• Shuffle
    Toggle On
    Toggle Off
  • Alphabetize
    Toggle On
    Toggle Off
  • Front First
    Toggle On
    Toggle Off
  • Both Sides
    Toggle On
    Toggle Off
  • Read
    Toggle On
    Toggle Off
Reading...
Front

Card Range To Study

through

image

Play button

image

Play button

image

Progress

1/198

Click to flip

Use LEFT and RIGHT arrow keys to navigate between flashcards;

Use UP and DOWN arrow keys to flip the card;

H to show hint;

A reads text to speech;

198 Cards in this Set

  • Front
  • Back
Epidemic vs. Pandemic
Epidemic= an increase in incidence of disease in a population

Pandemic= epidemic that spreads across a large area (ex: a continent)
What were the top 3 leading causes of death in the early 1900s and How did they decrease in incidence?
Top 3 killers: Pneumonia & Influenza, TB, Diarrhea.

Decrease due to 1. hygiene, 2. antibiotics (1940s) , 3. vaccinations (1960s)
Why are microbes more powerful than human brains?
- Increased Quantity
- Increased Diversity
- Short generation time (minutes)
- Evolve rapidly (superbugs, XDR TB, HIV, etc.)
- We've helped them (travel, antibiotic abuse, immunosuppression)
Commensal vs. Viral organism

(give an example)
Commensal= an organism that neither harms nor helps the host (neutral)
Viral= an organism that harms the host

ex: Staph Epidermidis (C) vs. Staph Aureus (V)
What are 5 major types of infectious agents?
A. Viruses
B. Bacteria
C. Fungi
D. Parasite
E. Prions
What are "constitutive" and "induced" defenses?
Host Defenses
- Constitutive= barriers (skin, mucosa), complement, phagocytosis
- Induced= adaptive immunity, humoral and cellular
What is the "sequence of events" in a typical host-pathogen interaction?
A. Encounter
B. Entry
C. Spread
D. Multiplication
E. Damage
F. Outcome
Give some examples of Exogenous infectious agents. Where do they come from?
Outside the body, environmental.
ex: Legionella, common cold, typhoid, Enterotoxic E.coli (ETEC)
What is a fomite?
Foreign body, anything that carries infection (ex: cat bite, mop, stethoscope, etc.)
What is a parasitic infection transmitted by a Tick?
Babesia
How many bacteria are there per human cell in the body?
10 bacteria per human cell

We are outnumbered.
What is "colonization"?

What is "infection"?
Colonization= presence of microorganisms (organism enters body)

Infection= presence of microorganisms with resultant damage & signs and symptoms of disease (organisms damage body)
What are Endogenous infections? Give 3 examples of ways of getting these infections.
Infections by agents that are on or within the body.

ex: wound, aspiration, retrograde (UTI)
What are 2 major routes of entry of microorganisms? Give examples of each.
1. Enter into body cavity: Cholera (GI), Cystitis (bladder infection), also respiratory infections

2. Penetrate into deeper tissue- pass through epithelium (wound, organ transplant, blood transfusion)
What is an Inoculum?
A gob of pathogens that a host is exposed to at the time of an infection.
What is an Incubation period?
the time from entry of a pathogen to onset of first symptom of disease
What is an example of "One organism- One disease"?
Variola (Smallpox)
Rubeola (Measles)
What is an example of "One organism- Many diseases"?
Staphylococcus aureus
- skin abscesses, brain (meningitis), bone infections, etc.
What is an example of "One Disease- Many Organisms"?
Pneumonia

- viral (influenza, Hanta)
- bacterial (Streptococcus pneumoniae, etc.)
- fungal (Aspergillus)
What is the equation for Disease?
(Bolus of infection x Virulence)/Immunity
What is the key difference between Extracellular and Intracellular pathogens?
Extracellular = attach and enter host blood stream and disseminate

Intracellular = Replicate inside cell. Spread by infection through blood or other cells.
What are the 3 layers of defense of the immune system?
I. Barriers
II. Innate = nonspecific= natural
III. Adaptive = specific= acquired
What is the immune system's 1st line of defense comprised of?
Barriers:
skin, saliva + tears (lysozyme), stomach acid, mucosa, flushing action of urinary tract, commensal organism in gut, vagina, skin
What are the key players of the 2nd line of defense in the immune system?
Innate Immunity:
- Macrophages
- Granulocytes
- NK Cells
- Complement
- Other chemicals
Which branch of the adaptive immune system is better at fighting extracellular pathogens? intracellular pathogens?
Humoral (antibody mediated)- better at extracellular pathogens (Abs float around in blood)

Cell mediated- better at intracellular (attack viruses)
What cell is a component of both the innate and adaptive immune system?
Natural Killer T cell

(shares properties of both T and NK cells)
What is the common ancestral lineage of all blood cells?
multipotent hematopoietic stem cells
What are the two main lineages that derive from hematopoietic stem cells and what players do they contain?
1. Lymphoid Lineage: T-cell, B-cell, NK- cell

