While fighting off infectious agents, our immune defences must take extreme care to avoid harming any cells belonging to its own host. Achieving this requires a sophisticated self-identification system, and this is centred on a collection of genes called the major histocompatibility complex, or MHC, which encode proteins known collectively as histocompatibility antigens. Each individual carries a unique combination of these antigens on the surface of their cells, providing a form of biological ID system for distinguishing one individual from another.

Uncovering such a complex system involved piecing together observations from unconnected areas over the course of decades, and the 1980 Nobel Prize in Physiology or Medicine rewarded these achievements.  George Snell discovered the first components of the MHC in the 1940s through their role in rejecting transplants in mice. At that time, the search for genetic factors that reject tumour transplants had been narrowed down to a number of possible locations on mouse chromosomes; and Snell spent years carefully creating strains of mice that allowed him to examine the effect of each one in turn. One location stood out as providing the strongest barrier to transplantation, which housed a gene encoding an immune-stimulating protein called H-2 that had been described previously by Peter Gorer. On closer inspection, what appeared to be a single gene in the neighbourhood turned out to be a surprisingly large number of genes that were closely linked together.

Around a decade later, Jean Dausset uncovered the first compatibility antigen in humans. He noticed that a patient receiving several transfusions of ABO compatible blood still suffered an unexpected immune reaction. Dausset discovered that in this case antibodies were being launched against white blood cells belonging to the donor only, and that these antibodies in the patient’s serum triggered a similar reaction in half the samples of white blood cells taken from other people. He called the factor responsible MAC, and this turned out to be the first of a series of human leukocyte antigens, or HLAs. Thanks to the efforts of researchers worldwide, it became clear that the HLA region constituted the human version of the MHC, and that the HLA genes are so variable and yet so specific for an individual that this provides a form of fingerprint at the cellular level.

Experiments by Baruj Benacerraf in the 1970s provided the first indication that immune reactions are controlled by genes. Benacerraf was surprised to discover that different strains of guinea pigs launched different levels of attack towards the same foreign antigen, and he traced the cause to what he termed immune response genes. Over the years, many of these immune response genes have been found and traced to the same location, all being members of a previously undiscovered cluster of genes lying within the MHC.