Major Histocompatibility Complex


Major Histocompatibility Complex Definition

Download PDF
Bookmark added to your notes.
View Notes

The major histocompatibility complex (MHC) is a large gene cluster on vertebrate DNA that codes for cell surface proteins required by the adaptive immune system. MHC molecules are the name for such cell surface proteins. 

Since it was identified through the study of transplanted tissue compatibility, this locus has been assigned its name. Later research found that tissue rejection owing to incompatibility is indeed an experimental artefact masking the true function of MHC molecules, and that is to connect an antigen extracted from self-proteins or pathogens and display that one on the surface of the cell for identification by T-cells.

Leukocytes, also known as white blood cells (WBCs), communicate with other leukocytes and body cells via MHC molecules. The MHC establishes organ donor viability and also autoimmune disease susceptibility by cross-reacting immunisation. Protein molecules from the host's phenotype or other biologic entities are constantly synthesised and degraded in a cell. A small peptide (a molecular portion of a protein) named an epitope is shown on the cell surface by each MHC molecule. Self-antigens are proteins that prohibit an organism's immune system from attacking its very own cells.

Discovery of MHC Major Histocompatibility Complex

In 1936, British immunologist Peter Gorer published the first description of the MHC. MHC genes were first discovered in inbred mouse strains. Clarence Little transplanted tumours into various strains and discovered that transplanted tumours were rejected based on host versus donor strains.  George Snell specifically bred two mouse strains, resulting in a new strain that was virtually identical to one of the progenitor strains but varied crucially in histocompatibility (tissue consistency after transplantation), and thus established an MHC locus. 

Later, Jean Dausset discovered MHC genes in humans and identified the first human leukocyte antigen, which we now refer to as HLA-A2. Baruj Benacerraf demonstrated a few years later that polymorphic MHC genes not only establish an individual's special antigen composition but also control the function of the immune system's different cells. The Nobel Prize in Physiology or Medicine was awarded to these three scientists in 1980 for their findings involving "genetically determined complexes on the cell surface that control immunological reactions."

In 1999, a group of sequencing centres from the United Kingdom, the United States, and Japan released the first completely sequenced and annotated MHC for humans in Nature. Since it was a mosaic of multiple people, it was referred to as a "virtual MHC." In the same issue of Nature, a much shorter MHC locus from chickens was reported. The development of the MHC has been observed in many other animals, including the grey short-tailed opossum (Monodelphis Domestica), a marsupial, whose MHC spans 3.95 Mb and contains 114 genes, 87 of which are shared with humans.

Major Histocompatibility Complex Proteins

MHC Class I: 

  • Both nucleated cells, as well as platelets, express MHC class I molecules—in other words, all cells except red blood cells. Killer T cells, also known as cytotoxic T lymphocytes, are presented with epitopes (CTLs). CD8 receptors, as well as T-cell receptors (TCRs), are expressed by CTLs.

  • When a CTL's CD8 receptor binds to an MHC class I molecule, and the CTL's TCR matches the epitope inside the MHC class I molecule, the cell is conditioned to die through apoptosis. 

  • As a result, MHC class I plays a role in mediating cellular immunity, which is a key mechanism for combating intracellular pathogens like bacteria or viruses, which include bacterial L types, bacterial genus Rickettsia and the bacterial genus Mycoplasma. HLA-A, HLA-B, and HLA-C molecules make up MHC class I in humans.

MHC Class II: 

  • MHC class II are being represented conditionally by any cell type, but it is most commonly found on "trained" antigen-presenting cells such as macrophages, B cells, and, in particular, dendritic cells. 

  • An APC picks up an antigenic protein, processes it, and then restores a molecular fraction of it—the epitope—to view on the APC's surface, which is bound to an MHC class II molecule. 

  • Immunologic structures such as T-cell receptors (TCRs) may identify the epitope on the surface of the cell. The paratope is the molecular region that connects with the epitope.

CD4 receptors and TCRs are located on the membranes of helper T cells. Whenever the CD4 molecule of a naive helper T cell docks to the MHC class II molecule of an APC, the TCR might reach and attach the epitope coupled inside the MHC class II.

Major Histocompatibility Complex Function

Below Mentioned Are the Major Histocompatibility Complex Function:

  • MHC is a tissue-antigen that helps the immune system (specifically T cells) to recognise, bind to, and accept itself (auto recognition). MHC also serves as a chaperone for intracellular peptides that are complexed with MHCs and introduced as potential foreign antigens to T cell receptors (TCRs). MHC interacts with TCR and its co-receptors to improve antigen linking sensitivity and selectivity, as well as signal transduction effectiveness, for the TCR-antigen interaction.

  • The MHC-peptide complex is essentially an auto-antigen/alloantigen complex. T cells should accept the auto-antigen after binding but activate when exposed to the alloantigen. When this theory is violated, illness arises.

  • Antigen Presentation: MHC molecules bind to both T cell receptors and CD4/CD8 co-receptors on T lymphocytes, and the antigen epitope retained in the MHC molecule's peptide-binding groove interacts with the TCR's variable Ig-Like domain to activate T cells.

  • Autoimmune Reaction: Certain MHC molecules are more likely to cause autoimmune disorders than others. A strong example is HLA-B27. While it is uncertain how developing the HLA-B27 tissue-type raises the risk of ankylosing spondylitis and other inflammatory diseases, pathways including abnormal immune response or T cell induction have been proposed.

  • MHC molecules in combination with peptide epitopes are basically ligands for TCRs in tissue allorecognition. T cells are activated when they bind to the peptide-binding grooves of some MHC molecule that they haven't been taught to identify during positive selection in the thymus.

Major Histocompatibility Antigens

Two Classic Pathways Are Used to Process and Present Peptides:

  • In MHC class II, phagocytes such as macrophages and premature dendritic cells phagocytose entities into phagosomes, which fuse with lysosomes, whose acidic enzymes cleave the uptaken protein into a variety of peptides (though B cells show the more general endocytosis into endosomes). A certain peptide exhibits immunodominance and loads onto MHC class II molecules through physicochemical dynamics in molecular structure with the specific MHC class II variants carried by the host, encoded in the host's genome. These are transported to the cell surface and externalised.

  • MHC class I, any nucleated cell presenting cytosolic peptides, mainly self-peptides derived from protein turnover and defective ribosomal products. Such proteins degraded in the proteasome are loaded onto MHC class I molecules and shown on the cell surface during viral infection, intracellular microorganism infection, or cancerous transformation. T lymphocytes can detect a peptide that is present in 0.1 per cent to 1% of MHC molecules.

FAQ (Frequently Asked Questions)

Q1. What is the Significance of the MHC Restriction?

Ans. MHC restriction is especially critical for self-tolerance, as it ensures that our immune system does not attack us. The association of TCRs and the peptide-MHC complex is important for the immune system's defence against foreign antigens.

Q2. What does MHC Have to Do With Autoimmune Diseases?

Ans. The current theory for this connection would be that disease-associated MHC molecules bind autoantigens [HN7] that have been engaged in the disease's pathophysiology. This leads to an immune response to the autoantigen induced by peripheral T cells, as well as autoimmune sequelae [HN8].