2. Myeloid Lineage: monocyte/macrophages, dendritic cells, granulocyte (neutro, baso, eosino), megakaryocytes
Which branch of the adaptive immune system is better at fighting extracellular pathogens? intracellular pathogens?
Humoral (antibody mediated)- better at extracellular pathogens (Abs float around in blood and specifically recognize soluble antigens)

Cell mediated- better at intracellular (attack viruses)
What cell is a component of both the innate and adaptive immune system?
Natural Killer T cell

(shares properties of both T and NK cells)
What is the common ancestral lineage of all blood cells?
multipotent hematopoietic stem cells
What are the two main lineages that derive from hematopoietic stem cells and what players do they contain?
1. Lymphoid Lineage: T-cell, B-cell, NK- cell

2. Myeloid Lineage: monocyte/macrophages, dendritic cells, granulocyte (neutro, baso, eosino), megakaryocytes
What are 3 types of granulocytes? What are their main functions?
Neutrophils (Acute Inflammation, phagocytosis + degranulation)

Basophil (Degranulation, Histamine)

Eosinophil (Degranulation, Parasites + Allergies)
What is a plasma cell?
Terminally differentiated B cell that secretes antibody.
Where do immune cells develop? Where do immune responses occur?
Develop in Primary organs (bone marrow and Thymus)

Response occurs in Secondary organs (lymph nodes, lymph tissue)
What are cytokines and what cells primarily secrete them?
Cytokines = soluble protein molecules used for communication

Secreted primarily by leukocytes
What are 4 major types of Cytokines?
1. Interleukins (IL)
2. Interferons (IFN)
3. Tumor necrosis factors (TNF)
4. Transforming growth factor (TGF)
What are the key players of the adaptive immune system?
T-cells
B-cells
Antibodies
APCs
What are the key differences between "innate" and "adaptive" immunity in terms of: specificity, speed, role, and secondary response?
1. Innate is fast (min-hrs), Adaptive is slow (days)
2. Innate is non-specific, Adaptive is specific
3. Innate is 1st line of defense, Adaptive prevents disease progression
4. Innate- repeated response is not enhanced, Adaptive- secondary response is enhanced
What are the 3 major APCs of the immune system?
Macrophage
Dendritic Cells
B-lymphocytes
What is the complement system?
~25 circulating serum proteins and proteolytics enzymes that get activated in sequence and destroy invaders.
What are 3 complement activating pathways? What is the common protein central to all pathways?
1. Alternative: foreign cell surfaces (LPS)
2. Lectin (mannose)
3. Classical (antibody-antigen complexes, IgG and IgM)

Common protein= C3
What is the role of C5a (complement protein)?
Inflammation (increase blood vessel permeability and attraction of phagocyte)
What is the role of C3b (complement)?
C3b Binds Bacteria (opsonization)- marking the invader so it is tasty to phagocytes
What is the MAC and what is it made up of?
Membrane attack complex- drills hole in invader (cytolysis)

C5-9
Which cells are the "foot soldiers" of the immune system and why?
Neutrophils-
1. most abundant
2. patrol body to eliminate invaders
3. first responders (Professional Phagocytic Killers)
Which cells are the "sentinels" of the immune system and why?
Macrophages (monocytes in tissue)

Because they check for invaders
What cell secretes IFN-gamma and what is it's role?
NK cells secrete IFN-gamma

POTENT ACTIVATOR OF MACROPHAGES!
What happens in Chediak-Higashi syndrome (CHS)?
mutation in CHS1 gene, encodes protein that helps fusion of lysosome. Patients are unable to form phagolysosome and pathogen killing is impaired. Recurrent infections.
What is Chronic Granulomatous Disease caused by?
mutation in NADPH oxidase (enzyme that is required for ROS formation- respiratory burst). Ineffective killing of phagocytes and recurrent infections.
What is Leukocyte Adhesion Deficiency Type 1 caused by?
Impaired B2-integrins. They help neutrophils extravasate into site of infections. Patients present with recurrent infections.
What is a PAMP? Provide some examples.
Pathogen-associated molecular patterns. Conserved structural features or patterns on microbes recognized by innate system leukocytes.
ex: LPS (gram -)
peptidoglycan (gram +)
DNA, RNA sequences
Fungal cell wall
Provide some examples of PRRs (Pattern Recognition Receptors). Which is the most prominent?
1. Scavenger Receptors (bind lipid-related ligands on bacterial surface)
2. Mannose binding receptors (can activate complement)
3. TLRs **
What is opsonization? What are the 2 most common opsonins and to which receptor do they bind?
Opsonization= protein attach to exterior of microbe to facilitate eating by phagocyte

1. Antibodies --> Fc receptor
2. C3b --> CR1 receptor
What is a chemokine?
A type of cytokine (cell signaling molecule) that induces chemotaxis or cell movement. (F) Mediate immune cell trafficking.
What is Extravasation? What must a cell do to extravasate? (Hint: there are two main phases of this process)
The migration of cell (leukocytes) from blood into a tissue under attack.

