Introduction
The major histocompatibility complex is genetically encoded molecules that help the body produce an immune response to various antigens. They decide whether an antigen is histocompatible and produces the required immune response. They are present in all nucleated cells. In clinical scenarios, they are essential as they are the principal mediators for an organ transplant rejection.
What Is Histocompatibility Complex?
The major histocompatibility complex (MHC) is located on chromosome 6 in humans. It contains more than two hundred genes in humans. It is also called the human leucocytic antigen (HLA) system. They are an essential part of the immune system. They help the T lymphocytes identify the cells that have ingested infectious microorganisms.
What Are the Different Types of MHC Molecules?
Two types of significant compatibility complex molecules are involved in the immune response called Class 1 and Class 2. A, B, and C are three unique loci codes for Class 1 MHC molecules.
On the other hand, Class 2 MHC molecules are coded by loci called DR, DQ, and DP.
Genes of all major histocompatible complexes are codominant (can express themselves independently).
Hence all alleles code for a specific molecule to express itself on a cell surface.
How Was the Major Histocompatibility Complex Discovered?
The major histocompatibility complex was discovered while studying transplant acceptance and rejection in mice. In 1954, Jean Dausset and Jan van Rood described the same genetic complex and called it Human Leukocytic Antigen (HLA). It was based on the presence of antibodies in people who had undergone blood transfusions multiple times. These antibodies were particularly against antigens present in leukocytes. Gradually, the two classes of MHC molecules were also discovered and named MHC Class 1 antigens and MHC Class 2 antigens. The class 1 antigens were expressed on all nucleated cells, including the platelets (except the central nervous system cells).
On the other hand, the class 2 antigens are expressed on antigen-presenting cells (APC). Antigen-presenting cells include B lymphocytes, dendritic cells, macrophages, monocytes, Langerhans cells, endothelial cells, and thymic epithelial cells. These studies helped to understand the different classes of major histocompatible complex molecules before preparing a patient and a donor for an organ transplant. The studies in this area revolutionalized transplant practices. It helped to get more insight into the development of various diseases, like autoimmune diseases. It also influenced genome medicine and genetic population studies.
What Are the Characteristics of MHC?
There are three regions in the major histocompatibility complex - class I, class II and Class III. Genes are coded for molecules HLA-A, -B, and -The Class I region codes C. HLA-DR, -DQ, and –the Class II region codes DP. The Class III region codes proteins of the complement system and TNF family genes. Class I and II regions' primary functions are to bind peptide antigens and their exhibition so that antigen-specific T-lymphocytes recognize them. The peptide antigens related to HLA Class I molecules are identified by CD8+ T cells. On the other hand, HLA class II molecules are identified by CD4+ T cells.
The most polymorphic gene cluster in the entire human genome is in the human leukocytic antigen system. The IMGT/HLA Database has reported 9,154 HLA alleles up to date. When the alleles of polymorphic Class I and Class II are compared, it is seen that the nucleotide substitutions are concentrated in the exons that encode the peptide-binding groove and the site of interaction with the T Cell receptor (TCR). Polymorphism in Class I and Class II affects the amino acids in the peptide binding groove. Hence their binding specificity can be altered. However, the more open structure of the HLA class II peptide binding groove and the longer length of peptides allows greater flexibility in peptide binding.
What Are the Functions of MHC in the Immune System?
The primary role of the MHC is in antigen presentation. The MHC molecules display peptide fragments for recognition by the appropriate T cells. This essential process in the immune system helps destroy the pathogens that invade.
The MHC plays a vital role in identifying foreign bodies and not destroying the body's normal cells. Another critical function of the MHC is tissue allorecognition (identifying a foreign tissue of the same species). This is an essential factor in organ transplants.
How Are Gene Histocompatibility Inherited?
The histocompatibility genes are inherited as a group, one from each parent. This type of inheritance is called haplotype inheritance. Hence, the HLA genes are codominant expressed. A human (who is heterozygous ) inherits two haplotypes, one maternal and one paternal. Each haplotype contains three Class I (A, B, C) and three Class II (DP, DQ, and DR) loci. A maximum of two alleles for each locus is generally inherited. The number of class I HLA gene products that can be maximum expressed in an individual is six. Hence, each chromosome is found twice. This is called a diploid cell. The normal tissue of an individual will contain twelve HLA antigens. Generally, haplotypes are inherited intact. Hence, antigens coding different loci can be found together. However, there can sometimes be a crossing-over between two parental chromosomes. This results in new recombinant haplotypes.
What Is Linkage Disequilibrium?
Due to the proximity of the genes in the HLA complex, there can be preferential associations between different loci. Hence, these loci are inherited as haplotypic blocks with a minimum chance of genetic recombination. As a result, some combinations of alleles occur more often or less often in a given population than what is expected from a random formation of haplotypes. This is known as linkage disequilibrium.
What Is MHC Restriction?
A remarkable feature of the complex is its polymorphism. This is important in the antigen recognition by the T cells. The T cell recognizes an antigen as a peptide bound by a particular allelic variant of an MHC molecule. It would not recognize the same peptide when bound to another MHC molecule. This is called MHC restriction.
Conclusion
The major histocompatibility complex consists of genetic loci linked to each other. They code for proteins that are involved in antigen presentation to the T-lymphocytes. The MHC restriction is a critically important feature of the immune system. Each MHC molecule differs from each other by multiple amino acid substitutions. These variations are based on peptide-binding sites and adjacent regions, which make direct contact with the T-cell receptor.
