Major histocompatibility complex

The major histocompatibility complex (MHC) is a group of polymorphic genes consisting of 30 units (still identified), located on the short arm of chromosome 6 (in mice on chromosome 17). The most known encode proteins expressed on the cell membrane that have the function to be recognized by T lymphocytes, but also contains genes for other important peptides such as 21 hydroxylase, the fractions of complement C4B, C4A, BF and C2, the chaperone protein HSP70 (Heat Shock Proteins) and genes of the TNF family (Tumor Necrosis Factor).

The typical gene products of the MHC complex are proteins that, in nucleated infected tissue cells, bind molecules typical of the pathogen and expose them on the membrane. They thus function as antigens that make infected cells visible to T lymphocyte receptors. In fact, while the products of MHC-I genes are antigens directly involved in the phenomenon of rejection, those derived from MHC-II are active in the phenomena of cellular cooperation that occur within the immune response.

In humans the MHC takes the name of Human leukocyte antigen (HLA). This system of histocompatibility is formed by molecules located on the cell surface that act as antigens: in contact with the immune system of a subject, they generate an immune response because they are recognized as foreign. The HLA system is the basis of rejection in transplantation. If the cells of the transplanted tissue do not have the same HLA antigens as the recipient (i.e. the tissue is not HLA-compatible), the tissue is recognized as foreign, offensive, and rejected. For this reason, by means of a procedure called tissue typing, before the operation it is ascertained that the two subjects (donor and recipient) are HLA-compatible.

MHC proteins are able to develop the rejection reaction, because each animal of a given species contains genes whose sequence is different from that of other individuals (the only transplants that do not give rejection are those between identical twins). There are two classes of MHC molecules, but the mechanisms by which they present antigen on the surface of cells is very similar. Each MHC molecule has in the part that exposes outside the cell membrane a deep cavity in which it can bind the peptide that constitutes the antigen; in normal cells these peptides come from proteins of the organism itself.

However, when foreign molecules are present and the MHC complex presents them on the surface, the immune system understands that the cell has been infected. Foreign peptide-MHC complexes are recognized by T-cell receptors that, as we mentioned, have a structure similar to that of the membrane-bound antibody molecule presented on the surface of B lymphocytes. When a receptor of a T lymphocyte binds to the peptide-MHC complex it begins its action to kill the infected cell or, if it is presented on the surface of a B lymphocyte, to make it produce the specific antibody.

The MHC molecules are produced inside the cell as long chains of amino acids, but to reach the final conformation they must bind to the peptide that they will present on the surface, which acts as the nucleus of aggregation. The peptide-MHC complex then migrates to the surface to present this molecule for its recognition. The genes encoding for MHC proteins represent the most variable population in the human genome, and this variability allows our organism to survive a large number of pathogens. On the surface of cells, coupled to the T-cell receptor and MHC molecules, there is another set of recognition molecules called CD-4 and CD-8 that increase the precision of the immune response and coordinate with the T-peptide-MHC receptor complex. Lymphocytes presenting the CD-4 molecule are, for example, the target of HIV.

When T helper lymphocytes are activated they secrete proteins called lymphokines which have specific receptors on the surface of the target cells. We know several types of lymphokines and the most important family is represented by interleukins, which stimulate the growth of T cells and the production of antibodies by B lymphocytes. Lymphokines are also involved in some of the body’s hypersensitivity reactions.

The activation, maturation, and differentiation processes that result from antigen encounter and coordination between B and T cells occur in the lymphatic system, and once B lymphocytes are activated and specialize in the production of a single antibody, they are called plasma cells and are found in the bloodstream. Maturation of B lymphocytes also produces memory cells that retain the memory of previously encountered antigens, preserving variable regions of antibodies that have proven useful. These cells, which remain in the body throughout life circulating in the bloodstream, allow for a rapid response to the same type of infection.

Discovery and name origin

The first descriptions of the MHC were made by British immunologist Peter Gorer in 1936. MHC genes were first identified in inbred mice strains. The discovery of MHC in mice is the result of studies on transplant rejection carried out in the 1940s by George Snell. At that time it was already known that transplantation of tissues in different animals caused rejection, which did not happen between identical twins.

Clarence Little transplanted tumors across differing strains and found rejection of transplanted tumors according to strains of host versus donor. George Snell selectively bred two mouse strains, attained a new strain nearly identical to one of the progenitor strains, but differing crucially in histocompatibility—that is, tissue compatibility upon transplantation—and thereupon identified an MHC locus. Snell showed that a single gene region is responsible for rejection and called it major histocompatibility locus. In particular, Snell analyzed the H-2 region bound to antigen II. The vision of recombinations within the locus allowed to understand that this region contained several genes all involved in rejection and took the name of major histocompatibility complex.

Later Jean Dausset demonstrated the existence of MHC genes in humans and described the first human leucocyte antigen, the protein which we call now HLA-A2. Some years later Baruj Benacerraf showed that polymorphic MHC genes not only determine an individual’s unique constitution of antigens but also regulate the interaction among the various cells of the immunological system. These three scientists have been awarded the 1980 Nobel Prize in Physiology or Medicine for their discoveries concerning “genetically determined structures on the cell surface that regulate immunological reactions”.

The first fully sequenced and annotated MHC was published for humans in 1999 by a consortium of sequencing centers from the UK, USA and Japan in Nature. It was a “virtual MHC” since it was a mosaic from different individuals. A much shorter MHC locus from chickens was published in the same issue of Nature. Many other species have been sequenced and the evolution of the MHC was studied, e.g. in the gray short-tailed opossum (Monodelphis domestica), a marsupial, MHC spans 3.95 Mb, yielding 114 genes, 87 shared with humans. Marsupial MHC genotypic variation lies between eutherian mammals and birds, taken as the minimal MHC encoding, but is closer in organization to that of nonmammals. The IPD-MHC Database was created which provides a centralised repository for sequences of the Major Histocompatibility Complex (MHC) from a number of different species. The database contains 77 species for the release from 2019-12-19.

As for humans, research was carried out by the team of Jean Dausset and Jan van Rood to better understand how people who had received numerous transfusions or transplants possessed antibodies that recognized donor cells. It was discovered that these cells expressed proteins that were recognized by the antibodies and were called Human Leukocyte Antigens (HLA).

Subsequent analysis showed that the protein structures of H-2 and HLA are identical. It was concluded, therefore, that genes that cause rejection are present in all mammalian species, and were called MHC genes. This appeared strange for many years because transplantation is not a physiological process, and it would not make sense to have genes that regulate it. Almost twenty years after the previous experiments, the team of Baruj Benacerraf and Hugh McDevitt discovered that their importance is much more relevant and concerns the inability to synthesize specific antibodies against certain peptides.