Major histocompatibility complex

• Major Histocompatibility Complex (MHC)


  Also called transplantation antigens
• HLA

  Human leukocyte antigens, the MHC antigens of humans
• 1. H - 2 antigens

  The equivalent MHC antigens of mouse
• MHC molecules forms

  • Class I
  • Class II
• MHC gene products were identified as responsible for graft rejection
• Essential role of HLA antigens

  Induction and regulation of the immune response and defence against microorganisms
• Physiologic function of MHC molecules

  Presentation of peptide antigen to T lymphocytes
• The MHC complex resides in the short arm of chromosome 6
• The overall size of the MHC is approximately 3.5 million base pairs
• Class I gene complex loci


  • A
  • B
  • C
• Class II gene complex loci

  • DP
  • DQ
  • DR
• Class III region


  Not part of the HLA complex but located within the HLA region
• Class III antigens


  Associated with proteins in serum and other body fluids (e.g., C4, C2, factor B, TNF)
• Class I MHC molecules

  Contain two separate polypeptide chains: heavier alpha chain and lighter beta chain
• The carboxyl end of a chain resides inside the cell while the amino end projects on the surface of the cell
• Alpha chain

  Coded by the MHC genes and has three globular domains: al, a2, and a3
• B2-microglobulin


  Encoded by a gene on another chromosome
• CD8


  Binds the a3 domain of MHC class I
• Both alpha chain and beta2-microglobulin are members of the Ig superfamily
• The a3 domain is non-covalently associated with the beta2-microglobulin
• Peptide-binding groove

  Formed between al and a2 helices with beta-pleated sheet as its floor
• A peptide of 8-10 amino acids long can be presented in this groove
• The greatest variability in amino acids or polymorphism occurs in the al and a2 sequences that line the wall and floor of the groove that binds the peptides
• The immunoglobulin-like region of the a3 domain is constant and shows no variation
• Importance of the highly conserved region of a3

  CD8 molecules present on CD8 T lymphocytes bind to this region
• MHC Class II Molecule

  Comprises two non-identical and non-covalently associated polypeptide chains (alpha and beta)
• Both alpha chain (34 kDa) and beta chain (28 kDa) are MHC-encoded and polymorphic
• With the exception of the al domain, all domains are stabilized by disulfide bridges
• Peptide binding groove in MHC Class II

  Formed between al and beta1 domains with a beta-pleated floor
• The greatest polymorphic variability in the amino acids is in the groove of MHC Class II
• Peptides associated with class II MHC are 13-25 amino acids long
• CD4

  Binds to beta2 domain of class II MHC molecules
• Class I antigens expression

  • All nucleated cells
  • Antigen presenting cells
• Cytokines, especially interferon gamma (IFN-y), increase the level of expression of class I and class II MHC molecules
• HLA typing


  Also described as "tissue typing"
• Sero-logic methods

  • MLR/MLC
  • PCR
• Histocompatibility genes are inherited as a haplotype
• Each individual inherits a maximum of two alleles for each locus
• They are codominantly expressed
• The maximum number of class I and class II MHC gene products expressed in an individual is six each