MHC

Question 1

Case study!

Answer 1

Caprine arthritis encephalitis virus (CAEV)
-retrovirus
-some affected & some unaffected
-affected = carry one or both of MHC alleles: Be1, Be14

Question 2

Describe the activation of T cells.

Answer 2

*main function of T cells = protect body against intracellular pathogens & activate other cells (macrophage & B lymphocytes)
-T cell require activation before becoming effector cells
-activation via interaction of T cells w APCs (dendritic, macrophages, B cells)
>interaction mediated by receptors on T cell & special proteins on surface of APCs
*role of presenting antigen to T cells via MHC on APCs

Question 3

Describe the history of MHC.

Answer 3

-discovered as a locus containing gene responsible for graft rejection
-recognition of a graft as self/foreign is inherited
-genes responsible for survival/rejection of graft = MHC
-animals w MHC haplotypes may not respond to stimulation w particular antigens
-originally found on WBCs = leukocyte antigen
*MHC of mice = H-2 & MHC of rates RT1

Question 4

Describe the 3 classes of gene loci on each MHC cluster.

Answer 4

Class I = receptor for endogenous antigen found on nucleated cells
Class II = receptors for exogenous antigen found on APCs
Class III = mixed group of proteins (incl complement components)

Question 5

Describe Class I MHC molecules.

Answer 5

-highly polymorphic (class Ia, Ib, Ic)
-class Id = less polymorphic & located outside of MHC on diff chromosome
-# of class Ia varies in diff species
-not all are functional (mice only 2 or3) & humans (A,B,C functional, rest are pseudogenes

Question 6

Describe Class II MHC molecules.

Answer 6

-3 paired loci
>primates: DPA & DPB, DQA & DQB, DRA & DRB
-genes for a chain are A , & b chains are B
-some but not all are polymorphic

Question 7

Describe Class III MHC molecules.

Answer 7

-encode proteins w diff functions which dont function as APCs
-proteins have other functions in the innate immunity (ex. complement proteins)

Question 8

Describe the MHC complex genetics.

Answer 8

-individuals have 2 sets of MHC (one maternal/one paternal derived chromosomes)
>each nucleated cell express 6 diff MHC I genes/antigens (A,B,C)
-MHC genes are codominantly expressed
-class II genes = greater diversity bc diff a & b chains pair to give diff class II products
-chromosomal DNA containing MHC is inherited in its entirety (rarely combinations occur)
*1 in 4 change that 2 offspring share the same MHC type

Question 9

Describe a haplotype.

Answer 9

set of MHC alleles on a chromosome

Question 10

Describe the role of MHC in adaptive immunity.

Answer 10

-transplantation
-antigen presentation
-MHC class I & II = main antigen presentation molecules
1. MHC class I on all nucleated cells (not found on RBCs, gametes, neurons, or trophoblasts)
>present peptide antigens to CD8+ cytotoxic T lymphocytes
2. MHC class II expressed on APCs
>present antigen to CD4+ T lymphocytes (helper)
*MHC Class III dont do antigen presentation

Question 11

Describe the structure of MHC class I molecule.

Answer 11

-MHC class I = heterodimer
>a chain (a1, a2, a3)
>b2-microglobulin chain
>bound peptide
-stable expression of MHC class I = requires all 3 components
*each MHC I molecules has:
1. extracellular domain = makes antigen binding groove
>most variable part
2. immunoglobulin like extracellular domain
3. transmembrane region
4. cytoplasmic region
*8-10 amino acids

Question 12

MHC class I molecule (picture).

Answer 12

-a1 & a2 = variable region
-a3 = CD8 binding region
*T cell coreceptor CD8 binds to non variable region a3 of MHC I

Question 13

Describe the structure of MHC class II molecule.

Answer 13

-a (a1, a2) & B (B1, B2) chains
-peptide binding groove = a1 & B1
-stable expression = 2 chains + bound peptide
*>13 amino acids

Question 14

Describe the outcomes of antigen presentation through MHC molecules. (Picture)

Answer 14

Question 15

Describe the characteristics of peptide-MHC interactions.

Answer 15

-each class I or II MHC has one peptide binding area that binds one peptide at a time
-each MHC can bind diff peptides
-MHCs have a broad specificity for peptide binding in contrast to the T cell receptors

Question 16

Describe an example of peptide binding of T cells VS MHC.

Answer 16

-T cell recog peptide presented by one MHC
-diff peptide binds to same MHC = inhibits presentation of peptide that the T cell recog
-peptides that bind to MHC share features that promote this interaction
-MHC of an individual dont discriminate between microbial peptides & peptides from proteins
*if self peptides are being presented, why dont ppl get autoimmunity?
>no T cells to bind to antigen
>no T cell helpers to support the reaction bc they only recognize foreign

Question 17

Describe the regulation of MHC expression.

Answer 17

-MHC expression increases in the presence of cytokines during innate & adaptive immune responses
>ex: IFNa, IFNb, or IFNy increase MHC I expression

Question 18

Describe what increases MHC II expression.

Answer 18

-IFNy increases MHC II expression on macrophages & dendritic cells
-recognition of pathogens by dendritic cells (PAMPs) through TLR
-cytokines by CD4 helper T cells
-macrophages increase expression of MHC II in the presence of IFNy secreted by NK cells

Question 19

Describe MHC molecules & disease.

Answer 19

*MHC regulates immune response
-foreign antigenic peptide doesnt fit MHC = doesnt stimulate immune response
-MHC I & II are polymorphic, each allele can bind to a set of diff antigenic peptides
-more variety in animals MHC = more antigens it can respond to
-heterozygous animals express more alleles & bind more antigenic peptides
-homozygous has less variety & less likely to generate immune response to certain antigenic peptides

Question 20

Describe the optimal # of MHC genes.

Answer 20

-balance between need to respond to microbial antigen & need to avoid autoimmune disease

Question 21

Describe how MHC can be used in diagnostics.

Answer 21

-changes in expression of MHC proteins during disease
-define polymorphism in class I & II to determine resistance to disease