1. Migration (adhesion to endothelial cell)
2. Diapedesis (transmigration through basement membrane of cell)
What is the role of selectin-selectin ligand binding?

What is the role of ICAMs (integrin-intracellular adhesion molecules)?

What is the role of chemoattractants?
Selectin-selectin: involved in leukocyte rolling

ICAM: stop the leukocyte and make it bind.

Chemoattractant: facilitate leukocyte exit from the blood
What are the cardinal signs of inflammation?
Rubor
Calor
Dolor
Tumor
Functio Laesa (loss of function)
What are the three major events in an Acute Inflammatory response?
1. Vasodilation (increase blood flow)
2. Increased vascular permeability (facilitate influx of cells)
3. Influx of Polys and Macrophages into tissues (immune response)
What is PUS?
Dead neutrophils and fluid.
What are NK cells? What do they target?
Large granular lymphocytes that kill virus-infected cells (and cancer cells).

SECRETE INF-gamma!
Describe the feedback loop between macrophages and NK cells during the killing of microbes.
NK cells secrete INF-gamma
--> potent activator of macrophages which secrete IL-12
--> IL-12 stimulates NK to secrete more INF-g
In what situations is ADCC (antibody dependent cellular cytotoxicity) used?
Typically when killing something larger than macrophages (ex: Helminth or parasitic worm)
Describe the process of killing a parasitic worm in the body.
Fab portion of antibody binds to epitope on cells infected by virus. Then the NK cells bind to Fc portion of the antibody and release perforins and granzymes. Granzymes pass through pores and lead to apoptosis.
What is the principle of Clonal Selection?
1. Clonal "Selection": pathogen specific Antigens produce B or T-cells specific for that Ag

2. Clonal "Expansion": identical B or T-cells are produced

3. "Differentiation": Daughter cells give rise to short-lived effector cells (ex: plasma cells, secrete Ab) as well as memory cells that stay in tissue waiting for re-exposure to same pathogen.
What is "central" vs. "peripheral" tolerance?
Tolerance- responding to foreign Ag without harming self tissue.

Central= early in lymphocyte development. Eliminate cells that recognize self aka attack self antigen (we don't want it to attack us)

Peripheral= if some lymphocytes that recognize "self" antigen and attack it escaped the screening, they are silenced in the peripheral tissue
What are the 3 phases of a macrophage?
1. Garbage collector: surveillance
2. APC: when activated by cytokines such as IFN-gamma
3. Hyper activated: when directly contacted by pathogen, produces cytokines such as TNF to call in recruitments
What receptors do NK cells have? What triggers it?
Activating receptor- virus infected cell, MCH I with virus peptide

Inhibitory receptor- MCH I with self peptide
What is required for an NK cell to get activated?
Both a "kill" signal by a virally infected cell and the loss of MHC Class I expression
What is the role of resident macrophages that live in the infected tissue, in the extravasation of leukocytes?
Secrete cytokines (ex: TNF, IL-1) that activate endothelial cell surface molecules (selectins, etc.) involved in the tethering and rolling of leukocytes.
What are the major characteristics of the adaptive immune response?
1. Specificity (ag specific receptors)

2. Division of labor (B cells direct killing, T cells only through presentation by APC)

3. Memory (enhanced secondary response)

4. Tolerance (self/nonself recognition)
What is the proposed mechanism in the adaptive immune response that provides the basis for specificity, recognition, and memory?
Clonal Selection!
What is an epitope?
A small molecular domain of an antigen that is recognized by immune system. Aka. antigenic determinant.
What MHC complex is recognized by CD8+ T cells? CD4+ T cells?
Cytotoxic (CD8)- MHC I
Helper (CD4)- MHC II
What are some differences between B and T lymphocytes in terms of their receptors and what they recognize?
Receptors: B-cell Ab receptors can be secreted vs. T-cell is membrane bound

Recognize: B cells recognize
soluble extracellular Ags, T cells recognize processed and presented intracellular Ags
How does an APC internalize an antigen? What is involved in it's maturation process?
Internalizes Antigen via phagocytosis or Receptor-mediated endocytosis

APC Maturation: After processing Ag, it travels to lymph nodes it upregulates MHC expression and expression of co-stimulatory molecules such as B7.
What are MHC molecules?
What is an MHC locus?
What are Human MHC molecules called?
Basically proteins on APC that display peptide Ags for recognition by T-lymphocytes.

The locus is where the genes for the MHC molecules are located.

HLAs= human leukocyte antigen
How are MHC genes expressed?

