MHC General Characteristics

• Large complex of linked genes with related function

MHC in Humans

• Expression of Class I and II
• Presentation to T_H and Tc
• Disease Association

• There are 50,000 - 100,000 MHC molecules on a typical cell
• Most 'normal' MHC molecules are occupied by self peptides

Structure of  Class II

• Made up of a heterodimer (α and β chains)
• Present to T_H cells
• Highly polymorphic genes (huge # of alleles)

Class II MHC molecules contain two different polypeptide chains

33 kDa α and 28 kDa β

They are membrane bound glycoproteins that contain external domains, and transmembrabe domain and a cytoplasmic domain

External domains consist of α 1 and 2 as well as β 1 and 2

This cleft is large enough to bind a peptide of 13-18 amino acids

Structure of  Class I

• Class I molecules consist of a 45 kDa α chain associated with a 12 kDa β2 microglobulin molecule
• Present to Tc cells
• The α chain is a transmembrane glycoprotein encoded by the genes within the A, B and C regions (Humans)
• β2 microglobulin is encoded on a different chromosome and is required for expression of the MHC class I molecule on cell membranes
• α chain has 3 domains 1,2 and 3
• α 1 and 2 domains form the peptide binding cleft
• This cleft is large enough to bind a peptide of 8-10 amino acids
• Tumor Cells: in an attempt to evade death they have stopped expressing β2 M, therefore are unable to express MHC class I and will not be able to be presented to Tc cells.

Both class I and II MHC molecules can display a huge # of peptides
 

There is no specificity as to what is displayed, rather what fits in the cleft

Expression of Class I MHC

Since the MHC alleles are codominantly expressed, a heterozygous individual expresses on its cells the gene products encoded by both alleles at each MHC locus

Ex

From parents you would inherit B1 C1 A1 - Mother
                                                      B2 C2 A2 - Father

 Mouse H-2

• The expression of so many Class I molecules allows each cell to display a large number of peptides in the peptide binding cleft of its MHC molecule
• Most variation exists within the peptide binding region

Expression of Class II MHC

• Because each of the class II MHC molecules is composed of two different polypeptide chains, which are encoded by different loci, a heterozygous individual expresses not only the parental class II molecules but also molecules containing the α and β chains.

Ex

What are possible combinations for the Class II molecule?

DPα1β1
DPα1β2
DPα2β1
DPα2β2

So there is a huge number of receptors possible!

Thus there is a enough heterogeneity in class I and II to account for the almost infinite # of Ag

MHC expression

1. Type I     all nucleated cells
2. Type II    B, M0, dendritic cells, thymus epithelial

Haplotype

• a set of alleles of linked genes present on one parental chromosome
• a set of genes that determine different antigens but are closely enough linked to be inherited as a unit
• the observed patterns (various combinations) of alleles for the genes in a particular gene
  
   

Disease Association

• The diseases associated with particular MHC alleles include autoimmune disorders
• The association between the HLA alleles and a specific disease may be determined by looking at the frequency of the HLA alleles expressed in a particular person afflicted with the disease.
• Compare to the frequency of this allele in the general population.
• Relative risk can then be calculated.