell brief overview

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1) These are the lymphocytes. Derived from antigen non-specific precursors in the BM and after several rounds become antigen specific. B-cells mature in the BM and T-cells in the thymus

2. Each lymphocytes generates a unique receptor that recognizes a distinct antigen or epitope

3. Although they circulate blood and lymph tissue, they only encounter antigen in the lymph tissue

4. Lymphocytes are activated by two signal, one if it binding its antigen that the receptor is specific for. Once activation it gives rise to clones of antigen-specific cells (clonal selection theory)

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T-Cells

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-Response for cell mediated immunity where it interacts with a cell that presents a specific antigen
-The TCR is made by 4 genes that rearrange at random, this is antigen independent. Some TCR have a alpha/beta chain (most that we will talk about), and others which are like sentinals at the epithelial and mucosal surface have a gamma/delta chain that receptor peptides and lipids
-Once activated they undergo clonal expansion to produce helpers, suppressor, cytotoxic, and memory cells
-They require several accessory proteins to become activated like CD3, CD4, and CD8 (cytotoxic and suppressor)

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T-Cell Populations

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1) CD4+ - Helper T-cells that release cytokines when activated.Recognize antigen + MHC II (only on APC)
-H1 is involved in delayed-type hypersensitivity
-H2 makes cytokines for Ig production and acts as a connection between cellular and humoral immunity

2. CD8+ Suppressor/Cytotoxic - Recognize antigen + MHC1. Either kill a target cell through apoptosis or suppress immunity

3. T-regulatory
4. T-effector
5. T inflammaotry cells or T-DTH

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T-Cell Regulatory and Accessory

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CD3 - Accessory group of 5 proteins on the membrane next to the TCR. Helps stabilize the TCR
-Always need a second signal, one is CD28 binding to the M-phage B7-1
-MHC gene is polymorphic but we only inherit one from each parent. MHC differ on what they can bind
-Not everyone can present the same antigens on their MHC so this is where we get different responders

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Functions of T-cells

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-Regulate or destroy but the goal is always to kill cells infected with viruses and other parasites
-Cytotoxic kill directly by releasing perforin and TNF. This either forms holes in the plasma membrane or induces the cell to undergo apoptosis
-T-helper activate other kills that will destroy the target. For example, T-cells control intracellular bacterial infections in macrophages

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B-Cells

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-Basis of humoral immunity
-Can interact directly with a antigen whereas T-cells are MHC restricted
-Differentiate from lymphoid stem cells into immature B-cells (IgM) and then mature b-cells (class switch). When these are activated you get one memory cell and one plasma cell
-B-cells have either IgM or IgD, but the specificity at the receptor before activation is the same as the specificity when activated and secreting soluble Ab
-While B-cells can interact directly with antigen, they do need help in the form of cytokine from Th-cells, if they bind only antigen then they produce only IgM

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Monocytes

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-Important immune regulator and effector
-The APC include macrophages, Langerhan-Dendritic, and B-cells (interesting)
-APCs have 3 functions, take up and protein antigens, express them on MHC II, and release cytokines to help contact/activation of T-cells
-Macrophages do nto require specific antigens to become activated, although they do have TLR
-Monocytes are readily able to carry out immune function, but once as a macrophage in tissue, they are even better

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Dendritic Cells

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-Subtype of macrophages
-Include langerhans and follicular langerhans
-Langerhans act as sentinels at body entry points and may be the first to present Ab and taking it to the lymph tissue
-Follicular are present in lymph tissue like the spleen

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Antigen Processing

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1) APC take up antigen
2) Once the Ag is engulfed, it will migrate to the lymphatics
3) In the lymphatics it will degrade the Ag and express it as a epitope on its surface with MHC II

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MHC Molecules

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-Expressed on ALL nucleated cells
-MHC are the genes which encode the HLA proteins
-Principle role is T-cell activation via antigen presentation
Class 1 -Binds peptides derived from proteins synthesized inside of cells, hence viral proteins. So if ANY nucleated cell is infected, it will present the pathogens antigen as a help signal. The receptor is a heterodimer with beta-microglobulin
MHC 2 - Found on APC and only expresses peptides from exogenous proteins that are internalized and processed. It is a heterodimer

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Natural Killer Cells

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-Part of the innate host defense
-Do not have a antigen binding receptor made of rearranged genes
-Does not express CD3
-Believed to play a role in tumor resistance, host immunity to viruses and other microbes, and regulation of lymph and hemopoietic cell populations
-It can induce apoptosis through direct contact or antibody contact (has Fc receptors)
-Like CD8+ T-cells, direct contact leads to perforin and granzyme release
-NK only react against OUR OWN cells, not foreign material
-NK have two types of receptors, one that's activating when binding foreign protein on a own cell, and one that is a inhibiting receptor that functions when it binds a self-antigen
-NK kills cells that have activating receptors upregulated or inhibiting receptors downregulated (for example, a infected cells will have more viral protein expressed and therefore activate more of the NK activating receptors)

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Mast Cells/Basophils

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-Mast cells are in the tissue and basophils are in the blood
-Granular cells that store histamine, proteoglycan, and proteases and expresses Fce receptors for IgE
-Once two IgE molecules bind and crosslink there is calcium dependent activation of the degranulation process

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Eosinophils

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-Have secretory and phagocytic function
-Play a role in defense against parasites

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Stimulators of the Immune Response