T or F
MHC proteins are unique to individuals?
Codominant expression (maternal and paternal contribution is equally expressed)

True! We are all unique (thus difficult to exchange tissue graft)
What is allotypic polymorphism and why is it useful?
Variation among population (in reference to MHC molecules). Ensures that human species will survive diverse pathogens and even superbugs.
What are subdivisions of human MHC class I genes? Where are they found?

What are subdivisions of human MHC class II genes? Where are they found?
MHC I: HLA-A, HLA-B, HLA-C; found on ALL nucleated cells

MHC II: HLA-DP, HLA-DQ, HLA-DR; found on APCs
Which type of MHC-T cell complex is good at eliminating intracellular pathogens?

What about extracellular pathogens?
MHCI-CD8 T cells: intracellular pathogens (because MHCI on nucleated cells)

MHCII-CD4: extracellular pathogens (because stimulate B cells that release Ab which recognized soluble antigen, i.e. in blood)
What are the key structural differences between MHC I and MHC II proteins?
MHC I: 1 transmembrane domain; closed ends on binding groove (smaller peptides 8-11 AA)

MHC II: 2 transmembrane domains; open ends in binding groove (larger peptides 10-30AA)
What part of the MHC molecule does the TCR bind to and what part do the CD8 or CD4 co-receptors bind to?
TCR binds to both the peptide and the ends of the MHC molecule.

CD8 binds to a3 domain of of MHC I. CD4 binds to B2 domain of MHC II.
Describe the process of Class I MHC antigen processing.
* Load INTRACELLULAR peptides

1. Proteins produced in cytosol
2. Proteolytic degradation (via ubiquitination and proteosome)
3. Peptides transported to ER via TAP
4. Assembly of peptide-MHC I complex in ER
5. Transportation to cell surface
Describe the process of Class II MHC antigen processing.
* load EXTRACELLULAR peptides


1. Ingestion of extracellular protein and processing in lysosome
2. Biosynthesis of class II MHCs and transport to endosome
3. CLIP comes off, Ag peptide gets associated with MHC in vesicle
4. Transportation to cell surface
What is the "invariant chain"?

What is DM?
In the processing of MHC II antigens, the invariant chain occupies the cleft of the newly formed MHC molecules. When it enters the endosome, it is clipped into a peptide called CLIP which occupies the groove before the exchange process.

DM facilitates the exchange process of CLIP for the processed antigen.
Why is the "two-key system" of Lymphocyte activation needed?

What are the 2 signals involved in full T-cell activation?
To safe-guard (because B and T cells are potent weapons)

1. Ag-MHC complex presentation
2. Co-stimulatory molecules (ex: B7)
What is B7 and where is it expressed?

What receptor is it recognized by and where is the receptor found?
Costimulator molecule expressed on surface of activated B cells or macrophages.

Binds to CD28 receptor on T-cells.
What are the accessory proteins that help deliver activation signals in B cells and T cells?
B cell: Ig-alpha, Ig-beta

T cell: CD3, made up of delta, gamma, epsilon, and zeta
What is the structure of an antibody?

Where are the "variable" and "constant" regions located?
Shaped like a Y. Two heavy chains and Two light chains are bound by S-S bonds and Covalent bonds.

The amino end contains the variable region. The carboxy end contains the Fc region.
What is the Fc region of the antibody?
The carboxy end that is recognized by certain receptors and allows the antibody to bind to specific cell surfaces (ex: can bind to macrophage in the destruction of a helminth)
How do the receptors of different B cells recognize different antigenic structures?
MIX-and- MATCH = Modular Design = Somatic Recombination = VDJ recombination

Gene rearrangement process that randomly recombines gene segments encoding the variable regions of BCR and TCR proteins.
What is the structural region that allows for specific recognition of B cell receptors to antigens?
CDR (Complementarity determining region) = Hypervariable region

The variable region of each chain (heavy and light) contains three short stretches of AAs which make up the CDR.
T or F
B cell receptors are only secreted proteins
False

There can be "Membrane bound Igs" which recognize antigens and INITIATE the humoral response
Which Ig molecule is important in local (mucosal) immunity?
IgA is important in local immunity.
Which Ig molecule is the first to be made by the fetus?
IgM is first to be made by fetus
Which Ig is the first to be produced in a primary immune response?
IgM is made first in a primary immune response.
Why is IgM good at fixing complement?
Because of it's structure. It is pentameric (thus binds a lot of antigen, robust complement activation)
Which Ig molecule is capable of crossing the placenta?
IgG (placental cells bind Fc region of the antibody)
Which Ig molecule is the most predominant isotype in secretions (tears, saliva, milk, etc.)
IgA is the most predominant type in secretions.
What is the most abundant Ig molecule in the serum?
IgG is most abundant (75% of serum Igs)
What two Igs act as opsonins?

