MHC genes and their inheritance

In this article, I briefly describe MHC genes and their inheritance.

Table of Contents

Major Histocompatibility Complex (MHC)

Vertebrate DNA consists of a large locus known as the major histocompatibility complex (MHC). The MHC locus consists of a cluster of closely linked polymorphic genes coding for cell surface proteins vital for adaptive immunity. Different MHC proteins bind and present different antigenic fragments.

Three classes of MHC molecules can be classified as class I, class II, and class III. The class I and class II MHC molecules share some common features as members of both classes have a similar shape and display antigens to T cells. However, members of both class I and class II vary in their roles. Members of class III MHC do not directly present antigenic fragments to T cells, and they play more varied roles than members of class I and class II.

The MHC is also known as the human leukocyte antigen (HLA) complex in humans and the H2 complex in mice, the most researched model. The MHC is a collection of genes arranged within a long continuous stretch of DNA on chromosome no 6 in humans and chromosome no 17 in mice.

The arrangement of genes differs in humans and mice. However, in both species, the genes are organized into regions encoding three classes of molecules. The genes in these can be classified as classical and non-classical genes.

MHC Classical genes

Classical MHC genes are the most talked about MHC genes and can be divided into class I, class II, and class III genes.

MHC class-I genes

MHC class-I genes were first discovered among three types and are expressed widely in nearly all cell types. Every nucleated cell in humans and mice consists of the protein products belonging to this region of the MHC. The surfaces of nearly all nucleated cells consist of glycoproteins encoded by MHC class-I genes. MHC class I gene products mainly present endogenous(cytosolic) peptide antigens to CD8⁺ T cells.

MHC class-I molecule consists of two chains, the α chain, and the β₂ microglobulin chain. The α chain is more variable than the β₂ microglobulin chain and binds to antigens. The molecules of the α chain are encoded by the H2-K and H2-D genes in mice. Whereas, in human beings, the HLA-A, HLA-B, and HLA-C loci encode the class-I genes.

The molecules of β₂ microglobulin are encoded outside the MHC locus on a separate chromosome both in mice and in human beings. These α chains are known as classical class-I molecules efficient in presenting peptide antigenic fragments to CD8⁺ T cells.

MHC class-II genes

MHC class-II genes are not widely distributed like class-I genes and possess more varied levels of expression. Professional antigen-presenting cells have class-II molecules on their surfaces, which can alert T cells about a certain antigen. MHC class-II genes mainly present exogenous or extracellular antigens to CD4⁺ T cells.

MHC class-II molecules are composed of two polymorphic chains, α, and β, both having a peptide binding site. In human beings, the class-II region of MHC consists of three loci, HLA-DP, HLA-DQ, and HLA-DR.

The coding sequence for both an α chain and a β chain is present within each of these three loci. In mice, there are two loci, H2-A and H2-E, which encode for both α and β chains. In some cases, within a locus, multiple genes are present for individual or both chains.

MHC class-III genes

MHC class III molecule has no structural and functional similarity with class-I and class-II molecules. The class-III gene cluster with an MHC locus is conserved in all species. The class-III region encodes proteins, which play a role in other critical immune functions. The complement components C2, C4, and factor B, various inflammatory cytokines, e.g., tumor necrosis factor, present within the class-III region.

Though the genes in the class-III region are less polymorphic than class-I and II genes, allelic variants of some genes of the class-III region have been associated with certain diseases. One example of this is the polymorphism in the tumor necrosis factor (TNF) gene results in many infectious diseases.

The TNF gene codes for a cytokine that is engaged in many immune processes. Thus, polymorphism in the TNF gene is associated with susceptibility to certain infectious diseases and some autoimmune disorders like Crohn’s disease and rheumatic arthritis.

MHC non-classical genes

The MHC locus also consists of extra genes which encode nonclassical molecules. The nonclassical genes are less diverse, having a restricted tissue expression and a more diverse role in immunity. Non-classical MHC class-I proteins are expressed on specific cell surfaces with specialized functions.

In human beings, the HLA-G class I molecules are present on the fetal cell surface at the maternal-fetal interface. It prohibits the rejection from maternal CD8⁺ T cells by giving protection to the fetus from being identified as foreign. This can occur when antigens from the paternal side start to appear on the developing fetus.

Similar to the class-I region, extra non-classical class-II molecules are encoded inside the class-II region. These non-classical molecules show bit polymorphism and specialized immune functionality.

All antigen-presenting cells express human DM genes and code for HLA-DM, which is a class-II-like molecule. It streamlines the loading of antigenic peptides intracellularly into MHC class-II molecules.

Similarly, another type of class II molecules, e.g., class-II DO molecules, take part in the processing and presentation of antigens. These molecules are limited in expression and found in B cells and subsets of dendritic cells. These are found during certain stages of development and specifically in certain precise locations in the thymus.

It is believed that DO molecules play a role as an intracellular regulator of the processing and presentation of class-II antigens. In the cells expressing both DO and DM proteins, DO proteins may be inhibiting or modifying the function of DM proteins.

MHC genes inheritance in the form of allele

Genes residing in the MHC locus are highly polymorphic. Polymorphism means many alternative forms of individual genes exist inside the population. Each gene of the MHC locus of class I, II, and III lies very close to each other. This arrangement, therefore causes their inheritance to be linked. Therefore, recombination is not possible as genes are not far away from each other.

Inside the mouse H2 complex, the crossover frequency is as low as 0.5%. Thus, crossing over happens only once per two hundred meiotic cycles. So, these genes encoding all the alleles are inherited as a set known as a haplotype. One haplotype from the mother and one haplotype from the father, or two alleles get inherited by the offspring.

In human beings, the offspring carry different alleles from both parents and, therefore, are heterozygous at the MHC locus. The offspring can be homozygous by expressing identical MHC molecules as the haplotypes from both father and mother are identical.

Strains of a species, e.g., in mice when homozygous at the MHC locus for specific alleles, are known as prototype strains. The MHC haplotypes in mice can be written as H2^a, H2^b, etc. The haplotype can be designated by an arbitrary italic superscript after the H2 alleles.

Mice are said to be syngeneic in a traditional inbred strain. However, two strains are said to be congenic if they are bred to be genetically identical at all places except at a single genetic region. This region is located at the MHC locus.

Conclusion

The MHC locus consists of a cluster of closely linked polymorphic genes coding for cell surface proteins. These proteins are vital for adaptive immunity. Three classes of MHC molecules can be classified as class I, class II, and class III. The MHC locus consists of both classical and non-classical MHC genes.

The inheritance of MHC genes takes place in the form of alleles. The genes residing in the MHC locus are highly polymorphic. In human beings, the offspring carry different alleles from both parents and, therefore, are heterozygous at the MHC locus. The offspring can be homozygous by expressing identical MHC molecules as the haplotypes from both father and mother are identical.