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Antigen - Elicit a specific immune response, either humoral and/or cell mediated

Haptens - A simple substance that does not illicit a immune response by itself, but when coupled to a large carrier molecule they provoke a response. Include drugs and metals

Adjuvant - Something that enhances the immunogenicity (able to provoke a immune response) of a antigen. Help boost the strength of a vaccine by either prolonging half life or reducing the speed at which m-phage will degrade. Induce non-specific inflammation which helps disseminate the antigen

Superantigens - A substance that stimulates a lot of B/T-cells, often with diasterous consequences. Produced by several bacteria. Can interact with B/T w/o being processed and w/o a MHC complex. Once the cell is stimulated it undergoes apoptosis. These can wipe out a entire immune response. So if we build up response to the flu, these can wipe out all the memory cells, so next time we're infected it's like it's the first time seeing the pathogen

Polyclonal Cell Activators - Plant and bacteria substances that non-specifically activate the immune system. Implicated in autoimmune and hypersensitivity disease. Can activate several B and T cells at once
-Good in the lab as a probe for lymphocyte function

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Lymphoid Tissue

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-Provide a spot where lymphocytes can encounter antigen and mature via antigen dependent maturation
-Primary: thymus and BM
-Secondary - lymph nodes as well as non-capsulated diffuse and solitary mucosa-associated lymphoid tissue (MALT). Also the spleen as well as lymphoid nodules of the GI tract (GALT) and bronchail associated (BACT)

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Lymph Nodes

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Afferent lymph vessel - brings things into the capsule
Efferent lymph vessel - Exit
-the lymph artery/vein both perfuse the tissue and bring in lymphocytes
-Germinal centers is where B-cell mature/proliferate
-T-cells do not proliferate in the germinal centers, they reside mostly in the deeper cortex in the subcortical zone
-Efferent lymphatics flow to the thoracic duct and return to the blood stream through the left subclavian vein

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Efferent and Afferent Limbs of the Immune Response

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-The afferent and efferent limbs of the immune system must be stimulated to eliminate a pathogen
-Afferent involves transit of antigen via the lymphatics to the node and stimulation of lymphocytes
-The efferent limb represents the effector component. Products of the efferent system are brought to the pathogen (infection site) and help eliminate it

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Immune Extra

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-Antigens can be ANYTHING, lipids, carbs, but proteins are the best
-Immune system doesn't recognize antigens, it recognizes epitopes, of which hundreds can be in one antigen
-Antigen should have a weight of 10,000D
-A toxin can be broken down into 100 epitopes, and everyone might respond to different epitopes. As long as we reponse against a epitope that is important in the toxin's function, we'll mount a efficient response
-If we cannot recognize the dangerous parts of the enzyme then a insufficient response will be mounted
-If we recognize a epitope that is shared on our own body then we'll mount a autoimmune response

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Type 4 Hypersensitivity

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-Also known as delayed type hypersensitivity
-Involve T-cells, macrophages, and lymphokines
-What's important in this disease is that on second exposure the T-cells release very potent macrophage stimulators (IFN-y - IL-4 and CSF) that super activate macrophages which upon chronic exposure go on to
form granulomas
-Seen in TB, leprosy, poison IVY, contact dermatitis, metal allergy, GVHR

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TB Test

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1. PPD Purified Protein Derivative - Once you have CD4+ memory cells to tuberculin proteins (need first exposure) then re-exposure of purified protein in the skin leads to a sort of contact dermatitis with erythema, perivaascular cuffing, induration. Tb+ for the rest of your life

Chest X-Ray: Shows the granuloma and destruction of lung tissue

Sputum Test: If you have TB bacteria in your spit then you have an active infection

BCG: TB vaccine called bacilli calmette guerin. A attentuated strain if used to generate a immune response. No clear evidence that it is protective in adults so not used in US

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Contact Dermatitis

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-Usually involve hapten binding to carrier proteins
-Good example is the pentadecylcatechol component of poison ivy
-On first exposure in the epidermis langerhans cells take up and present the neoantigen to the lymph node T-helper cells
-On re-exposure to the ivy the sensitized CD4+ cells accumulate to the epidermis and release cytokines that damage keratinocytes causing separation of the cells and formation of a intraepidermal vesicle
-Additionally there is perivascular cuffing
-The CD4+ cells recruit macrophages and CD8+ T-cells which destroy it through cytokiens, apoptosis, and phagocytosis. This is called spongiosis since the tissue starts to look like a sponge
-The intracellular glue is destroyed and a blister usually forms

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Causes of contact dermatitis

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-Detergents or soaps
-cosmetics like makeup
-household cleaning products
-rubber or latex
-jewelry and metals like nickel
-perfumes
-weeds and plants like poison ivy and oak

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Contact Dermatitis Histology and Clinical SIgns

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Histology: Begin to see space within the tissue characteristic of early spongiosis. Will also see perivascular cuff (BV surrounded by lymphocytes. Over time these will become a blister. Should see lymphocytes and macrophages mainly

Clinical:
Erythema, papules, blisters, indurated or oozing lesion, tissue sloughing off

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DTH associated with intracellular parasites

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-Most commonly TB but also includes viruses, fungi, other bacteria, and anything else that the phagocytes cannot eliminate

