MAJOR HISTOCOMPATIBILITY COMPLEX

 MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)

MHC describes a collection of genes that in human represents about 0.1% of the whole genome

 

MHC LOCATION

¢  Situated on the short arm of chromosome 6.

¢   Many of the genes in MHC are involved in immune function

¢  In human MHC -human leukocyte antigen (HLA system)

¢  HLA molecules are designated with greek letters α and  β  to describe the structure of polypeptide chain,

Structure of HLA

HLA consists of 3 major classes

¢  Class I

¢  Class II

¢  Class III

¢  Genes in HLA are designated using capital italic letters (A, B, C and D).

          

 

                                         

            MHC Class I molecules includes

¢  HLA –A,

¢  HLA- B

¢  HLA –C

¢  The class I heavy chain consists of 3 extracellular domains –α₁ (N-terminal)α₂  and α₃

¢  Joined to a polymorphic heavy chain glycoprotein (44 kDa) that bind non-covalently to β₂-microglobulin

¢  α1 and  α2 domain form the antigen binding groove

¢  α₃ domain is structurally homologous to Ig  constant region domain (c)

¢  α₃ contains a site that interacts with CD8 on cytotoxic T-cell

¢    β domain is an invariant  molecule called β₂-microglobulin (the gene is on chromosome 15)

¢  Once α and β chains are assembled, they present peptide antigens to T-lymphocyte

 

HLA II

¢  The human MHC II is located in HLA –D

¢  Class II molecules-

¢  HLA DP,

¢  HLA DQ,

¢  HLA DR

¢  It encodes at least 6α  and 10β chains for MHC class II molecules

¢  Are formed from 2 glycoproteins , an  α chain (34kDa) and a β chain (29 kDa) both encoded in the HLA region

HLA CLASS 11 STRUCTURE

The α2 and β2 domain (class II) are similar to the class 1 α3 domain and β2 microglobulin, possessing structural xteristics of Ig constant domains

 

The DR sub-region

¢  The DR sub-region contains

1.  One α chain  gene (DRA)1 therefore, all HLA-DR molecules have the same α chain

2.  9 β genes –DR β genes (DR β 1-9)

v  5 are non-functional pseudogenes (DR β 2, 6, 7,8 and 9)

v  4  are functional β chains genes (DR β 1, 3, 4 and 5)

 Each of the 4 functional β chains genes encodes a distinct β chain which can combine with the single invariant α chain to form 4 HLA molecules

¢  In HLA –DR molecules, the difference are due to DR β genes (they determine the DR type)

DQ region

¢  DQ region contain 2 pairs of genes for the α and β chains.

¢  One is a pair of pseudogenes,

¢  the other pair, Functional one is DQα1 and DQ β1, encode the α  and β chain

¢  the DQ β chain bears the majority of the Polymophism/diversity

¢  DP region – contains 2 sets of α and β chain genes, one is a set of non-expressed pseudogenes, the other DPα1 and DPβ1 encodes the α  and β chains that form the expressed DP molecules. DP β chain is polymorphic.

 

Tissue distribution of HLA molecules

Class I molecules are expressed on the surface of virtually all cells except for mature erythrocytes and trophoblast cells

2. Class II molecules are only expressed on the surface of MQ, monocytes, follicular dendritic cells and B lymphocytes (APC)

3. Cells which only express class I may be induced to express class II molecules and to upregulate the no. of MHC class I molecules, if induced by interferons & TNF ,

4. Regulation of MHC expression helps in eradication of intracellular viral infection and generation of auto-immune disease

¢  In MQ –only DR molecules are expressed

B lymphocytes, all are expressed but DR is exposed in a higher density than DQ or DP.