Major Histocompatability Complexes

()Map\Tab IMMUNOLOGY (Map/Tab) ADAPTIVE IMMUNE SYSTEM

Structure and Function of MHC Class I

Structure

• MHC class I is expressed on virtually all nucleated cells.
• MHC class I consists of a membrane-associated heavy chain bound non-covalently with a secreted light chain.
  • Heavy chain:
    • Made up of three distinct extracellular protein domains.
      • α1, α2 and α3.
    • The C- terminus is cytoplasmic.
  • Light chain:
    • Known as β2-microglobulin.
    • Similar in structure to one of the heavy chain domains.
    • Not membrane associated.
      • But binds to the α3-domain of the heavy chain.
• The MHC class I domains are structurally and genetically related to immunoglobulin and TcR domains.
  • The outer domains (α1 and α2) are like the variable domains.
  • The α3 domain and β2m are like thrconstant domains.
• MHC class I molecules are folded to form specific 3-dimensional structures.
  • The α1 and α2 domains are folded to produce an antigen-binding groove.
    • This groove can bind molecules of a limited size only.
      • 8-10 amino acids.
      • This limits the size of epitope seen by the T-cell receptors.

Function

• MHC class I molecules bind antigenic peptides derived from within the cell and present these to the T-cell receptors of CD8+ T-cells.
  • E.g. virus-encoded antigen.
• Endogenously produced proteins are produced in the cell cytoplasm.
  • Intracellular pathogens utilise this cellular metabolic machinery for protein synthesis.
  • Many of the proteins synthesised are not used and are re-utilised by the cell.
    • Peptides from these proteins are transported to the Golgi apparatus by specific transporter molecules.
    • These peptides then interact with newly synthesized MHC class I molecules.
• Only MHC class I that is associated with peptide will be expressed at the surface.
  • The immune system is therefore able to see antigen from intracleeular pathogens.

Structure and Function Of MHC Class II

Structure

• MHC class II is expressed mainly on macrophages, dendritic cells and B-lymphocytes.
• MHC class II consists of membrane-associated α and β chains.
  • Each chain is a transmembrane glycoprotein.
  • The extracellular parts of each chain have two Ig-like domains.
    • α1 and 7alpha;2, β1 and β2.
      • The outer domains (α1 and β1) are variable-like.
      • The inner domains (α2 and β2) are constant-like.
• The 3-dimensional structure of MHC class II is similar to MHC class I.
  • The outer domains of the α and β chains fold in a similar way to the α1 and α2 domains of class I.
    • Produce the antigen-binding groove.

Function

• MHC class II molecules bind antigenic peptides and present them to TcR on CD4+ T-cells.
• The antigen-binding groove is larger and more open than that of MHC class I.
  • MHC II can therefore interact with larger peptides.
• MHC class II are present on those cells that have antigen-processing ability.
  • Interact with antigenic peptides originating from an extracellular source.
• After synthesis, MHC class II molecules are transported into special endosomes.
  • These endosomes fuse with lysosomes that contain the digested remnants of phagocytosed microorganisms.
    • The peptides from the lysosome interact with the MHC class II molecules.
      • The peptide-MHC class II complex gets transported to the cell surface.

Interaction of MHC With Antigen

• The MHC molecules do not recognise specific amino acid sequences of antigens.
  • Instead, they recognise particular motifs of amino acids.
• The association of any MHC allele with a peptide may be determined by the presence of as few as two amino acids.
  • However, these determinants must be present within a particular array.
• The actual identity of the amino acids in not important for MHC binding.
  • Instead, the physical and chemical characteristics of the amino acid are vital.
• Interactions of individual amino acids at the head and tail of the peptide-binding groove control the binding of peptides.
  • Are mainly positioned at the floor of the antigen-binding groove, or within the helices facing into the groove.
  • These MHC amino acids associate with amino acids near the ends of the peptides.
    • The intervening stretch of peptide folds into a helix within the groove.
    • Is the target for T cell receptor recognition.

TcR-MHC Interaction

• Only peptide associated with self-MHC will interact with and activate T-cells.
  • T-cells cannot be activated by a peptide on a foreign cell.
  • T-cells will react against foreign MHC molecules.
    • This is the basis of graft rejection.

The Genetics of the MHC

• Different individuals have different critical amino acids within the MHC.
  • I.e. different amino acids that determine peptide binding.
  • This variation is termed MHC polymorphism.
• There are millions of variations in antibodies and TcR.
  • However, with MHC there is very limited variation between molecules.
• MHC polymorphism has been best studied in the human.

In the Human

• Humans express:
  • Three types (loci) of MHC class I molecules.
    • HLA (Human Leukocyte Antigen)- A, B, and C.
  • Three loci of MHC class II molecules.
    • HLA-DP, DQ and DR.
• In the entire human population there are only approximately 50 different variants (alleles) at each MHC class I and class II locus.
  • The variation within MHC class I is entirely on the class I heavy chain.
    • The β2m is invariant.
  • The variation within MHC class II is mainly within the β chains.
• Every individual has two alleles at each MHC locus.
  • One inherited from each parent.
  • Any individual will therfore express two variants at most at each locus.
    • This gives a maximum variability for an individual of:
      • 6 different variants of MHC class I.
        • 2 each of HLA- A, B and C.
      • 6 different variants of MHC class II.
        • 2 each of HLA- DP, DQ and DR.
• Many animal species have fewer loci than the human.
  • E.g. ruminants have no MHC class II DP.

MHC and Disease

• Antigen from a pathogen has to be seen by the host MHC before an efficient immune response can occur.
  • There is therefore a constant evolutionary battle between the host and the pathogen.
    • There is selective pressure on the pathogen to evolve proteins that do not interact with the host MHC.
    • There is selective pressure on the host to continue to recognize the pathogen.
• The consequence of this parallel evolution is that host-pathogen relationships can lead to the selection of particular MHC variants, for example:
  • MHC class II alleles DR13/DR1*1301 are prevalent in Central and Western Africa .
    • Impart resistance to malaria.
  • MHC-DRB1 is prevalent in Western Europe, but rare in the Inuit populations of North America.
    • Associated with the clearance of hepatitis B infection in Western Europe.
    • Inuits have the highest incidence of hepatitis B in the world.
  • In humans there are also strong associations between certain alleles and some autoimmune diseases, for example:
    • Diabetes mellitus.
    • Ankylosing spondylitis.
    • Rheumatoid arthritis.