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TB in the book

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First Exposure to TB: CD4+ recognize tuberle bacilli associated with MHC II on APC leading to effector and memory CD4+ cells
Reexposure: On subsequent exposure to the same antigen the memory CD4 cells are activated at the tissue site and secrete IFN-y which brings on macrophages
-Macrophages release PDGF and TGF which stimulate fibroblast proliferation and matrix secretion
-Macrophages also release IL-12 which stimulates more CD4+ response, and this cycle continues until the antigen is eliminated
-Additionally, other cytokines like TNF lead to vascular dilation and permeability
-Prolonged reaction leads to granulomatous inflammation with giant cells in the middle, then the large, flat, eosinophilic epitheloid cells, regular macrophages, a layer of lymphocytes, and finally a rim of fibroblast

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TB Additional in the notes

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-TB usually inhaled leading to alveolar macrophage recruitment
-Sometimes this is enough to stop the TB spread, but if not then a CD4 infection will insue
-Once CD4 recruits more m-phages you usually form a granuloma which undergoes caseous necrosis and you end up with a dormant infection. At this point you would be negative for the sputum test but positive for PPD and chest x-ray

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More TB Notes

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-Mycobacteria tuberculosis is acid fast and has a waxy coat which makes it hard to eliminate
-It can spread to any part of the body
-Has no known toxin but the indigestable toxins prob. play the most imp. role
-Induces hypersensitivity and a chronic infection. The CD4 cells role in m-phage superactivation is two fold. On the one hand m-phages are better able to phagocytize and digest the TB, on the other, more host tissue is damaged
-Both cellular and humoral immunity play a role

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Macrophage Clinical Notes

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Signs/Symptoms: Bad cough with mucous and blood, weight loss, fatigue, fever

Treatment: Antibiotics (rifampin/isoniazid) including 6-12 months of treatment which is the main problem since people stop taking them once the symptoms disappear and the TB reemerges as super TB
-In 90% of cases the body handles the TB leading to a dormant organism that may re-effect
-in 10% where the body cannot handle (children, elderly, immunocompromised) there is a systemic disease called milliary TB and it infects the entire body
-Another form of the disease is caused by mycobacterium leprosy but this is localized to cutaneous lesions

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Transplant Rejection Introduction

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-The degree of tissue injury is directly proportional to the genetic dissimilarity between donor and recipient
-HLA similar determines success rate as does blood type
-Involves both cell and antibody mediated hypersensitivity
-Highest survival rate is the kidney and lowest is the lung

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Types of Transplant Recognition

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Direct: Host T-cells recognize allogenic MHC expressed on graft cells. MHC molecules mimic self-MHC and foreign peptide, and so our T-cells are able to directly recognize them. Host CD4 helper T cells drive the DTH response and CD8+ T cells recognize the MHC I and become CTL

Indirect Recognition:Host CD4+ T cells recognize donor MHC after they are processed by the host's APC. CTL will be activated but they cannot directly recognize and kill graft cells. The indirect pathway also involves Ab production

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MHC Information

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-2 classes of histocompatibility genes (H-Genes), the MHC and minor histocompability genes
-There are 4 genes responsible for the MHC complex, HLA-A through HLA-D and they are all inherited together. You get one haplotype from each parent
-25% chance of two siblings being perfect matches
-We carry two genes for each locus, 2 genes for HLA-A through HLA-D
-The genes are co-dominant so they are always expressed on cells,

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MHC Classes

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MHC 1 - Single chain of 3 alpha domains associated with B-2 microglobulin which is expressed on all tissues and nucleatede cells. Has HLA-D

MHC 2 - Two chains, an alpha and beta chain which are expressed on m-phages, dendritic cells, B-cells, activated T-cells, and the vascular endothelium. Made of HLA-A through HLA-C

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Tissue Typing

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1) Lymphocyte Defined Antigens - Mix the lymphocytes and irradiate one of them. If nothing happens they are matched, otherwise you'll need immunosuppresants

2) Serologically defined antigens - draw lymphocytes and use antibodies bound to immunofluorescence to see what HLA you have

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Hyperacute Rejection

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-Preformed antidonor antibodies (usually against MHC 1 or ABO) are present in circulation before transplant and usually attack the vascular endothelial cells. This can occur in women who have anti-HLA antibodies against paternal antigens countered during pregnancy, or someone who was exposed to foreign HLA from prior blood transfusion. With the current practice of screening potential recipients for preformed anti-HLA antibodies this rarely occurs
-Happens within minutes to a few hours after. An example is the kidney due to antibody attack and complement, it becomes cyanotic, flaccid, and non-functional. This is followed by arteritis, ischemic necrosis, edema, and local hemorrhage due to binding of these preformed antibodies to the graft endothelium.

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Acute Rejection

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-Occurs days to weeks after transplantation due to cellular or humoral mechanisms
-See a T-cell response (CD4 and CD8) leading to cytokines and macrophage
-Histologically marked by interstitial mononuclear cell infiltrate with edema, and interstitial hemorrhage due to CD8 mediated endothelial damage (endothelitis)

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Chronic Rejection

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-Most likely due to several episodes of acute rejection and it does not respond well to immunosuppressive therapy
-Occurs months to years post-transplant with the same mechanism as acute rejection
Histopathology: intimal smooth muscle proliferation, ECM synthesis and fibrosis, obstruction of the endothelial leading to ischemia
-All this damage leads to progressive loss of function

