MHC/HLA Structure, Function and Genes

Question 1

Major Histocompatibility Complex

Answer 1

Cluster of genes located on a single chromosome that code for cell-surface molecules that present antigen to T cells
Histocompatibility gene products are responsible for transplantation rejection
MHC molecules expressed by an individual influence the antigens to which the individual’s T cells can respond
Located in H-2 complex in mice and HLA complex in humans
Class 1, 2, 3

Question 2

Class 1 MHC

Answer 2

Coded for in H-2 K and D regions in mice and HLA A, B and C regions in humans
Present in nearly all nucleated cells, present to CD8+ cytotoxic T cells
Polymorphic 45kDa transmembrane peptide alpha chain that is non-covalently linked to an invariant 12kDAbeta2 micro globulin molecule
Alpha chain has 3 globular domains, hydrophobic sequence (membrane anchor) and short hydrophilic sequence
Alpha1 and alpha2 domains form a cavity that is occupied by antigen as a linear peptide
Alpha3 domain is highly conserved and interacts with beta2 microglobulin as well as the CD8 coreceptor on cytotoxic T cells
Peptide contact is by H bonds

Question 3

Class 2 MHC

Answer 3

Immune responsiveness to exogenous antigens
Coded for the H2 IA/E region in mice and HLA DP/Q/R region in humans
Expressed primarily on antigen presenting cells (to CD4+ helper T cells)
Polymorphic 33kDa alpha and 28kDa beta transmembrane peptide chains which associate by non covalent interactions
Alpha and beta chains have 2 external globular domains, hydrophobic membrane anchor and short hydrophilic cytoplasmic tail
Alpha1 and beta2 domains form antigen binding cleft able to hold peptides of 13-18aa
(A2 and B2 are proximal to cell surface)
H bonds

Question 4

Class 3 MHC

Answer 4

Soluble gene products that are associated with immune responses (complement proteins, TNF alpha/beta) but are not directly involved in T cell recognition of antigens

Question 5

MHC polymorphisms

Answer 5

Differences in aa sequences of alpha1/2 domains of MHC1
Differences in alpha1 and beta1 domains of MHC2
Multiple allelic forms of MHC molecules generated by mutations
Ensures enormous number of antigenic peptides can be presented to T cells

Question 6

MHC haplotypes

Answer 6

Denote the set of allelic forms of H2 (MHC1/2) genes expressed by a particular type of mice
Haplotype is designated by a subscript: H2a
or superscript

Question 7

MHC1 expression

Answer 7

Regulated by transcription factors
On most nucleating cells
Highest level on lymphocytes
Lowest level on muscle cells and neural cells
Neurons lack all together

Question 8

MHC2 expression

Answer 8

Regulation by transcription factors
Expressed constitutively on professional antigen presenting cells (macrophages increase upon activation)
Epithelial cells and endothelial cells can be induced to express

Question 9

IFN-gamma

Answer 9

Able to increase MHC1/2 expression by cells

Question 10

Determinant selection model

Answer 10

Different allelic forms of MHC2 differ in their ability to bind processed antigen

Question 11

Holes in the repertoire model

Answer 11

T cells bearing T cell receptors that recognize foreign antigens that closely resemble self-antigens have been eliminated during thyme development

Question 12

Reduction in MHC polymorphism

Answer 12

May predispose species to ideas by limiting the dance of processed antigen that can interact with MHC molecules
High level of polymorphism is advantageous since is provides broad range of antigen-presenting MHC molecules