Hint (they are also the two that fix complement)
IgG and IgM
Abundance of what Ig isotype might you look for to diagnose parasitic infections?
IgE (also mediates allergic reactions by binding to basophils and mast cells!)
What is the structure of T Cell Receptors (TCRs)?
aB heterodimers (95%)
gamma delta chains (5%)
(chains are linked by S-S bonds)

Each chain has a variable and constant region
T or F
Only antibody receptors undergo Mix-and-Match rearrangement
False

T Cell receptors also undergo VDJ recombination
What is the role of co-receptors (CD4, CD8)?
Tighten the interaction between an APC and a T Cell.
T or F
Mix and Match recombination takes place after the encounter of an antigen
False

It takes place before the T or B cells encounter an antigen. Remember, it gives them the specificity to bind a particular antigen.
T or F
The variable segment of the a, B, Heavy, and Light chains are made from the random combination of one V, one D, and one J gene segment.
False

alpha and light chains do not have D segments. So it should technically be "V(D)J recombination"
Ig chain loci contain the greatest number of variable region (V) genes at what stage?

(Hint: where do we find germline Ig cells)
In the germline configuration (i.e. Hematopoietic stem cells in the bone marrow).
What are two mechanisms to maximize diversity in the CDR regions of T cell and B cell receptors?
1. Combinatorial diversity: millions of different combinations of V(D)J segments

2. Junctional diversity: addition and removal of nucleotides at the junction of segments is unlimited
What cells are the "educators" in the maturation of T lymphocytes?
Cortical thymic epithelial cells aka epithelial reticular cells (throwback!)
What is the Positive selection vs Negative selection process that takes place inside the thymus?
Positive selection: during maturation of T cells, only cells that recognize MHC + antigen can survive (others apopotose)

Negative selection: Only Tcell receptors that weakly bind MHC+antigen will survive, those that too strongly bind will be eliminated
What is the rationale behind Negative selection during T cell maturation?
The body wants to protect against too strong of a response of T cells to the body's self MHC/antigen to prevent autoimmune like attacks.
Briefly, describe the stages of T cell maturation and where each process takes place.
Start= Stem cell (Bone marrow)
1. transport as Double Neg precursor to Thymus
2. Rearrangement of TCR genes --> now it's Double Pos
3. Education via thymic epithelial cells (positive and negative selection)
4. Mature T is either CD4 or CD8 coreceptor and is shuttled out to periphery (lymph nodes, etc.)
T or F
Only about 1% of T cells pass through the maturation process and become mature T cells
True
99% fail (either too strongly bind or don't bind at all)
T or F
Cortical thymic epithelial cells are like APCs in the sense that they can present MHC molecules with peptide to T cells.
True

They present MHC + antigen to T cells to see if they have weak recognition. They also do not elicit a kill response like MHCs.
Patient's with cleft lip and palate, hypocalcemia, and a thymic shadow will likely have what genetic condition?

From an immunologic standpoint what is to be expected in these patients.
DiGeorge

Decreased Thymus size, thus decreased circulating T-lymphocytes and more susceptibility to infection.
What clinical constellation of findings are seen in patients with Chediak-Higashi syndrome (CHS)?
MT defect and genetic defect affecting granules:

- hypopigmentation (melanin granules, silver hair)
- recurrent infection (can't form phagolysosome)
- large granules in neutrophils
Where do T cells undergo clonal expansion and differentiation into effector cells?
Secondary lymphoid tissues (lymph nodes, spleen, MALT, etc.)
What three signals are required for the complete activation of a naiive T cell?
1. Engagement of antigen receptor by antigen
2. Costimulation
3. Interaction with cytokines
What is the most important APC during the initial phase of an attack and why?
Dendritic Cell (DC)
Has everything needed to activate naiive T cells (Class I, Class II MHC loaded with antigens and B7 costimulatory proteins)
T or F
A naiive T cell is fully activated when it's antigen-receptor comes into contact with the MHCI+ peptide complex on the surface of an APC?
False

Both engagement of receptor AS WELL AS costimulatory molecules (ex: B7 on APC and CD28 on T cell) are typically needed for full activation of T cell.
What is the main role of IL-2 in T cell activation?
It participates in an autocrine loop (produced by T cells and delivers signal for clonal expansion)
What is the 3rd signal involved in T-cell activation?
Upregulation of IL-2 receptors (autocrine loop) by Helper T cells or CTLs that permit proliferation of effector and memory cells.
T or F
CD8+ T cells are abundant and self-sufficient producers of IL-2 cytokine?
False

They are poor producers. Whereas, CD4+ cells make IL-2 and T-helper cells can provide this service to CTLs.
What are the two main duties of activated CD4+ helper T cells?
1. Remain in blood and travel to lymph nodes helping B cells and CTLs
2. Exit blood vessel and help activate macrophages
What is the process of activating a naive T helper cell to become a Th1? What does it do when activated?
Dendritic Cell that samples an intracellular pathogen will present it to the naive CD4+ AND secrete IL-12.