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Graft v. Host Disease

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-GVHD occurs when T-cells from the donor recognize the host tissue as foreign and react against it with CD4 and CD8 cells
-Occurs most often in bone marrow transplants because of HLA mismatching and the recipient is immunocompromised at this point
-Leads to problems in 3 principle areas, liver, skin, and gut.
-Liver you have bile duct destruction leading to jaundice
-In the GI you have mucosal ulceration leading to diarrhea
-On the skin you get a generalized rash and desquamation
Also occurs in the lungs with you get interstitial pneumonia and alveoli thickening
-GVHD is minimized by HLA matching or donor T-cell depletion before marrow transplant. However, reducing T-cells also reduces the efficient engraftment of the BMSC, because w/o them the success rate is minimized

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Avoiding Rejection

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1) Minimal HLA disparity and ABO matching
2) Immunosuppressive therapy - Goal is to knock down specific immunization to just the non-matching HLA
a) Antimetabolites - inhibit DNA replication
b) Corticosteroids - anti-inflammatory by binding nuclear receptor and preventing lymphocyte proliferation
c) Calcineurin Inhibitors - Inhibit metabolic target of lymphocytes
d) Anti-Lymphocyte Antibodies - Treat acute phase rejection and target CD4, CD3, and CD8
e) Cytokine Action Inhibitors - Largest and biggest growing group. Block cytokines at the signaling or receptor stage.
f) Rapamycin - interfere with phosphorylation and lymphocyte activation leading to G1 arrest
g) Deoxyspergulin

Complications of Immune Suppression
-Increase oporuntistic infection, as well as cancrs like EBV, HPV, and Kaposi Sarcoma
-Less likelihood of the transplant taking hold since T-cells needed for this

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Autoimmune Introduction

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-Autoantigens may be fixed in tissues like the glomerular basement membrane, present on cells in circulation, or soluble in spaces
-Under a variety of conditions tolerance breaks down and you produce autoantibodies or self-reactive T-cells
-Damage can be localized or generalized depending on the autoantigen distribution (soluble antigens usually more generalized)
-It can involve any organ
-Autoimmune disease can occur at any time but not contribute to disease
-Most common are thyroid disease, diabetes, and SLE with women as the most affected

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Tolerance

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-Tolerance is unresponsiveness to an antigen that is induced by exposure of specific lymphocytes to that antigen
-Immature lymphocytes are more susceptible to tolerance than mature ones
-Central tolerance is deletion of self-reactive T/B cells during their maturation. . Any developing T cell that expresses a receptor for a self-antigen is negatively selected or turned into a regulatory T-cell. Immature B cells that recognize self-antigens in the BM die by apoptosis

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Peripheral Tolerance

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1) Anergy: Functional inactivation of lymphocytes induced by encounter with antigens. Can be due to a missing second costimulatory signal which are usually no expressed on normal tissue, so a autoreactive T-cell would be missing this signal
2) Suppression by Regulatory T-cells: The responses of T-cells to self-antigens may be actively suppressed by regulatory T-cells which will secrete IL-10 and TGF-B
3) Activation-induced cell death: Apoptosis of mature lymphocytes as a result of self-antigen recognition. T cells which are repeatedly stimulated by antigens in vitro undergo apoptosis due to the death receptor FAS being engaged by its ligand xoexpressed on the same cell

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Breaking Tolerance

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-Autoimmune diseases have a tendency to run in families and can be linked with several HLA locus like DR8, DR3, and DR4 (big risk of ankylosing spondylitis)
-Microbes may induce autoimmune reaction via sharing cross-reacting epitopes with self-antigens, this is known as molecular mimicry and is involved in rheumatic heart disease
-Microbial infection can cause up-regulation of costimulatory molecules on resting APC in tissue and thus favor a breakdown of T-cell anergy
-A autoimmune response may itself promote furhter autoimmune attack via epitope spreading

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Breaking Tolerance Notes

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1) Mutation of T/B cell receptor so now the recetpro recognizes a self antigen
2) Altered antigens via protein mutation of hapten binding
3) Infection - Can activate many B/T cell clones, problem is that many B cells aren't tolerant because they rely on T-cells
4) Degradation - Can lead to formation of new epitopes
5) Sequestered Antigens - We have no tolerance to and the immune system is not accousted to
6) Maturation Antigens - appear later in life and so we're not tolerant to them. Any tolerance is peripheral which si easier to break

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Mechanisms of Tissue Injury

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1) Cell-Mediated (Type IV Like) - Autoreactive T-cells activated by autoantigen leading to clonal expansion and production of cytotoxic cells, cytokines, and recruitment of macrophages

2) Antibody Mediated Reactions -
Autoantibody interact with antigen on a cell leading tissue injury via
a) Cytotoxic reaction via type II hypersensitivity. Involves complement, opsoniation, or ADCC destruction
b) Autoantibodies may bind to cell surface receptor and either inhibit or stimulate them. This can lead to altered cell/organ function
c) May form a immune complex like type 3 hypersensitivity. This activates complement and leads to the accumulation of neutrophils. If they occur in the blood vessels you get vasculitis and they can be deposited in several organs leading to multi-organ autoimmune disease

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Pernicious Anemia

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Antigen: Intrinsic factor produced by pareital cells which usually binds to vitamin B12 in the stomach and protects it from gastric acid
Pathogenesis: Forms a autoantibody that binds intrinsic factor not allowing B12 to bind
Clinical Symptoms:
a) Malabsorption of B12
b)Megaloblastic anemia and reduced hematocrit
c) Bone marrow is hypercellular with large megakeryocytes
d) PMN are hypersegmented
e) RBC are oval
f_Destruction of erythroid progenitors leading to pallor, and easy fatigability

