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MHC: Role of Major Histocompatibility Complex in Immunity
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During organ transplantation, blood group as well as tissue type is considered. Tissue type refers to a group of proteins on the cell surface with antigenic properties of a person. As the compositions of these proteins are decided by a large number of alleles, these are almost unique to a person. These proteins are called as human leukocyte antigen (HLA) system or MHC proteins. MHC is major histocompatibility complex, composed of large cluster of genes located on the short arm of chromosome 6. As it indicates, this is important for the compatibility of tissues during transplantations. On the basis of structural and functional differences, these genes are classified in to three classes, two of which class I and class II genes correspond to human leukocyte antigen (HLA) genes which play an important role in regulating genetic response in tissue transplantation between unrelated individuals. MHC molecules play a major role in antigen presentation during immune response.

HLA class one and class two genes encode the cell surface proteins that play a critical role in the initiation of immune response and specifically in the presentation of antigens to lymphocytes, which cannot recognize and respond to an antigen unless it complexes with a HLA molecule on the surface of an antigen presenting cell. Many hundreds of different alleles of HLA class one and class two genes are known.

The class one genes; HLA-A, HLA-B, HLA-C encode proteins that are integral parts of plasma membrane of all nucleated cells. A class I protein consists of two polypeptide subunits. Peptides derived from intracellular proteins are generated by proteolytic degradation by a large multifunctional protease; the peptides are then transported to the cell surface and held in a cleft formed in the class one molecule to display the peptide antigen to cytotoxic T cells. Class I molecule is made up of two polypeptide subunits; a variable heavy chain encoded within MHC and nonpolymorphic polypeptide, β2 microglobulin that is encoded by a gene outside MHC, in chromosome 15.

Class II region composed of several loci such as HLA-DP, HLA-DQ, HLA-DR that encode integral membrane cell surface proteins. Each class two molecule is a heterodimer, composed of alpha and beta subunits which are encoded by MHC. Class II molecules present peptides derived from extracellular proteins that had been taken up into lysosomes and processed into peptides for presentation to T cells.

According to the traditional system of HLA nomenclature, the different alleles were distinguished from one another serologically. An individual’s HLA type was determined by seeing how a panel of different antisera or reactive lymphocytes reacted to his or her cells. These antisera and cells were obtained from hundreds of multiparous women who developed immune reactivity against paternal type I and type II antigens expressed by their fetus during the course of their pregnancies. If cells from two unrelated individuals show the same pattern of reaction in a typing panel of antibodies and cells, they are considered to be of the same HLA type and the allele represented would be given a no such as B27 class I HLA B.
When MHC class I and class II genes were identified and sequenced, a single HLA allele initially defined serologically were shown to consist of a multiple alleles defined by different DNA sequence variants even within the same serological allele. Most of the DNA sequence variants change a triplet codon and therefore amino acid in the peptide is encoded by that allele. These alleles are codominant. Each parent has halotypes and expresses both.

Most of the autoimmune conditions that are associated with abnormal immune response directed against one or more antigens thought to be related to variation in the immune response resulting from polymorphism in immune response gene. In some cases, it’s due to a particular MHC allele being present at a very high frequency on chromosomes that also has a disease causing mutation in another MHC gene. Perhaps different polymorphic alleles result in structural variations in these cell surface molecules leading to differences in the capacity of proteins to interact with antigen and T cell receptor in the initiation of an immune response and affects critical processes as immunity against infections and self-tolerance to prevent autoimmunity.

Some HLA alleles are found commonly while others are rarely or never seen. It results from a situation referred as linkage equilibrium which is a complex interaction of many factors such as low rates of meiotic recombination, in small physical distance between HLA loci, environmental influences and historical factors Because acceptance of transplanted tissues largely correlates with degree of similarity between donor and recipient HLA halotypes, the donor for bone marrow or organ transplantation should be ABO compatible and HLA identical sibling of the recipient. The differences in the distribution and frequency of all the alleles and halotypes within the MHC are the result of complex genetic, environmental and historical factors play in each of the different populations.
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