Major histocompatibility complex (MHC)

The major histocompatibility complex (MHC) is a group of genes that code for a series of proteins found on the surface of many cells in the body. Also known as human leukocyte antigens (HLA) within the human body, these proteins help the immune system to tell the difference between self-proteins and foreign proteins. In practice, special white blood cells called T cells interact with MHC proteins to determine whether material found in a particular cell should actually be there. If the material is found to be self, the cell is left alone. If the material is found to be non-self, however, the immune system automatically works to remove the foreign material and kill the cell in question. In this way, the MHC and the immune system work together to protect the body from bacteria, viruses, and other potentially dangerous foreign materials.

Brief History

Scientific understanding of the MHC and how it works developed gradually over a long period. The roots of this development can be traced back to some of humankind’s first observations about the immune system. Specifically, it began with Thucydides, a skilled historian from Athens, Greece. Around 430 BCE, Thucydides observed that people who survived after contracting the plague could subsequently treat other plague sufferers without risk of becoming infected for a second time themselves. Although this observation had little effect at the time, it eventually proved to be a critical step forward. A number of nineteenth-century scientists recognized Thucydides’s ideas as a gateway to modern medicine. In particular, French chemist and biologist Louis Pasteur used the idea of an immune system that could adapt to disease to create an early laboratory-developed vaccine made from an attenuated pathogen to prevent the further spread of disease. Likewise, German physician Paul Ehrlich introduced a Nobel Prize–winning theory that explained how immune system proteins called antibodies interact with toxins and other foreign substances and the important role these interactions play in the body’s ability to fight disease. While breakthroughs like these helped to shed some light on the workings of what would eventually become known as the MHC, there was still much more to learn.

By the twentieth century, organ transplantation was becoming an increasingly common therapeutic procedure, but there was a significant problem: Although it was relatively easy to transplant tissue from one part of an individual’s body to another, transplants between different individuals were often rejected by the recipient’s body. In order to uncover the cause of this rejection, American geneticist George Snell and British geneticist Peter Gorer conducted a series of tests on mice beginning in the 1940s that revealed the truth. Through their efforts, Snell and Gorer discovered a group of genes that was responsible for coding the special proteins that determine whether the body will accept or reject foreign materials. This gene system later became known as the major histocompatibility complex (MHC). Later, French immunologist Jean Dausset identified the human leukocyte antigens (HLA) in humans. Baruj Benacerraf later showed that immune responses are also influenced by genes linked to this system. Continued study of the MHC and HLA has further broadened scientific understanding of the immune system and how living things fight disease.

Overview

The MHC is found on chromosome 6, which is one of the twenty-three pairs of chromosomes that make up human DNA. In total, the MHC is composed of more than 200 different HLA genes. Each individual HLA gene exists in several different forms, known as alleles. Different alleles are expressed on the surface of different types of cells. As a result, the MHC is very diverse. This diversity is both advantageous and disadvantageous. On one hand, it greatly improves the body’s ability to defend itself from a wide range of diseases. On the other hand, it makes transplanting tissue from one person to another a more challenging task because the HLA antigens of donor and recipient must match in order for the transplant to be accepted.

The genes in the MHC are divided into three different classifications: Class I, Class II, and Class III. Class I MHC genes, which are expressed on the surface of virtually every type of cell found in the body, include HLA-A, HLA-B, and HLA-C. These genes primarily serve to present potentially dangerous antigens in cellular immunity, which is a type of immunity driven by T cells. Class I genes play a key role in the rejection of foreign tissue after transplantation. Beyond that, Class I genes are known for being especially polymorphic, which means that each gene has numerous different alleles. Specifically, there are thousands of known alleles for HLA-A, HLA-B, and HLA-C.

Class II MHC genes, which also play a key role in supporting the immune system, include HLA-DP, HLA-DQ, and HLA-DR. Rather than contributing to cellular immunity like Class I MHC genes, Class II MHC genes primarily enable humoral immunity. In this type of immunity, the MHC genes display foreign antigens to helper T cells, which then help B cells produce antibodies. Also, unlike Class I MHC genes, Class II MHC genes are mainly found on antigen-presenting cells that display MHCs on their surfaces.

Class III MHC genes encode molecules involved in inflammation, including some complement proteins. The complement system includes proteins that help the immune system clear microbes and damaged cells from the body. Among other things, the complement system also promotes inflammation during an immune response.

Aside from helping the body fight disease, one of the most important functions of the MHC and its HLA genes and antigens is the key role they all play in the process of transplantation. Although blood, organs, and other tissues can be transfused or transplanted from one patient to another, the success of such procedures is dependent on the patients’ HLA antigens. If the HLA antigens in the donor material match the recipient’s antigens, the material is more likely to be accepted. If the two do not match, however, the recipient’s immune system will identify the donor material as a threat and will seek to neutralize it. This ultimately leads to the rejection of transplanted organs and tissues. To prevent this from happening, patients typically undergo special MHC testing to determine whether available donor material is a match for them prior to having a transplant.

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