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Autoimmune Hemolytic Anemia

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Antigen: Neoantigen on RBC due to drugs
Pathogenesis: AutoAb (IgG/IgM) leads to RBC removal
Clinical: Jaundice, splenomegaly, and Renaud's Phenomenm (pallor blanched fingers, toes, ear, and nose with cyanosis caused by cold agglutinin
-Cold Agglutin (IgM) - React with RBC below 30 degrees
-Warm Agglutin (IgG) - Cause hemolysis when it binds to RBC at temps above 30 degrees

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Autoimmune Thrombocytopenia

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Antigen: Membrane glycoprotein IIb/IIIa
Pathogenesis: IgG and IgM autoAb lead to to platelet destruction, removal, and agglutination
Clinical Symptoms: Low platelet count, megakaryocyte in bone marrow, risk of bleeding, petechiae/purpura all over the body

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Type 1 Diabetes

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-Type 1 is insulin-dependent diabetes mellitus, IDDM)
Antigen: Pancreatic B-cells
Pathogenesis: T-cell infiltrate
Cause: People with certain HLA MHC II are more likely to be affected, shown in children. Also evidence that chemical agent or viral infection may contribute, and the virus/chemical plus the genetic MHC II is a risk factor
Clinical Symptoms
a) Increase hyperglycemia increasing serum osmolarity and more thirst and more urine so polyuria
b) Polydypsia
c) Weight loss
Cure: Require exogenous insulin, w/o which they rely on protein and fatty acids for energy leading to acute ketoacidosis and coma

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Other DIabetic Problems

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1) Insulitis
-Marked by lymphocyte infiltrate in the islets with CD4 and CD8 cells
-Also found is antibodies to the islet cells
-Can use immunoperoxidase staining with insulin to see beta cells and with glucagon for alpha cells
2) Nodular glomerulosclerosis with hyaline arteriosclerosis leading to chronic renal failure.
3) Prone to infections in the kidney from bacteria/fungus called pyelonephritis
4) Blindness - diabetic retinopathy, glaucoma, and cataract of the crystalline lens with opacification
5) Early and accelerated atherosclerosis
6) Oral Pathology: Incidence of periodontal disease is greater due to vascular pathology

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Myasthenia Gravis

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-A disorder of neuromuscular transmission
-The number of functional acetylcholine receptors (ACRs) is decreased at the post-synaptic skeletal muscle membrane
-This is due to autoantibodies which bind the alpha-subunit of AChRs leading to receptor cross-linking and internalization, destruction via complement, or just neutralization
-As a result the muscle end plate potential is reduced and insufficient to trigger a muscle action potential, hence no contraction
-You get abnormal fatigability of skeletal muscles
-Patients treated with anti-cholinesterase medication so the acetylcholine has a longer half life and can outcompete the autoantibody
-Can also use plasmapheresis to filter out the autoantibodies. This only helps short term
-The immunosuppressive therapy consists of prednisolone and azathioprine

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Hashimoto Thyroiditis

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-Organ specific autoimmune disease
-THe immune system, possibly due to HLA-DR5 recognize the thyroid as foreign (antigen might be thyroglobulin) leading to destruction
-The thyroid gland is infiltrated and replaced by lymph tissue, often the thyroid looks like a lymph node germinal center
-The condition usually occurs in middle agent
-You get hypothyroidism (low T3 and T4) leading to goitrous enlargement (nontender)
-Clinical symptoms are elevated TSH, myxedema, macroglossia, puffy features

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Graves Disease Intro Book

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-Most common cause of endogenous hyperthyroidism
-Triad of thyrotoxicosis, ophthalmopathy/exophthalmos (bulging eyes), and dermopathy (scaly thickening and induration of the skin)
-Affects people 20-40 years old and much more common in women
-Genetic factors play a large role with a HLA haplotypes to HLA-B8 and DR3 being common

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Graves Disease Pathogenesis Book

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-Antibodies to the TSH receptor, thyroid peroxisome, and thyroglobulin present in the serum due to loss of T-cell tolerance

Thyroid-Stimulating IgG: Binds TSH receptor and stimulates adenyl cyclase to release thyroid hormones. Specific to Graves
Thyroid Growth-Stimulating IgG: Directed to TSH receptor and leads to proliferation of thyroid follicular epithelium
TSH-Binding Inhibitor IgG: Bind to TSH receptor preventing TSH from binding normally. Some mimic TSH and others inhibit thyroid cell function leading to hypothyroidism which is seen in some Graves patients

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Graves Disease Ophthalmopathy Causes Book

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-Volume of the retro-orbital connective tissues and extra-oculae muscles is increased due to
1) Infiltration of the space by mononuclear cells
2) Inflammatory edema and swelling
3) Accumulation of ECM components like GAGs which absorb more water
4) Increased number of adipocytes

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Graves Disease Morphology Book

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-Thyroid gland enlarged due to diffuse hypertrophy and hyperplasia of the thyroid follicular epithelial cells
-These thyroid cells become tall, columnar, and crowded turning the thyroid from smooth to filled with papilla which project into the follicular lumen
-You find a lot of T-cells
-When given iodine you see involution of the epithelium and accumulation of colloid by blocking thyroglobulin secretion
-Generalized lymphoid hyperplasia
-Dermopathy is seen as thickening of the dermis due to depoisition of GAGs and lymphocytes

