Classes

MHC I

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

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

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

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

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

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

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

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

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