The history of the major histocompatibility complex
Emma Rhule investigates how we came to discover the MHC
Many major scientific discoveries are the result of work by many researchers, often separated by both geography and time. The discovery of the major histocompatibility complex (MHC) and its vital role in the vertebrate immune system is no exception.
As early as 430 BCE, the Athenian philosopher and historian Thucydides noted that a person who had survived infection with the plague could tend to others infected by the disease without contracting the illness a second time.
In the 19th century, several scientists built upon this knowledge of an immune system that could adapt based on prior exposure to a disease. Louis Pasteur (see ‘The history of vaccination’) developed the first vaccine to use a live attenuated (weakened) strain of the pathogen, and Paul Ehrlich (see ‘The history of antibodies’) proposed a theory to explain how antibodies react and interact with antigens, earning him a Nobel Prize. But still, there were vital elements of the immune system picture that were missing.
These gaps were particularly noticeable in the field of organ transplantation. The large number of casualties from World Wars I and II, many of whom sustained life-changing injuries, drove research into how tissue or organs could be transplanted from one individual to another. Successful examples of transplanting material from one part of an individual’s body to another part, such as moving skin from the thigh to the nose, date back centuries. However, attempts to transplant tissue and organs between different individuals had largely ended in failure.
Snell, Gorer, Dausset and the MHC
The work of George Snell, an American mouse geneticist, took science one step closer to solving the problem of transplant failure. Earlier research by Clarence Little had shown that tumour tissue transplanted between genetically distinct mice was rejected. This is because the tissues of the donor and recipient were incompatible.
Working with British geneticist Peter Gorer and a large number of selectively bred mouse strains, Snell worked out that a group of closely related genes, which they named the major histocompatibility complex (MHC), was the cause of the rejection. The prefix ‘histo-’ is used in medicine to mean tissue – it comes from the Greek histos, which means ‘loom’ or ‘web’.
Inspired by Snell’s work in mice, the French immunologist Jean Dausset looked for, and found, the MHC in humans. Located on human chromosome 6, the proteins encoded by the genes he found present foreign antigens on the surface of cells, which stimulate an immune response. He called the set of genes the human leukocyte antigen (HLA) – they are the most extensively studied of all the vertebrate MHC genes.
Benacerraf and immunological memory
Baruj Benacerraf, a Venezuelan-born American immunologist, demonstrated that genetic factors determine an individual’s immune response. He discovered the immune response genes that were later found to code for a type of MHC molecules known as class II. These are involved in the presentation of bacterial proteins.
Class II MHC molecules also play a role in the process that stimulates the production of memory B cells. These cells help our immune system to remember past infections and respond stronger and faster if we encounter the same pathogen again. (For a reminder on how the immune system works, see our colour poster.)
The combined work of Snell, Dausset and Benacerraf led to them being awarded the 1980 Nobel Prize in Physiology or Medicine for their independent discoveries of “genetically determined structures on the cell surface that regulate immunological reactions”.
Their work, as well as further discoveries by other scientists in the 1950s, made widespread organ transplantation possible. Donors and recipients could be matched to see if they were compatible, thereby dramatically decreasing the risk of rejection following transplantation.
Zinkernagel and Doherty
In contrast to the independent work of Snell, Dausset and Benacerraf, Rolf Zinkernagel, a Swiss immunologist, and Australian Peter Doherty were awarded the 1996 Nobel Prize for their collaborative discoveries concerning the specificity of the cell-mediated immune defence.
Although the vital role of the MHC in the immune response had been determined, the exact mechanism by which it worked was still not clear. Zinkernagel and Doherty found that in order to recognise and kill virus-infected cells, immune cells called T cells need to be presented with an MHC molecule as well as parts of the virus (called the antigen).
They realised that the MHC has a role in enabling the immune system to distinguish between ‘self’ and ‘non-self’. This discovery also led to the distinction between antibody-mediated (humoral) and cell-mediated immunity.
The importance of the MHC beyond transplants is now well appreciated. Scientists have shown that failure to accurately recognise ‘self’ can lead to a range of autoimmune disorders, including rheumatoid arthritis, multiple sclerosis and type 1 diabetes. The MHC has also been implicated in mate recognition in mice, fish and birds, and potentially in humans too.Lead image:
North Dakota National Guard/Flickr CC BY NC
- Forces War Records blog
- American Association of Immunologists biography of Jean Dausset
- American Association of Immunologists biography of Baruj Benecerraf
- American Association of Immunologists biography of Rolf Zinkernagel
- American Association of Immunologists biography of Peter Doherty
- Wikipedia page on organ transplantation
- Nobelprize.org’s page on the 1980 Prize