Major Histocompatibility Complex, aka MHC

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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)

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MHC- I MHC-II
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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 13-18 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

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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

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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

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What are the genetic mechanisms?

• Polygenecity
• Polymorphism
• Co-dominance
• Linkage disequilibrium

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What does the syntenic organization of a
haplotype look like?

• Remember
• polygenecity
• polymorphism
• co-dominance
• linkage disequilibrium
• There are no rearrangements!

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What is polygenecity?

• Humans have DP, DQ, and DR regions specifying ?
  and ? chains of MHC-II.
• Why are these called regions?

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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 Igs
  which are constantly being generated in response
  to new foreign proteins and carbohydrates in the
  environment.
• The loci which specify MHCs 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.