Th1 then produces Th1 cytokines (IL-2, TNF, and IFN-g) that promote phagocytic killing of INTRACELLULAR PATHOGENS.
The classical Th1 cytokines are...
TNF- inflammatory response

INF-g potent macrophage activator

IL-2 autocrine loop
How is a naive T helper cell activated to become a Th2 cell? What does it do when activated?
Dendritic cell that encounters an extracellular pathogen travels to lymph node and activates a Th2 cell. IL-4 (from other sources) directs proliferation of Th2 profile.

Th2 then promotes humoral immunity (IgE production) and eosinophil-mediated killing of helminths/parasites.
The major Th2 cytokines are...
IL-4 stimulates neutralizing antibody production (IgG and IgE)

IL-5 activates eosinophils

IL-13 ?

and IL-10 Cuts down Th1 production when Th2s are activated (negative feedback)
T or F
CD4+ Helper T cells directly participate in the killing of a microbe
False
They do so indirectly via cytokines (they are the "cytokine factories"). This 1) activates macrophages and 2) inflammation
What is the "quarterback" of the immune system? why?
Helper T cell. Uses cytokines to "call the plays"
What cell is CD40 on and what cell is CD40 Ligand on?
CD40 Ligand = on T cells (helper and other T cells)

CD40 = on APCs and B cells and Macrophages (anything interacting with T cells via costimulatory molecules)
What cells are the "serial killers" of infected cells?
CTLs = Cytotoxic T lymphocytes
What cytotoxins are released by CTLs and what do they do?
Perforins: polymperize to form pore in cell membrane, cell can burst/lyse

Granzymes: serine proteases that can enter through perforin pores and induce apoptosis
What mechanism does the mycobacteria use to resist Cell Mediated Immunity (CMI)?
It inhibits fusion of the phagolysosome (interestingly, it wants to be engulfed and thrives in phagosome)
What mechanism does the Herpes Simplex Virus (HSV) use to evade cell mediated immunity?
It inhibits antigen presentation on surface of APC (via interference with TAP transporter- remember this is the MHCI type, intracellular processing)
What mechanism does the Epstein-Barr virus (EBV) use to resist cell mediated immunity?
Produces IL-10 (the cytokine produced by Th2 cells) that inhibits macrophage activity.
What is the function of Th17 cells?
Secretes IL-17. Host defense against some bacteria; inflammatory disorders.
Generation of a humoral immune response occurs through what 3 steps?
1. Hematopoiesis
2. Induction (Activation and Differentiation)
3. Antigen Elimination
What Ig isotypes is a B cell capable of making without induction?

Why are these two types commonly seen together on the surface of antigen-naiive B cells?
IgM and IgD

They are close to each other on the constant segment of the genome. Thus transcribed and expressed simultaneously.
What structural feature do all secondary lymphoid organs have in common?

What is it made up of?
All contain lymphoid follicles

Islands of follicular dendritic cells within a sea of B cells.
Where are T cells and follicles located in:
- lymph nodes
- spleen
Lymph nodes: Follicles- periphery/cortex, T cells- paracortex

Spleen- T cells- in PALS (periarteriolar lymphoid sheaths)
T of F
Large, multivalent antigens are not as good as small antigens when it comes to initiating a humoral immune response?
False
Multivalent, large antigens are preferable because they initiate cross-linking between BCRs and this promotes activation of B cells

*typically seen with polysaccharide antigens
What two signals are needed for the T-cell INDEPENDENT activation of B lymphocytes?
1. Cross linking of BCRs
2. CR2 receptor on B cells recognizing C3d (fragment of C3b). The C3d comes from complement bound to a pathogen.
What three things do Helper T cell signals stimulate to give B cells the ability to respond to protein antigens?
1. Class switch recombination (CSR)
2. Somatic hypermutation
3. Affinity maturation
Why do germinal centers stain darkly on slides?
Because of intense proliferation (this is where B and T cells interact and differentiation and proliferation of B cells occurs).
T or F
Ag sensitivity changes with Class switching?
False

Antigen sensitivity is encoded for in variable regions. In Class Switching, Variable regions are NOT affected! Only constant regions are.
What happens to patients who have "X-linked hyper-IgM syndrome"?
CD40L mutation (located on X chromosome).
- They have a lot of IgM antibodies (because unable to class switch)
- They have decreased CMI response (because CD40L important in that)

*increased susceptibility to infection
T or F
Mutations that occur in the variable region of Igs after class switching occur at a rate that is 100x higher than mutation rates in most genes
True!
This is called somatic hypermutation and is characterized by High-frequency point mutations in H and L chains (increases Ag-binding specificity)
What happens during "affinity maturation" ?
B cells that have undergone somatic hypermutation are given the chance to bind antigen on Follicular Dendritic Cells (FDCs)

Those that bind are selected for (others undergo apoptosis).
How does the body inhibit further antibody production during the decline of the humoral immune response?
This is "Antibody Feedback"

A B cell that has bound antigen has an Fc tail that can be recognized by an Fc receptor on other B cells. When antibody is secreted it can bind to the Fc receptor and this will produce negative signals and block B cell receptor signal transduction.
Which Ig isotype is best at activating complement?

