PowerPoint PresentationSlide 2Major Histocompatibility Complex, aka MHCMHC- I & MHC-IIMHC- I MHC-IIThe “cleft”… where processed Ag is presentedWhat are the genetic mechanisms?Slide 8What does the “syntenic” organization of a haplotype look like?What is polygenecity?There are no rearrangements!IMMUNOLOGYBios 328a textbook-based study of immunologySpring 2003http://www.lehigh.edu/~sk08/Courses/Bios328/mainpage.htmMajor 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-IIMHC- I MHC-IIMHC-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 AgProcess Ag is optimally a nonomerMHC-IIAn 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 AgProcessed Ag is optimally 13-18 aa2 & 2 are part of immunoglobulin super familyMicroglobulin (12 kDa) associates non-covalently with 3Microglobulin and 3 are part of immunoglobulin superfamilyMicroglobulin is the only member of the superfamily that does not have a component linking it to a membraneThe “cleft”… where processed Ag is presentedComposed of two alpha helices plus eight beta sheets“Two bananas on a plate”MHC-I: 1-2MHC-II: 1-1Clefts can be superimposed; thus, two genetic solutions to a common needWhat 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 chromosomeWhat are the genetic mechanisms?•Polygenecity•Polymorphism•Co-dominance•Linkage disequilibriumWhat does the “syntenic” organization of a haplotype look like?Remember:polygenecitypolymorphismco-dominancelinkage disequilibriumThere 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 allelesHLA B locus ~110 allelesHLA C locus ~40 allelesThe high level of allelism creates diversity within a species (thus restricting allografting) but does not produce diversity within an