The expression of MHC genes and diversity between different MHC classes

In this post, I briefly describe the MHC genes, haplotypes, and the diversity between different MHC classes.

Table of Contents

The MHC genes

Vertebrate DNA is marked with a large locus known as the major histocompatibility complex (MHC). It contains closely linked polymorphic genes that code for cell surface proteins. These cell surface proteins are known as the MHC molecules essential for adaptive immune response. After the process of antigenic digestion, peptide fragments are generated, which bind to the MHC molecule. The complex of the antigenic peptide with the MHC molecule is transported to the cell surface.

There are three classes of MHC molecules:

Class I MHC molecules
Class II MHC molecules
Class III MHC molecules

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

In both mice and humans, the MHC genes are organized into regions encoding three classes of molecules, and within these regions, both classical MHC genes and non-classical MHC genes are present.

Classical MHC genes

The Classical MHC genes are the first identified and characterized groups of MHC genes and are categorized into

MHC class I genes: The surface of nearly all nucleated cells express glycoproteins encoded by the MHC class I genes. The MHC class I gene products mainly present endogenous peptide antigens to CD8⁺ T cells.
MHC class II genes: Antigen-presenting cells like macrophages, dendritic cells, and B cells express glycoproteins encoded by the MHC class II genes. These genes mainly present exogenous peptide antigens to CD4⁺ T cells.
MHC class III genes: A set of diverse proteins is encoded by the MHC class III genes, which do not have a direct involvement in presenting antigens to T cells.

Non-classical MHC genes

The additional genes present within the MHC locus secrete the non-classical molecules. The non-classical MHC genes have a more restricted tissue expression, more varied roles, and less diversity in immunity. Specific cell types with more specialized functions express non-classical class I proteins.

The HLA-G class I molecule in humans is present on the surface of fetal cells at the maternal-fetal interface. It helps in inhibiting rejection by maternal CD8⁺ T cells, thus protecting the fetus from identification as foreign. This (identified as foreign) may happen when paternal antigens start to appear on the developing fetus.

The genes within the MHC locus encode the non-classical MHC proteins. These proteins are similar in structure to the class I and class II MHC but show very little polymorphism.

Haplotypes

The MHC genes are highly polymorphic and also very firmly linked with each other. Thus, the set of alleles present within the entire MHC locus is passed down as one unit. This set of linked alleles is referred to as a haplotype. In general an individual inherits one haplotype from the mother and one from the father, or two sets of alleles.

In humans, the offspring are normally heterozygous at the MHC locus, with different alleles from each parent. However, if the maternal and paternal haplotypes are identical, then the offspring are said to be homozygous. Some specific strains of mice are knowingly inbred to be homozygous at the MHC and are designated as prototype strains. This means the strains are homozygous at the MHC locus for precise alleles.

The distinctive MHC haplotype expressed by each prototypic strain is designated by an arbitrary italic superscript after the H2 nomination for the MHC region of mice, e.g., H2^a, H2^b, etc.

Co-dominant expression of MHC molecules

A co-dominant form of expression is exhibited by the genes within the MHC locus. It means both maternal and paternal gene products (both haplotypes) are expressed at a time in the same cells.

Thus, if mating is done between two mice from inbred strains with different MHC haplotypes, the F₁ generation inherits both parental haplotypes and will express all the MHC alleles twice as many as each parent.

Crossing of two inbred mouse strains with different haplotypes

When a mouse homozygous for the H2^b MHC haplotype is crossed with a mouse being homozygous for the H2^k haplotype (Figure 1), the F₁ progeny expresses the MHC proteins of both parental strains on its cells, and it is denoted as H2^b/k. It is said to be histocompatible as its MHC matched with both the parental strains. This explains that the offspring can receive grafts from both parents. However, none of the inbred parental strains can accept a graft from its F₁ offspring as half of the MHC genes will be recognized as ”non-self or foreign” and, therefore, get rejected by the immune system.

Inheritance of HLA haplotypes in a human family

If we take an example of an outbred population like humans, it shows that each individual shows heterozygosity at each locus with the simultaneous expression of all alleles. In a human highly polymorphic HLA complex, the genes are closely linked, and all the alleles are inherited as haplotypes.

In a hypothetical cross between two individuals (one male and one female) having different haplotypes, there is a 25% chance that any two siblings will inherit the same maternal or paternal haplotypes and thus be histocompatible with each other.

Within the HLA complex of humans, though the rate of crossing over is low, still diversity of the loci is observed. New allelic combinations are produced from genetic recombination, and so new haplotypes, such as haplotype R (Figure 2) are produced. The extensive recombinations and other mechanisms cause mutations. The mutations make it hard for two unrelated individuals to have similar HLA alleles. For this reason, transplantation between two non-identical twins is quite difficult, for which even partial histocompatibility in any family member is searched by physicians.

Diversity shown by class-I and class-II MHC molecules

A host cell can respond to different pathogens as a specific MHC molecule can bind different peptides. The MHC region includes multiple genetic loci codes for the same functional proteins. The class-I HLA-A, class-I HLA-B, or class-I HLA-C molecules in humans present peptides to CD8⁺ T_C cells.

