What is Major Histocompatibility complex (MHC) or Human Leukocyte Antigen( HLA)?
• Cluster of highly polymorphic genes present in short arm of chromosome .
• Product of which is associated with various functions in immune response particularly in rejection or acceptance of foreign tissue in a host.
• They are alloantigen.
• The Major Histocompatibility complex (MHC) is referred to as the Human Leukocyte Antigen( HLA) complex in humans
• During 1950 it was recognized that people who had multiple blood transfusion or repeatedly pregnant had antibodies in their serum against a new surface glycoproteins on leucocytes from other members of the population.
The antigen was named as Human Leukocyte Antigen( HLA) . Later it was realized that these Human Leukocyte Antigen( HLA) molecules are target of cellular immunity. And they are the main targets of cellular immune reactions that cause rejection of the solid organ transplantation. They are the major barrier to histocompatibility – the ability of tissue transplants from one person to be accepted by other person.
MHC encodes three major classes of molecules
• Class I MHC genes encode glycoproteins expressed on the surface of all nucleated cells except spermatozoa & trophoblasts, platelets.
• Class II genes encode glycoproteins expressed on APCs ( MQ, dendritic cells, B cell)
•Class III genes encode secretory proteins like complement component (C2, C4, Factor B and α TNF) , molecules involved in inflammation.
Major Histocompatibility complex (MHC) polymorphism
• Class I MHC molecules encoded by A,B, C loci.
• Class II MHC molecules encoded by DP, DQ, DR regions.
• A person usually inherits two copies of each gene locus so carries total of six I and six II class loci.
• Multiple of each locus may persist in human population
• There are at least 151 HLA –A alleles, 301 HLA- B alleles and 282 HLA- DRβ alleles. Diversity of this type is called
Allelic polymorphism and the MHC genes are the most polymorphic gene.
[The expression of nonclassical class I HLA-G on the cytotrophoblast at the fetal metarnal surface has been implicated in protection of the fetus from being recognized as foreign and from being rejected by maternal Tc cells.]
The alleles are “Codominantly expressed”
• Each set of allele is referred to as Haplotype. An individual inherits one haplotype from the mother and another haplotype from the father.
• The alleles are “Codominantly expressed” that is both maternal and paternal gene products are expressed in the same cell.
• MHC polymorphism benefits humanity ? Because it increases the likelihood that at least some individuals will be able to present antigens from any new pathogens , thus helping to ensure the survival of the whole population.
• MHC is also known as HLA as because they are found in high concentration on lymphocytes & other WBCs.
• Peptide antigens associated with class I MHC molecules are recognized by CD8+ cytotoxic T cells.
• Class I MHC recognized endogenous antigens. They include –
a. viral proteins produced during viral replication
b. proteins produced by intracellular bacteria such as Rickettsiae and Chlamydia during their replication
c. proteins that have escaped into the cytosol from the phagosome of phagocytes such as antigenpresenting cells
d. tumor antigens produced by cancer cells
e. self peptides from human cell proteins
MHC class I
• The major function of the class I gene products is presentation of peptide antigens to Tc cell
MHC class II
• MHC-II molecules recognize exogenous antigens. Exogenous antigens enter from outside the body such as bacteria, fungi, protozoa, and free viruses
• MHC-II bind exogenous peptides and present them to TCR on CD4+ T lymphocytes.
Functions of Major Histocompatibility complex (MHC)
• Self versus nonself discrimination in the initiation & effector phase of immune response.
• Restricted cell to cell interactions involving suppressor T cells.
• Associated with some diseases.
• Contains genes for TNF α & TNF β.
• Associated with graft rejection.
Biologic effects of Major Histocompatibility complex (MHC)
• It is necessary for humoral and cell mediated immune response
• Associated with rejection of transplant tissue
• Antigen is presented in association with MHC for immune response
• Polymorphism in MHC is important for survival of the species.
Regulation of Major Histocompatibility complex (MHC) expression
• Cytokines : IFN α,β,γ and TNF increases the expression of class I MHC on cells
• IL-4 increases expression of class II molecules by resting B cell
• MHC expression is decreased in some viral diseases like CMV, HBV, Adenovirus 12 etc