Which complement pathway is activated?
IgM (pentameric) - activates classical complement pathway
Which Ig isotype participates in mucosal immunity and neutralization of microbes in GI and respiratory tracts?
IgA
Which Ig isotype is expressed in Hypersensitivity Type I and Allergic reactions?
IgE
Which Ig isotype is best at opsonizing microbes?
IgG (also activates complement, ADCC mediated by NK cells, and neonatal immunity)
What are the 4 major ways an antibody can eliminate antigens?
1. Neutralization of microbes and toxins
2. Opsonization and Phagocytosis
3. ADCC
4. Activation of Complement
Why are patient's who have undergone splenectomies highly susceptible to disseminated infections by encapsulated bacteria?
- the major defense against encapsulated bacteria is opsonization via antibody
- the spleen is an important site of phagocytic clearance
Cells coated with Ig__ can be killed by NK cells?
IgG
Cells coated with IgE can be killed by ____ cells?
Eosinophilic (kill parasites!)
What is vaccination?
The process of stimulating adaptive immune responses against microbes by exposure to non-pathogenic forms of microbes
What is a conjugate vaccine? Give an example.
An antigen that has been chemically coupled to proteins so that helper T cells are activated and higher affinity antibodies are produced (ex: polysaccharide antigens)

ex: Hib vaccine (haemophilus influenza type B)
What antibody is most effective at neutralizing microbes such as Poliovirus that are natural infections (inhaled)?
IgA

Most important for mucosal immunity because it is made in mucosal lymphoid tissue (MALT) and secreted across epithelia to target microbe in lumen.
What are 3 different means of peripheral tolerance (i.e. stopping fugative, self-reactive T cells)?
1. Anergy (rendering cell inactive)
2. ACID (activation induced cell death)
3. Suppression by Regulatory T cells
What are two mechanisms by which an auto-reactive T cell is rendered anergic (for instance when it escapes to the periphery)?
1. Costimulator-deficient APC (lack of costimulatory cytokines or molecules)

2. Inhibitory costimulation (using a CTLA-4 inhibitory receptor on T cells that binds B7)
What does a T regulatory receptor express and what receptors does it have on its surface?
It expressed Transcription Factor (Foxp2)

IL-2 receptor (requires cytokine activation)
TCR for self antigen (possibly to allow it to recognize other rogue T cells that recognize the same antigen?)
Why do we even need peripheral tolerance for T cells (in other words, how do T cells escape)?
- sometimes a particular self antigen is not abundantly expressed in thymus

- T cells might bind and react to self antigen but at a low enough affinity to slip under the radar
Where does central tolerance occur in:
T cells
B cells
T cell- thymus
B cell- bone marrow

Primary or Generative lymphoid organs
What are two mechanisms of ACID or Activation Induced Cell Death?
1) Fas-Fas Ligand (activated T cell express Fas)

2) Mitochondrial pathway: Lack of costimulatory or cytokines to sustain T cell growth trigger pro-apoptotic proteins
What cytokines are produced by regulatory T cells that suppress T cell proliferation/differentiation?
IL-10 and TGF-beta
What two things can normally happen to B cells that have too strong of a response to self antigen in the bone marrow?
1. Negative selection (B cells apoptosed)

2. They are given a Second Chance: Receptor editing to form new non-self BCR
If auto-reactive antibodies manage to escape to the periphery, how are they inactivated?
Anergy and Death by neglect (from helper T cells, whose signals they need to survive)

Also excluded from lymphoid follicles and apoptose from lack of survival signals (think of them as "outcasts")
Mutations in which genes might cause a risk of autoimmunity?
1. HLA/MHC genes (misrepresent self peptide so self-reactive T cell escapes)

2. Non-HLA genes: ex-
Foxp3 (important for T regs)
Ctla-4 (inhibitory molecule that induces anergy)
Fas/FasL
FcgRIIb- feedback inhibition of B cell
How might environmental exposure to infection/inflammation trigger autoimmunity?
During infection, APCs will produce cytokines and co-stimulatory molecules that activate T cells (awakes sleeping giants = autoreactive T cells)
Describe how "molecular mimicry" may eventually lead to autoimmunity in a susceptible individual?
Antigens can look like self antigen and cells develop ability to attack it.
How do Superantigens work? How might they lead to autoimmunity in a susceptible person?
They do not need to be processed by APCs and presented. They can directly bind and activate T cells, thus cause non-specific T cell activation (and autoimmunity).
What are cryptic antigens and how might they lead to autoimmunity in a susceptible individual?
Cryptic antigens are normal proteins that have undergone modification due to cell damage.