CD4⁺ T_H cells get antigenic peptides from class-II HLA-DP, DQ, or -DR molecules. The genes in the MHC cluster are known as polygenic genes. These genes have the same function with a bit of difference in structure.

Diversity shown by class-I MHC molecules

At each MHC gene locus, a heterozygous individual will express the gene products, which are encoded by both the alleles. Thus, it results in the expression of six unique classical class I molecules on each nucleated cell. A cell can express many individual MHC class I molecules. Each can bind with many different peptides, thus allowing the cell to display many different peptides.

The MHC class-II molecules show greater diversity than the MHC class-I molecules. Each MHC class-II molecule consists of two different polypeptide chains encoded by different loci. Both the chains merge to form one class-II binding pocket.

Diversity shown by class-II MHC molecules

When a cross is made between an H2^k mouse and an H2^d mouse, the F1 generation consists of offspring expressing four parental class II molecules. These are identical to their parents. It also includes four new molecules that contain mixed characteristics from both parents, i.e., from the alpha chain of one parent and the beta chain of another parent.

However, a human heterozygous individual expresses six class II molecules identical to the parents and six additional recombinations from alpha and beta chains. Any additional genes from α or β chain within a locus cause an individual to express more class II molecules. Thus, diversity increases, which increases the number of different antigenic peptides to be presented. Thus, it is ultimately beneficial for the organism in fighting infection.

Antigen diversity in MHC molecules

The MHC molecules display different types of peptides and the same diversity of antigens. They are bound by antibodies and T cell receptors as both need to interact with antigens never encountered before. However, the generation of antigen diversity differs in MHC molecules and antigenic receptors on T cells and B cells.

The process of gene rearrangement and the somatic mutations of rearranged genes are responsible for the generation of T cell receptors and antibodies. The generation of T-cell and B-cell receptors, is not fixed as they change over time within an individual. However, a fixed number of MHC molecules are expressed by an individual. So, all these processes collectively raise flexibility within a host to respond to any type of antigenic challenge.

MHC- The most polymorphic in higher vertebrates

The MHC possesses a colossal variety of alleles at each locus and is the most polymorphic in higher vertebrates. Within a species, the vast polymorphism brings in huge diversity too. When the most polymorphic of the HLA class I genes (A, B, and C) is taken into consideration, the theoretical number of potential class I haplotypes in the human population shows more than forty billion in number.

As each haplotype contains both class I and class II genes, there could be nearly 10²³ possible ways of combining both types (class I and class II) of alleles within the human population. As each MHC can bind different peptides, so combining this for individual MHC molecules gives a big advantage to TCRs in engaging with antigens.

According to some research, when MHC polymorphism reduces within a species, it increases the disease susceptibility. Species like captive cheetahs and certain wild cats show quite limited genome diversity and an increased susceptibility to viruses. This may result from a reduction in the number of different MHC molecules. The population of wild cheetahs does not have the same MHC homogeneity and shows less susceptibility to infectious diseases. So, diversity of species at the MHC locus cast an evolutionary survival vantage instead of susceptibility and mortality to diseases.

The boundary of MHC polymorphism

The alleles of the MHC within a species show high sequence divergence. However, it is not sprawled throughout the polypeptide chain. Instead, polymorphism is clustered largely within the α1 and α2 domains of the class I molecules. The same diversity patterns are also seen in the α1 and α2 domains of class II molecules.

The MHC alleles have the polymorphic residues cluster in the peptide binding pocket. It gives the ability of the MHC molecules to interact with a given peptide ligand. This polymorphic cluster around the region of antigen contact is the reason behind the association of the MHC genes with certain diseases.

The diseases linked to specific MHC alleles

People suffering from certain diseases have an expression of HLA alleles in higher frequency when compared to the normal population. The diseases linked to specific MHC alleles can be categorized into certain viral diseases, autoimmune disorders, and different types of allergic reactions.

The association between an HLA allele and a particular disease can be determined by knowing the frequency of that particular allele expressed by the disease-affected individuals. The data can then be compared with the frequency of the same allele in normal individuals in a population. From this comparison, an individual’s relative risk (RR) can be calculated. Low RR values signify a weak interaction between MHC alleles and diseases.

Multiple genes can influence susceptibility, among which only one gene may reside in the MHC locus. Diseases can be developed by multiple genetic factors along with some environmental factors. If there is an association exists between an MHC allele and a disease, it should not be interpreted that the disease is the cause of the allelic expression.

Conclusion

The MHC genes exhibit co-dominant expression patterns. This means any cell expressing that class of MHC molecules transcribes DNA from that specific genetic locus on both paternal and maternal chromosomes simultaneously. The different classes of MHC can be categorized into class I, class II, and class III. The MHC class II molecules show greater diversity than the MHC class I molecules. Each MHC class II molecule consists of two different polypeptide chains encoded by different loci.

The genes within the MHC locus encode the non-classical MHC proteins. These proteins are similar in structure to the class I and class II MHC but show very little polymorphism.

At both individual and specific levels, the class-I and class-II MHC molecules show diversity. Though the MHC alleles within a species show high sequence divergence, polymorphism is clustered largely within the α1 and α2 domains of the class I and class II MHC molecules.