Major Histocompatibility Complex (MHC) Molecule | Microbiology

In this article we will discuss about:- 1. Definition of MHC Molecules 2. Classes of MHC Molecules 3. Structure 4. Function  5. Gene Regulation.

Definition of MHC Molecule:

The term histocompatible refers to the individuals who the same tissues i.e. identical twins. This term is used to determine how identical two unrelated individuals are. In case of two histocompatible individuals, a tissue or organ from a donor (the person giving the organ or tissue) that will not be rejected by the recipient (the patient in whom the tissue or organ is transplanted).

Thus, histocompatibility is the property of having the same or mostly the same alleles of a set of genes called the ‘major histocompatibihty complex’. These genes are expressed in most tissues as antigens to which the immune system makes antibodies.

Major histocompatibility complex (MHC) is a tightly linked cluster of genes present on chromosome 6 in humans (and chromosome 17 in mice) which encodes the MHC proteins. The MHC proteins are present on plasma membrane of almost all human tissue/cells. The MHC proteins participate in intercellular recognition and antigen presentation to T lymphocytes.

Generally, a group of linked MHC genes is inherited as a unit from parents. These linked groups are called haplotypes. MHC genes are polymorphic {i.e. there are a large number of alleles for each gene). Also they are polygenic (i.e. there are a number of different MHC genes). Human MHC molecules are also called human leucocyte antigens (HLA).

In the mid 1930s Peter Gorer (England) established the concept of rejection of foreign tissue due to an immune response to cell surface molecules. This gave the birth to the study of histocompatibility antigens. He identified four types of genes (I to IV) which encode blood cell antigens.

During 1950 George Snell (U.S.A.) pioneered the concept that antigens encoded by the genes took part in the rejection of transplanted tumours. He called these genes as histocompatibility genes. For this work Snell was awarded the Nobel Prize in 1980.

Classes of MHC Molecules:

The MHC genes are organized into three classes I, II and III which express three classes of molecules Classes I, II and III, respectively (Table 22.5). Classes I MHC genes consists of A, B and C gene loci. They secrete glycoproteins which are referred to as Class I MHC molecule. Glycoproteins are expressed on the surface of about all nucleated cells. Class I MHC molecules present the peptide antigens to T_C cells.

The human Class I MHC gene spans about 2,000 kb (about 20 genes) at the telomeric end of the HLA complex, whereas the Class II MHC genes (about 1,000 kb) are located at the centromeric end of HLA. Class III genes (flanked by about 10,000 kb long) located between the two genes.

The DP, DQ and DR region of Class II MHC genes in humans encode the Class II MHC molecules called glycoproteins. They are expressed on antigen presenting cells such as macrophages, dendric cells and B cells, and present the processed antigenic peptides to T_H cells. Class II molecules have specialised function in the immune response.

Both Class I and Class II molecules have common structural features. They have role in antigen processing. In addition, the Class III MHC gene is flanked by Class I and Class II regions and encodes molecules critical to immune function. Class III MHC molecules consist of complement components C4, C2, BF, inflammatory cytokines, including tumour necrosis factor (TNF) and heat shock proteins.

Structure of MHC Molecules:

The Class I molecule is a trans-membrane glycoprotein consisting of two chains: a-chain or heavy chain (of 42 KD molecular weight) non-covalently associated with a light chain called β₂-micro-globulin (molecular weight 12 KD).

The α-chain is organized into three extracellular domains (α₁, α₂, α₃) and a ‘trans-membrane segment’ (hydrophobic) followed by a short stretch of hydrophilic ‘cytoplasmic tail’ (Fig. 22.20A). These are encoded by A, B and C regions of HLA complex and expressed on the surface of plasma membrane of almost all cells except erythrocytes.

Β₂-micro-globulin molecule is expressed by different chromosomes. Association of the α-chain with Β₂-micro-globulin is must for expression of Class I molecules on cell membrane. The α₁ and α₂ form the antigenic-binding cleft located on top of surfaces of molecule.

Class II MHC molecules are also trans-membrane glycoprotein encoded by separate MHC genes. They contain two different α and β chains of 33 and 28 KD, respectively. These two chains are associated non-covalently (Fig. 22.20B).

Further, both chains fold to give two domains (β₁ and β₂ domains in other domain), one is membrane proximal domain and the second is membrane-distal domain. Like Class I MHC molecules, the class II molecules also contain trans-segment and a cytoplasmic anchor segment. Each chain of Class II molecule contains two external domains (α₁ and a₂ in one chain) and β₁ and β₂ domains in other chain.

Function of MHC Molecules:

MHC provides both cell mediated and humoral immune responses, while antibodies react only – with antigens, and most of the T cells recognise antigen only when it gets combined with an MHC molecule. Hence, MHC molecules act as antigen-presenting structure.

The MHC partly determines the response of an individual to antigens of infectious microorganisms. Therefore, it is implicated in susceptibility to disease and in the development of autoimmunity. Recently, it has been explained that the natural killer cells express receptors for MHC Class I antigens. The receptor-MHC interaction result in inhibition/activation.

Both Class I and Class II MHC molecules present the processed endogenous antigen to CD8 T cells. Class II molecules present the processed exogenous antigen to CD4 T cells. Class I molecules identifies mostly all the cells of the body as ‘shelf. Also they induce the production of antibodies which introduced into host with different Class I molecules. This is the basis for MHC typing when a patient is to undergo for antigen transplantation.

Class II molecules comprise of the D group of MHC. They stimulate the production of antibodies. But they are required for T cell communication with macrophage and B cells. Part of T cells receptor recognises Class II molecules on the adjacent cell before cytokine secretion by T cells. This is necessary for immune response.

Both Class I and Class II molecules recognise the microorganisms. They are also involved in the susceptibility of an individual to a specific non-infectious diseases e.g. multiple sclerosis, acute glomerulonephritis, tuberculoid leprosy, paralytic poliomyelitis, etc. The Class III molecules (e.g. C₂, C_4a and C_4b) participate in the classical pathway and factor B in the alternate pathway of the immune responses.

Gene Regulation of MHC Expression:

Regulation of MHC genes has not been studied much. Understanding of complete genomic map of the MHC complex hopefully will accelerate the identification and coding, and regulatory sequences. Transcriptional regulation of the MHC is mediated by both positive and negative elements e.g. MHC II trans-activator (cll TA) and transcription factor (RFX) binds to promoter region of Class II MHC gene.

Any error in these transcription factor causes a type of disease in lymphocytes. Expression of MHC molecules is also regulated by many kinds of cytokines. Interferons and tumour necrosis factor increases the expression of Class I molecules on cells. Interferon-gamma induces the expression of cIITA.

Expression of MHC decreases after infection by certain viruses e.g. hepatitis B virus, and adenovirus 12, cytomegalovirus, etc. Adenovirus 12 causes a decrease in transcription of the transporter genes (TAP1 and TAP2). When these genes are blocked, class I molecules foil to assemble with β₂-micro-globulin.

Decreased level of Class I molecules promotes viral infection. Expression of Class II molecules by B cells is down-regulated by INF-gamma. Corticosteroids and rostaglandins decrease the expression of Class II molecules.