Major Histocompatibility Complex, aka MHC “ A complex of genes encoding cell-surface molecules that are required for antigen presentation to T-cells … ” Fundamentally important: –basis of self / not self distinction –presentation of processed antigen MHC-I ( on nearly all nucleated cells ) MHC-II ( on B-cells, macrophages, dendritic cells )
MHC- I & MHC-II
MHC- I MHC-II MHC-I Heavy chain (alpha) and “microglobulin” (beta two) Heavy is 45 kilodaltons, has three domains + a transmembrane component (40 aa) + a cyto- plasmic tail (30 aa) The three alpha domains are called: 1, 2, & 3 1 and 2 interact to present processed Ag Process Ag is optimally a nonomer MHC-II An alpha and beta chain, 33 kDA and 28 kDa, respecitvely. Chains are non-covalently associated. Each chain has two domains. 1- 1 interact to present processed Ag Processed Ag is optimally aa 2 & 2 are part of immunoglobulin super family Microglobulin (12 kDa) associates non-covalently with 3 Microglobulin and 3 are part of immunoglobulin superfamily Microglobulin is the only member of the superfamily that does not have a component linking it to a membrane
The “cleft”… where processed Ag is presented Composed of two alpha helices plus eight beta sheets “Two bananas on a plate” MHC-I: 1- 2 MHC-II: 1- 1 Clefts can be superimposed; thus, two genetic solutions to a common need
What are the genetic mechanisms? Nota bene: whatever are the genetic mechanisms, they must account for the huge diversity of “haplotypes” “Haplotype”: “the set of alleles of linked genes present on one parental chromosome…” cf. synteny “Synteny”: the association of genes in a distinct region of a chromosome
What are the genetic mechanisms? Polygenecity Polymorphism Co-dominance Linkage disequilibrium
What does the “syntenic” organization of a haplotype look like? Remember: polygenecity polymorphism co-dominance linkage disequilibrium There are no rearrangements!
What is polygenecity? Humans have DP, DQ, and DR “regions” specifying and chains of MHC-II. Why are these called “regions”?
There are no rearrangements! Thus, MHC proteins ( from the “haplotype” ) constitute a life-long cell surface character for any vertebrate. This circumstance is very different from Ig’s which are constantly being generated in response to new foreign proteins and carbohydrates in the environment. The loci which specify MHC’s are polymorphic. Many alleles may exist at a locus: HLA A locus has ~60 alleles HLA B locus ~110 alleles HLA C locus ~40 alleles The high level of allelism creates diversity within a species ( thus restricting allografting ) but does not produce diversity within an individual.