Immunology 3 - lectures 10-12

Question 1

How is immune system dysregulation responsible for atopic dermatitis?

Answer 1

1) Normal Th1/Th2 balance is altered to favor Th2 response.
2) Increase Th2 leads to increased levels of IL4 and IL5, increase in IgE antibodies, increase in eosinophils and activated mast cells.

Question 2

What is frequency-dependent selection?

Answer 2

individual with rarest allele has the best chance to survive an infection in an epidemic.

Question 3

What is heterozygote advantage?

Answer 3

individual with more MHC structures can present more, different pathogen peptides.

Question 4

What is a haplotype?

Answer 4

genes contributed by one parent.

Question 5

What pockets on MHC class I molecules confer the main peptide binding specificity?

Answer 5

B and F pockets allow for complementary interactions with amino acids at position P2 and P9 in the peptide.

Question 6

How do MHC alleles regulate immune responsiveness?

Answer 6

MHC alleles influence the number of peptides in a protein that can be recognized.

Question 7

How many different peptides can a given MHC class I molecule typically bind?

Answer 7

2,000-10,000 different peptides per cell.

Question 8

How do cytosolic viral peptides from within infected cells get loaded only class I while peptides from endocytosed bacteria get loaded only onto class II?

Answer 8

Separate pathways, Class I peptides are from those synthesized in the cytosol; Class II proteins are from those degraded in lysosomes from endocytosed organisms.

Question 9

How does peptide processing change in an immune response?

Answer 9

IFN-gamma secreted by NK, CD8 and CD4 T cells leads local cells to up-regulate the synthesis of proteasomal immunosubunits which change proteasomal specificity to make hydrophobic peptides with greater affinity for MHC pockets.

Question 10

Why is it important that MHC class I molecules without beta-2 micro globulin and peptide are unstable?

Answer 10

Prevents MHC I molecules from taking up pathogens from extra-celullar space and thus being targeted for destruction.

Question 11

What is the role of TAP proteins in peptide presentation?

Answer 11

TAP proteins allow peptide fragments from cytoplasm to leak into the ER so they can be loaded onto MHC class I molecules.

Question 12

How do MHC class II molecules avoid loading endogenous peptides in the endoplasmic reticulum?

Answer 12

a chaperone known as the invariant chain (Ii) blocks the class II peptide binding groove. The invariant chain contains a recognition sequence that traffics nascent MHC II to acidic endosomal compartment for Ii degradation and exogenous peptide loading.

Question 13

How is the invariant chain removing from MHC class II molecule so that it can bind exogenous peptide?

Answer 13

In the acidic endosome, Ii is degraded to CLIP (Class II-associated invariant chain peptide) by cathepsins. HLA-DM then catalyses the removal of the CLIP protein.

Question 14

How many MHC class I molecules are expressed on the surface of each cell, and what molecular combination accounts for this diversity?

Answer 14

six different types (HLA-A, B, C from each parent)- each unique HLA molecule binds the same beta-2 microglobulin.

Question 15

How many MHC class II molecules are expressed on the surface of each cell, and what molecular combination accounts for this diversity?

Answer 15

10 different types:

1) unique HLA-DRB1 from each parent binds with HLA-DRA (one allele in population) accounting for 2 MHC class II molecules.
2) HLA-DQA and HLA-DQB inherited from each parent combine to form 4 unique MHC class II molecules
3) HLA-DPA and HLA-DPB inherited from each parent combine to form 4 unique MHC class II molecules.

Question 16

What is the ‘Autoimmune Regulator’ gene and what is its importance?

Answer 16

Highly expressed gene in thymic epithelium, codes for a transcription factor that induces ectopic self expression of enzymes found particularly in pancreas, retina and ovaries. Enables T cell repertoire to recognize (and eliminate) more self-recognizing TCRs in the thymus during development.

Question 17

What 2 signals are necessary for successful T cell activation in the LNs?

Answer 17

1) TCR crosslinking (TCR and CD4 proteins bind MHC class II protein + antigen on APC).
2) CD28 protein on naive T cell must bind B7.1 or B7.2 proteins expressed on dendritic cells after the DC encounters a ‘danger’ signal vial TLR, NLR or RLR.

Question 18

What are the three T-cell intrinsic mechanisms for self-tolerance in the periphery (after thymic development)?

Answer 18

1) anergy due to lack of co-stimulation: TCR recognizes MHC but APC doesn’t present co-stimulation, T-cell goes to sleep)
2) ignorance: some self proteins are only expressed in walled-off locations, eg. CNS, so TCRs never find their peptides.
3) clonal deletion: persistant triggering in absence of costimulation leads to activation-induced cell death.

Question 19

What are the three cellular signals that mediate activation-induced cell death?

