Major histocompatibility complex, essential in antigen-presentation

MHC, a cluster of genes essential to immune functions


Major histocompatibility complex is a large group of genes that carry the genetic code for cell surface proteins, which help display fragments of foreign antigens to cells of the immune system. In humans, these large group of genes, cluster on a region along the short arm of chromosome 6. In other words, MHC is a cluster of genes, all occurring in a particular region on chromosome 6.

Major histocompatibility complex (MHC) and ‘major histocompatibility complex proteins’ or ‘major histocompatibility molecules’ are two distinct things. MHC is the gene complex, containing the genes that code for the formation of MHC ‘molecules’ or ‘proteins’.

The MHC, which occurs on chromosome 6, subdivides into three regions called class I, II, and III regions with each region containing genes of related functions.

Class-I region contains genes that code for proteins (class I MHC proteins) that occur on the surface membranes of virtually all nucleated body cells whereas class-II region contains genes that code for proteins (class II MHC proteins) that occur on the surface membranes of antigen-presenting cells. Genes of class-III region code for other important proteins that both modulate and regulate various aspects of immune function such as complement proteins and cytokines.

Thus, genes of the MHC code for two types of MHC proteins (MHC class-I, and MHC class-II proteins) and other factors that regulate immune functions. Some of the immune regulators encoded by class III genes are cytokines, complement proteins and certain enzymes of the immune system.

MHC proteins, a means of surveillance


There are two important classes of MHC proteins: class-I, and class-II MHC proteins. Class-I MHC proteins occur on the surfaces membranes of virtually all nucleated body cells whereas class-II MHC proteins occur on the surface membranes of antigen-presenting cells.

Since the immune system can only monitor the surfaces of body cells (immune and non-immune), the MHC proteins (both class-I and class-II), being expressed on the surfaces of different body cells allow the immune system to read what is going on inside our body cells. Thus, the immune system of an individual can distinguish healthy host cells from infected ones depending on the substances displayed on the MHC proteins.

Class I, and II MHC proteins help display fragments of antigens to cytotoxic T-cell and helper T-cells respectively. This role is very important because T-cell receptors can only recognize fragments of antigens, which are in complex with MHC proteins. (Recall that B-cell receptors can recognize intact antigens in blood and lymph).

Thus, without MHC proteins, there would be no means of presenting endogenous and exogenous antigens to T-cells. Moreover, without antigen presentation, other aspects of acquired immune response will fail to occur.

Host cells degrade foreign proteins (both exogenous and endogenous) into smaller fragments and display the antigen peptides on MHC proteins. This display function of MHC proteins helps the immune system to distinguish between host cells that are displaying normal self-proteins from those that are displaying harmful foreign proteins.

MHC

Class-I MHC proteins, a means for infected or cancerous host cells to present endogenous antigens to cytotoxic T-cells


Class-I MHC protein occurs on the surfaces of all nucleated body cells. (Red blood cells do not express MHC-I proteins). They display fragments of antigens (abnormal proteins) derived from proteins synthesized right inside host cells.

Host cells synthesize unfamiliar proteins either when an intracellular pathogen infects them or when they become cancerous. Intracellular pathogens (being mainly viruses) subvert normal cellular processes causing infected host cells to produce viral proteins instead of normal proteins. The infected host cells display fragments of the endogenous antigens on MHC-I proteins. Endogenous antigens are foreign proteins produced in host cells when become infected with intracellular pathogens.

In addition, abnormally growing host cells (e.g. tumor cells) also display unfamiliar antigenic peptides on MHC-I proteins.

In summary, when a host cells either get infected by an intracellular pathogen (e.g. virus) or become cancerous, they begin to synthesize abnormal protein molecules, which are unfamiliar to host immune system. In order to inform the immune system that something is wrong, infected or cancerous host cells couple the abnormal proteins they produce to class-I MHC proteins and display the complex on the surface membrane of affected host cells.

Cytotoxic T-cells (bearing receptors for the displayed antigen) recognize fragments of antigens displayed on MHC-I, and attack and destroy the infected host cells. This often prevents the spread of viral DNA and tumors.

Categorically, class-I MHC proteins present antigens to cytotoxic T-cells also called cytotoxic T-lymphocytes (CTLs).

Problem: why do only cytotoxic T-cells recognize antigens displayed on class-I MHC?

Solution: most cytotoxic T-cells are CD8 positive, i.e. they express CD8 glycoproteins on their cell surface. For a T-cell to bind to an antigen displayed on class-I MHC, the CD8 molecules act as co-receptors that must concomitantly bind to its domain on class-I MHC.

Class-II MHC, a means for antigen-presenting cells to present exogenous antigens to helper T-cells


Only APCs express class-II MHC proteins. APCs are special cells of the immune system that capture/pick-up foreign particles and cells digest proteins derived from the pathogen into peptide fragments. In order to inform the immune system about the presence of a pathogen in the body, APCs couple the pathogen-derived antigens to class-II MHC proteins and display the complex on their cell surfaces.

Helper T-cells (bearing receptors for the displayed antigen) recognize the antigen and stimulates B-cells to produce antibodies against the antigen.

Class-III MHC genes code for cytokines, complement and other immune regulators


Genes of class-III MHC region code for a good number of cytokines and several proteins of the complement system. Complement proteins and cytokines are important soluble factors that participate in host defense against pathogens.

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