The MHC has been divided into three regions on the basis of structure, function and alloreactivity of the gene products, which-are: 1. Class – I at the telomeric ends 2. Class – II at the centromeric ends 3. Class – III, which is located between class – I and II regions.
The classic class I and II genes code for the human leukocyte antigen (HLA), often referred to as histocompatibility or transplantation antigen (described above), while the non-classic genes encode non-HLA products with various immunologic functions.
Other genes with no obvious functions in the immune system have also been mapped to the MHC because defects in such genes include the clinical syndromes of haemochromatosis, congenital adrenal hyperplasia and olivopontocerebellar ataxia.
Class – I genes:
Serologic HLA typing has permitted the recognition of three highly polymorphic class – I genes loci that encode the heavy chains of the HLA – A, B and Cw molecules. More recently, molecular analysis of this region has identified additional non classic Class -1 genes which are HLA – E, F and G, whose protein products have similar structures to HLA – A, B and C, but a more restricted tissue distribution.
Similarly the class – 1 pseudogenes like HLA – H, J, K and L are also identified. The HLA – A, B and C antigen’s (glycoprotein) proton part (which is about 12 KD Molecular Weight) is encoded on chromosome 15. The nomenclature of individual class – I alleles -depend on whether they are identified and defined by serology or nucleotide sequence analysis.
Class – II genes:
The MHC class – II molecules are cell surface glycoproteins of which the protein part consists of two chain a and P, which are encoded by the class – II A and B genes in the MHC. There are at least 7 A genes and 16 B genes which can be divided into:
(a) Functional genes
(b) Pseudogenes
(c) Genes of unknown status.
The classic class – II molecules are HLA – DR, DQ and DP which are encoded by the DRA, DRB, DQA, DQB, DPA and DPB genes. The other expressed genes includes DNA, DOB, DMA and DMB. The number of genes in the DR subregion varies depending on the haplotype.
All haplotype carry a single a-chain gene DRA and 2-5 β chain genes, but only one or two of these are expressed, while the others are pseudogenes. It has also been found that there are high polymorphism occurs in the class – II molecules and which is mainly due to 3 hypervariable regions in the α1 and β1 domains encoded by the second exons of the genes.
Class – III genes:
The MHC class – III regions contains genes that encode serum proteins involved in the effector functions of the immune system. These include components of the complement system that mediate cytotoxicity, phagocytosis and inflammation following exposure to antigen- antibody complexes and the inflammatory mediators, tumor necrosis factor (YNF) α and β.
Other immunoregulatory molecules encoded by the class – III regions of the MHC may include three proteins of the heat shock protein Hsp 70 family, Hsp 70-1, Hsp 70-2 and Hsp 70-Hom which have been predicted to serve a variety of immune functions, including protein folding and intracellular chapteroning and may play a part in antigen processing. Several novel expressed genes in the MHC, to which functions have not yet been attributed, may also ultimately be implicated in the immune system.
MHC and Disease Susceptibility:
Because of the important roles played by the products of the MHC genes in the immune system, it is not surprising that these genes, have an important influence on immune disorders.
These disorders can be divided mechanistically into two types:
1. Autosomal recessive immune deficiency caused by genetic defects that aborgate the synthesis of MHC gene products.
2. MHC associated disease concerns genetic susceptibility to a large number of disorders that involve MHC alleles which are also present in the general population.
The most commonly occurring MHC associated” diseases are:
(a) Autoimmune disease
(b) Insulin dependent Diabetes Mellitus
(c) Adult Rheumatoid arthritis
(d) Juvenile Rheumatoid arthritis
(e) Systemic Lupus Erythematosus
(f) Lupus Nephritis
(g) Autoimmune Hepatitis.