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Graves Clinical Features Book

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-diffuse hyperplasia of the thyroid, ophthalmopathy, and dermopathy
-Increased blood flow through the thyroid heard as a bruit
-Sympathetic overactivity producing a wide, staring gaze and lid lag of the eyes
-Extra-ocular muscles are weak
-Dermopathy most often seen on the skin over the shins where the skin is scaly and thick
-Eelevated T4 and T3 in the serum with depressed TSH (autofeedback due to have T4 and T3 tells the pituitary to not release TSH)
-When given radioactive iodine the uptake is increased and radioiodine scans show a diffuse uptake of iodine

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Histology Notes

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-Too many follicular cells and too little colloid
-Oral manifestation include lose of teeth in children and osteoporosis in adults
-Thyroid enlargement is a goiter
-Disease can be passed to the fetus because the autoantibody is IgG but then it will go away after a while
-On microscope you see that epithelial cells protrude into the lumen so you begin to see scalloping of the colloid due to resorption

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Rheumatic Fever Intro

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-Autoimmune disease that occurs in 5-15yo children 2-3 weeks after pharyngeal infection with group A beta-hemolytic streptococci
-It is a case of antigen mimicry since the streptococci have a M protein in which a epitope cross-reacts with human cardiac epitopes (myocardial myosin). So only people who respond to this epitope get it
-When you diagnose this the bacteria gone but the antibody levels are high in the serum

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Rheumatic Fever Clinical

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Acute Phase - Get myocarditis causing arrhythmias, atrial fibrillation, chest pain, and dyspnea. Get fibrinous pericarditis where fibrosis between cardiac cells and their epithelial lining leading to ECH changes

Chronic:
1) Valvulitis: Typically the mitral valve develops vegetations due to inflammation and can become incompetent leading to a backflow of blood which is a heart murmur
2) Myocarditis - Can lead to CHF

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Rheumatic Fever Pathology

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-pathognomic lesions in the heart which are aschoff bodies.
-Basically a granuloma with antischkow cells (elongated nuclei) which group together to form the giant cell known as a aschoff cell. Additionally you have a foci of necrosis, collagen, lymphocytes, and macrophages.
-These aschoff bodies are replaced by a fibrous scar which leaves lesions all around the heart tissue and valves

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Sjogren Syndrome

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-inflammatory disease that affects the salivary and lacrimal glands causing dryness of the mouth and eyes
-Caused by a autoimmune T-cell reaction against an unknown self antigen expressed in these glands or against the antigen of a virus that affects these tissues
-Just dry eyes/mouth is primary SS, if there is connective tissue disease then it is secondary SS
-Dry eyes is xeropthalmia (burning with sticky eye lids) and the dry mouth (xerostomia) causes burning leading to hoarse voice and difficulty swallowing
-Enlarged salivary glands

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Sjogren Syndrome Causes

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-Lots of theories but nothing known
-May be due to B-cell dysfunction causing hypergammaglobulinemia
-Either way there is a inflammatory response in the lacrimal and salivary glands causing the keratoconjunctivitis and xerostomia
-The tissue shows infiltration of salivary glands by lymphocytes and plasma cells
-The oral mucosa can atrophy with inflammatory fissuring and ulceration
-Lack of tears in the eyes can result from secretory lesions of corneal epithelium drying
-Treated with artificial tears and saliva
-Can give immunosuppressive drugs too

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Goopasture DIsease

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Antigen: Basement membrane collagen IV a3 chain triggered by viral exposure or chemical exposure
Pathogenesis: AutoAb (IgG) leading to neutrophil infiltration and release of toxins causing damage
Clinical
Kidney: Glomerulonephritis, hypercellular kidney, and a smooth and regular fluorescence
Lung: Lung hemorrhage

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Multiple Sclerosis

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-MS is a demyelinating disease that involves loss of the myelin sheath that surrounds the axons due to autoreactive T-cells and macrophages
-The loss of myelin is seen by the appearence of plaque which are initially pink/swollen and then gray/sunken
-Demyelinated areas surrounded by lymphocytes and macrophages
-THe result is initially paresthesia, retrobulbar neuritis, and mild sensory and motor symptoms. Byt the end they have unsteadiness of gait, paralysis
-Can effect the CNS and PNS

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Lupus Book Intro

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-multisystemi autoimmune disease which is relapsing and unpredictable
-Affects the skin, kidney, serosal membranes, joints, and heart primarily
-Disease is associated with antinuclear antibodies (ANA)
-SLE is more prevalent in women, African Americans, and is fairly common. Usual onset in the 2nd-3rd decade of life

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Lupus Book Autoantibodies

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-In SLE people lose self-tolerance and from autoantibodies to a variety of tissue leading to direct tissue damage or the formation of immune complex deposits
1) ANA
a) Antibodies to DNA (pathognomic known as smiith antigen (Sm)
b) Histone
c) Nonhistone proteins bound to RNA
d) Nucleolar antigens

Detected via indirect immunofluroescence and depending on the pattern you can tell what the ANA is. The test is sensitive but not specific because people with other autoimmune disease could be positive for it
1) Homogenous stain is usually chromatin, histones, or dsDNA
2) Peripheral stain is usually dsDNA
3) Speckled pattern is usually non-DNA things like histones or ribonucleoproteins
4) Nucleolar pattern has a few discrete spots of fluorescence