Answer 19

1) fas is upregulated late during T cell activation, fas-fasL interactions lead to T cell death.
2) Late in T cell activation (maybe day 4 or 5), CTLA-4 is upregulated, binds to CD86 with an 100x greater affinity than CD28, has an ITIM in its tail, putting a break on proliferation (but doesn’t cause death).
3) T cell upregulates PD-1, a homologue of CD28, inhibits T cell activation as antigen is cleared, favors cell death (unregulated within hours of activation, effects as antigen is cleared).

Question 20

What are the major cell markers for Tregs discussed in this class, what signal do they need to remain T-regs, and what proteins do they produce constitutively unlike other T cells?

Answer 20

CD4+/CD25+
Require IL-2 to maintain regulatory phenotype and survival.
Constitutively express CTLA-4 and PD-1 without inducing apoptosis.

Question 21

What are the targets of Tregs?

Answer 21

CD4+ and CD8+ T cells, B cells, macrophages, NK cells, mast cells - suppress other cells.

Question 22

What is the decisive event in Treg cells of thymic origin?

Answer 22

Activation of FoxP3, a Treg transcriptional program regulator.
This occurs after TCR is triggered by self antigen during negative selection (alternative to cell death).
FoxP3-deficient subjects have no CD4+/CD25+ T-regulatory cells.

Question 23

What is the proposed mechanism for how FoxP3 controls T-reg cell fate?

Answer 23

FoxP3 represses TCR-triggered IL-2 transcription, induces CTLA-4 and CD25 transcription.

Question 24

What signals cause CD4+ cells in the periphery to become induced T-regs?

Answer 24

TGF-beta, IL-2 and suboptimal TCR stimulation (inflammatory cytokines such as IFN-gamma, IL-4, IL-6, IL-17 inhibit conversion of naive T cells to Tregs, but this inhibition is itself inhibited by RA, particularly in the gut, allowing for more iTregs to be produced).

Question 25

How do pathogens enter Peyer's Patches in the gut?

Answer 25

Via M cells, which take up antigen by endocytosis and phagocytosis. On the BL side of M cells, antigen is bound by dendritic cells.

Question 26

How do activated T cells home to the lamina propria of the intestinal epithelium?

Answer 26

Activated T cell expresses alpha4:beta7 integrin and CCR9 homing receptor. Gut epithelium expresses MAdCAM-1, which binds alpha4:beta7 and CCL25(TECK) for CCR9. MAdCAM-1 expressed in other mucosal sites, meaning T cells primed in GALT can recirculate as effector cells to other mucosal locations "common mucosal immune system."

Question 27

How does IgA get into the lumen of the gut?

Answer 27

1) IgA-secreting cell releases IgA, which attaches to poly-Ig receptor on BL membrane of epithelial cell, causing it to traffic across the cell and be secreted attached to a 'secretory component.'

Question 28

What are the three functions of the SIgA complex in the gut, and why is it unique in terms of the immune response its pathogen-binding causes?

Answer 28

1) neutralizes toxins and pathogens in lumen of gut. 2) Can bind and neutralize antigens in internalized endosome. 3) Can export toxins from lamina propria that it picks up on the way to being secreted. IgA does NOT activate complement pathway or trigger inflammatory response.

Question 29

Where are the three places lymphocytes are found in the gut?

Answer 29

1) intraepithelial lymphocytes 2) lamina propria lymphocytes 3) GALT

Question 30

What immune role do intestinal epithelial cells play?

Answer 30

1) secrete mucus 2) Have TLRs, RLRs, NLRs. 3) Secrete anti-microbial peptides. 4) transmit IgA antigens to the lumen.

Question 31

How does oral tolerance work?

Answer 31

dendritic cells in the lamina propria take food to mesenteric lymph nodes. These DCs produce TGF-beta and RA, induce T-cells to become tRegs. Expand in the gut and circulate to create systemic lymph nodes.

Question 32

How do epithelial cells in the gut cause an immune response?

Answer 32

TLRs, NOD1 and NOD2 recognize PAMPs, express inflammatory cytokines, chemokines, recruit and activate neutrophils, macrophages and dendritic cells.

Question 33

What is the difference in signaling between an immunogenic and a tolerogenic DC?

Answer 33

tolerogenic secretes IL-10, creates tReg with T cell with which in synapses. immunogenic secretes IL-12, activates T cell with which in synapses. .

Question 34

What are the three mechanisms by which commensals help resist pathogens?

Answer 34

1) direct inhibition (eg. change gut pH, killing pathogens) 2) nutrient/receptor competition - sheer numbers 3) stimulation of immune defenses: eg. IgA is induced by gut bacteria. without resident bacteria, very little IgA).