T cells see them as foreign and attack them. This can be a mechanism for autoimmunity.
What is AIRE? Where is it located and what is it's role?
Autoimmune Regulator
It is located in the Thymus (primary lymphoid organ) and controls the expression of self antigens that are normally in other peripheral tissues.
What is the primary cell that participates in tumor rejection?
CTL (CD8+ T cell)
What are oncofetal tumor antigens and give an example?
Proteins that were expressed early in life (in developing fetus) that are later aberrantly expressed and cause immune responses.

Ex: CEA or carcinoembryonic antigen (normally expressed in fetus gut & liver, however in colorectal cancer their levels are elevated)
What is an example of an oncogenic virus that is immunogenic?
Human Papilloma Virus (HPV). Has viral proteins (E6, E7) that serve as antigens to CTLs.

EBV (epstein barr virus) is another example.
Since all nucleated cells express MHC I, can tumors directly induce CTL responses? Why or Why not?
No, because...

1. No co-stimulation by tumor cells
2. Location: naive CD8+ T cells might not be able to access solid tumors (they can only circulate through blood, lymph, lymphoid organs).
What are three different mechanisms by which tumors evade immune recognition by CTLs?
1. No longer express antigen recognized by CTL (Carmen Sangiego)
2. No longer express MHC I molecules
3. Express immunosuppressive cytokines and/or inhibitory molecules
What are some immunosuppressive cytokines and inhibitory molecules that a tumor cell might express to evade a CTL?
CTL-4, PD-1 = inhibitory molecules (tumors may have ligands for these)

TGF-B and IL-10 = imunosuppressive cytokines
What are some mechanisms of cancer immunotherapy (i.e. boosting a patient's immunity to tumors)?
1. Give patients anti-tumor effectors (T cells, Antibodies, etc.)

2. Vaccinate patients against their own tumors

3. Provide appropriate signaling molecules so that tumor-itself can activate T cells

4. Expand T cells in a medium (T cells activated against tumors) and transfer into patient (power in numbers).

5. Generate antibodies specific to tumor growth factors (her2/neu) or angiogenic factors
Define the following transplant type:

Autograft
Allograft
Xenograft
Isograft
Autograft- self tissue is transplanted

Allograft- transplant from other animal of same species (ex: organ transplant)

Xenograft: transplant between species (pig heart into human)

Isograft: transplant between monozygotic twins
What is a graft?
The organ/tissue to be transplanted (from donor)
Why does Ag from a donor's graft produce a more Robust T cell response than, say, an infection?
Infection- not all MHC is presenting foreign peptide (only some peptide is being nibbled up by Dendritic cells and presented)

In graft, the donor cells themselves are presenting the genetically distinct MHC and so T cell is directly activated (ALL MHC's are presenting graft Ag)
What is "direct" vs. "indirect" antigen presentation of a graft cell.

How do they differ in response?
Direct: Graft's donor cells directly present antigen to T cells. CTL cytotoxicity causes graft damage.

Indirect: Graft's antigen is processed and then presented to T cells (like what normally happens). Rejection is mostly CD4+ T helper cell mediated.
What is the time frame for the following graft rejection scenarios:

1. Hyperacute
2. Acute
3. Chronic
1. Hyperacute = minutes

2. Acute = days/weeks

3. Chronic = year
What is the response in a Hyperacute graft rejection and how does it happen?
ANTIBODY Mediated
- preformed Antibodies will attack and activate complement
- thrombus can form against Ag-Ab complexes in vessel wall
- Ischemic Necrosis of graft
What is the response in an Acute graft rejection and how does it happen?
* Principal cause of EARLY graft failure

T cells: CTLs damage endothelial cells, CD4 causes cytokine production that recruit leukocytes and further damage graft

Antibody: classical complement pathway and clotting of graft vessels
What is the response in a Chronic graft rejection and how does it happen?
Chronic Delayed Type Hypersensitivity reaction (DTH). Affects vessel wall. Cytokines stimulate growth of fibroblasts and smooth muscle cells " Graft atherosclerosis"
What are two tests you can do to Match HLA/ ensure that a graft will take?
1. Microcytotoxicity test: Recipient and Donor cells are plated and anti-MHC antibodies are added. You look on the plate for donor cells that have the same profile as recipients (i.e. antibodies should affect the cells in the same way)

2. Mixed Lymphocyte Reaction (MLR)- Plate donor and recipient cells and tag recipient to see if it proliferates. If it does, it is reacting against the MHC of the donor and graft will probably not take.
What do the "A" and "B" or bloodtype A and B refer to?
They refer to terminal sugars on the surface of endothelial cells.
How do you enrich for donor bone marrow cells?
Add GM-CSF which mobilized immune cells from bone marrow, into circulation (makes it easier to collect)
What is GVHD (Graft vs. Host Disease) and what are two types of it the disease?
GVHD is a complication of bone marrow transplantation. Occurs when DONOR T cells react to HOST tissues.

1. acute = within 100 days (3 mo)
2. chronic = 3+ months
What type of hypersensitivity reaction is GVHD (graft vs. host disease)?
Type IV