Other Autoantibodies
-Against blood cells including both RBC, platelets, and WBC. Additionally, they can form antibodies against phospholipids

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Lupus Book Immunologic Factors

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-One model is a increased generation or defective clearance of nuclear antigens released from apoptotic cells and a failure of T and B cell tolerance to these
-Tolerance can fail for both CD4 cells and B-cells specific for the nuclear antigen
-Genetic variables include class II HLA genes specifically the HLA-DQ locus. Additionally, a genetic lack of complement impairs removal of immune complexes from circulation
-Nongenetic variables include UV radiation causing cell apoptosis as cell as certain drugs like procainamide

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Mechanism of Tissue Injury for SLE Book

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-Systemic lesions usually done by immune complexes (type III hypersensitivity). These DNA/anti-DNA complexes can be detected in the glomeruli or anywhere there is bifurcations leading to vasculitis
-Also autoantibodies against blood cells causes destruction and phagocytosis of these cells (type II).
-One mechanism is when other cells die the ANA binds to their nuclear material and form LE bodies. When a WBC engulfs the LE bodies these WBC are damaged

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SLE Manifestations

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Dermatologic: Malar rash, photosensitivity, oral ulcers. The lesions is erythematous and papular eruption over the bridge of the nose in a butterfly pattern.
-The areas of involvement show liquefactive necrosis of the basal layer with edema at the dermoepidermal junction and swelling and fusion of collagen fibers
-The rash can also occur on the neck, chest, back, stomach, and hands. Within the lesions you can also find IgG and complement
-20-30% of the patients form discoid lupus erythematosus (DLE)

Renal: Glomerulonephritis leading to proteinuria, hematuria (blood in urin)
-Capillary loops in the glomeruli become thickened. RBC/WBC casts in the urine. IF in the kidney is positive for IgG and C3 and is punctate and irregular (good to distinguish SLE form goodpasture)

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SLE Manifestations

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Serosal: Serous effusion or fibrinous exudation in acute cases to fibrous opacification in chronic cases. Edema, focal vasculitis with perivascular lymphocytic infiltration

Cardiovascular:
-Can be symptomatic or asymptomatic. Myocarditis with mononuclear cell infiltration. This leads to tachycardia and EKG abnormalities. There used to be Libman-Sacks endocarditis (nonbacterial) leading to single or multiple irregular vegetations on the heart valves

Oral Manifestions: Ulceration, erythema, and keratosis. Appear similar to skin lesions

-In chronic discoid lupus the lesions are confined to the skin due to sunlight exposure. It never progresses to fullblown SLE

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Rheumatoid Arthritis Intro Book

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-Systemic, chronic inflammatory disease
-In the joints there is a nonsuppurative proliferative synovitis leading to destruction of articular cartilage and underlying bone
-More common in women and frequent in the 20-40s

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Rhematoid Arthritis Morpholoyg in the Book

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-Usually see symmetric arthritis in the small joints of the hands and feets, ankles, knees, wrists, elbow snad shouders. Usually affects the interphalangeal and metacarpophalangeal joints
-Chronic synovitis characterized by 1) synovial cell hyperplasia and proliferation
2) dense perivascular inflammatory infiltrates of CD4 t-cells, plasma cells, and macrophages
3) increased vascularity
4) neutrophils and aggregates of organizing fibrin on the synovial surfaces and joint space
5) increase osteoclast activity
6) Eventual formationa of pannus which is formed by proliferating synovial lining cells admixed with inflammatory cells, granulation tissue, and fibrous connective tissue leading to lush, edematous, fronlike (villous) projections

Rheumatoid Subcutaneous Nodules - Develop in 25% of patients and occur along the extensor surface of the forearm. They are firm, nontender oval masses 2cm in diameter. Have a central focus of fibrinoid necrosis surrounded by macrophages and granulation tissue
-Patients with severe disease have high titers of rheumatoid factor RF (circulating IgM that binds IgG)

Oral:TMJ involvement later on and is bilateral. Pain due to pressure. Radiographs will show a flattened condylar head with a irregular temporal fossa surface

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Rheumatoid Arthritis Pathogenesis

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-Clear genetic predisposition
-Activation of CD4 cells due to some agent (microbial or self) leading to production of cytokines that activates macrophages which release enzymes perpetuating inflammation and the cytokines also activate B-cells leading to antibodies directed against self in tehe joint
-The synovium becomes filled with WBC which lease TNF and IL-1. TNF promotes leukocyte recuirtment and IL-1 causes proliferation of the synovial cells and fibroblast
-T-cell also release RANK-L which induces osteoclast differentiation
-There is a genetic association within families that has been ties to HLA-DR4 and polymorphisms in the PTPN22 gene. Also, infectious agents may play a role

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Rheumatoid Arthritis Clinical Course

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-Patients suffer from weakness, malaise, and low-grade fever due to the IL-1 and TNF
-They also have stiff joints in the morning
-Eventually the joints become enlarged and motion is limited with complete ankylosis ensuing
-In a minority of patients the disease becomes stabilized but in more there is progressive joint destruction leading to disability after 10-15 years
-The outcome has been improve by recent therapies including TNF antagonizers

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Immunodeficiency Disease Overview

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-can affect both humoral and cell mediated immunity
-Get frequent infections so treated by prophy
-Deficiency in humoral immunity due to problem with B-cells or regulation by T-cells/Macrophages. Very susceptible to infection by bacteria, especially pyogenic
-With cell mediated problems they have a t-cell deficiency leading to viral and parasitic problems and can be injured when given immunizations
-Deficiency in complement makes them susceptible to pyogenic bacteria (gonor/menin)

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Immunodeficiency Classification

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1) Primary - Usually inherited but can be acquired. Problem with cell development or function

Secondary - Arise due to some other existing condition like aging (immunologic senescence), being given chemo/immunosuppresents, viruses that turn off the immune system, malnourishment

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Primary B-Cell Deficiencies

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-B-cells don't differentiate into plasma cells or won't secrete immunoglobulin
-Known as agammaglobulinemic and the disease usually occurs early in life
Ex: Bruton's Disease
-Pre-B cells don't differentiate to mature B-cells due to a mutation in tyrosine kinase that preve3nts heavy chain rearrangement
-X-linked so seen in males
-Once mother's passive immunity disappears you begin to see problems at 6 months
-No B-cells in circulation and only the pre-B cells in the bone marrow
-Germinal centers of lymph nodes are underdeveloped and lack plasma levels so the blood serum has low immunoglobulin
Signs: Patient has recurrent pyogenic infection leading to pharyngitis, otitis media, and bronchitis. However, the cell-mediated immunity is normal so most viral/fungal fought off except echovirus, enterovirus, and pneumocystis carinii
-Intestinal infection with Giardia lambdia can lead to malabsorption
Testing: Look at serum levels of IgG and also total B-cell number

Treatment: Passive immunization with pooled human serum

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Common Variable Immune Deficiency (Acquired Agammaglobulinemia)

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-There are B-cells, just no plasma producing antibodies. So the B-cells just can't differentiate into plasma cells, not sure why
-Suffer from hypogammaglobulimia (mostly IgM)

Clinical:
Increase infection, more autoimmune disease, won't take a vaccine and run with it

Test: serum IgG and B-cell number

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Isolated or Selective IgA Deficiency

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-Problem with B-cells switching to produce IgA, so they have normal levels of IgG but no IgA in the mucosal linings
-They are usually asymptomatic except sinopulmonary infections and diarrhea due to the lack of IgA

Test: Look at serum IgA levels

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Di-Georges Syndrome

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-Not inherited but congenital due to a intrauterine accident where the thymus is destroyed and so there is no T-cell development
-These patients are susceptible to viral, fungal, protozoal infection
-Also more susceptible to bacteria since t-cell cytokines really helpful to increasing the immune response
-Also get parathyroid hypoplasia, midline development abnormalities, and cleft lip
Treatment: Thymic Transplant

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Hyper IgM Syndrome

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-No B-cell class switchng so only IgM is produced
-T-cells must contact B-cells for class switching and in this case the enzyme responsible for this or the act of touching is not around
-Patients get recurrent pyogenic infections and increase susceptibility to intracellular pathogens

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Mucocutaneous Candidiasis

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-Due to Candida albicans infection causing oropharyngeal candidiasis (oral thrust) with white pseudomembranes thatbleed when scraped away
-Due to deficiency in cell mediated immunity (t-cell) or newborns or people given antibiotics or corticosteroids

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SCID

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-Patients have both cell mediated and humoral defects so any infection can kill
-Their lymph nodes are difficult to find and they lack germinal centers and paracortical areas (t-cells)
-Several different types
1) X-linked: mutation in cytokine receptor
2) Adenosince Deaminase Deficiency: lymphocyte precursors are sensirtive to adenosine build up
3) MHC Class II deficiency

Test: lymphocyte transformation and adenosine deaminase level

Treatment: Bone marrow transplant

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Phagocyte Deficiency

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-Defect in lysosomal structures/phagocytosis
-Defect in chemotaxis
-Decrease in the number of macrophages
-Defect in bacteria killing ability (bacteriolysis)

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Secondary Immunodeficiency

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-more common than primary deficiencies
1) Result of other disease states
Ex: Cushings
2) Result of Therapy for other conditions
Ex: anti-inflaammatory, immunosuppressive agents, chemotherapy
3) Immunoinhibitory drugs like alkylating agents, cyclosporin A
4) Change in States
Ex: Pregnant, older age
5) Misc
Ex: Malnutrition, sickle cell anemia, sarcoidosis

Can lead to bacterial, viral, fungal problems as well as more cancers like Hodgkins disease (depressed CM1), multiple myeloma (depressed Ab), and chronic lymphatic leukemia (depressed Ab)

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AIDS (Not to be always associated with HIV)

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-Problem in cell-mediated immunity due to a microbial infection
-No genetic, no corticosteroids, no other problems
-AIDS commonly manifest itself with pneumonia (pneumocystis carinii), intestinal cryptosporidiosis, toxoplasmosis, candidiasis, disseminated aspergillosis, cytomegalovirus, herpes, and kaposi sarcoma
-Huge reduction in T-helper number due to infection of T-helper, often by HIV
-Monocytes have been shown to be susceptible to HIV and may cause the CNS infection and subacute encephalitis seen in AID patients
-HIV is transmitted via blood and semen (mostly)

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HIV Specifically

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-Infects T-cells and macrophages to impair function at first and then it destroys these cells
-Leads to many opportunistic infections
-Main oral lesion seen is oral hairy leukoplakia which is seen as a white plaque on the tongue which does not rub off
-Oral hairy leukoplakia is associated with EBV and leads to hyperkeratosis and hyperplasia