History and naming of human leukocyte antigens

Human leukocyte antigens (HLA) began as a list of antigens identified as a result of transplant rejection. The antigens were initially identified by categorizing and performing massive statistical analyses on interactions between blood types. This process is based upon the principle of serotypes. HLA are not typical antigens, like those found on surface of infectious agents. HLAs are alloantigens, they vary from individual to individual as a result of genetic differences. An organ called the thymus is responsible for ensuring that any T-cells that attack self proteins are not allowed to live. In essence, every individual's immune system is tuned to the specific set of HLA and self proteins produced by that individual; where this goes awry is when tissues are transferred to another person. Since individuals almost always have different "banks" of HLAs, the immune system of the recipient recognizes the transplanted tissue as non-self and destroys the foreign tissue, leading to transplant rejection. It was through the realization of this that HLAs were discovered.

Discovery The thought that the mammalian body must have some way of identifying introduced foreign tissues first arose during World War II. It started with a plane crash in the height of the London Blitz. The pilot sustained severe burns requiring skin grafts; however, skin grafts were a risky business at the time, often being rejected for unknown reasons. Numerous theories were proposed and it wasn't until 1958 that the first of these "identifying" proteins was found. The first standardized naming system was established in 1968 by the WHO Nomenclature Committee for Factors of the HLA System. HLA research didn't heat up until the 1980s when a group of researchers finally elucidated the shape of the HLA-A*02 protein (just one of many specific HLA proteins). Even more recently, in 2010, the WHO committee responsible for naming all HLA proteins revised their standards for naming to introduce more clarity and specificity in the naming system.

Identification of non-self Peter Medawar was a zoologist turned clinician, who specialized in burn trauma. A plane crash near his home changed the path of his career, turning his work with burns from mere academia to a full on quest to save lives. Medawar and a Scottish surgeon, Tom Gibson, were tasked with working the Burns Unit of the Glasgow Royal Infirmary. The first insight came when the pair decided to experiment, and grafted part of a wound with the patient's skin, and another part with skin from the patient's brother. Within days the skin grafts from the brother were completely destroyed. Successive skin grafts from the brother were destroyed even faster, a fact that gave them the evidence they needed to implicate the immune system. Medawar later repeated this experiment on rabbits and 625 surgeries later validated their initial conclusions. Medawar then set out in search of the reason why rabbits rejected non-self grafts. Medawar continued his work, this time with a team of three at the University College London during the 1950s. Medawar's coworkers were Leslie Brent, a PhD student, and Rupert Billingham, Medawar's first graduate student at Oxford several years prior. Through carefully planned experimentation, the trio showed that mice exposed to cells of unrelated mice as fetuses did not reject skin grafts from those same mice. For this discovery, Medawar and Australian scientist Macfarlane Burnet earned the 1960 Nobel Prize.

Learned self-tolerance Burnet, independently of Medawar, came to the conclusion that the immune system must learn to tolerate any self cells, and hypothesized that this must occur during fetal development. For this, he jointly was awarded the Nobel Prize in 1960. Burnet's work continued and in 1957 along with Niels Jerne published a paper that modified and revolutionized antibody theory. "Burnet speculated that one cell makes one particular shape of antibody and that all our antibody-making immune cells together make an unimaginably vast repertoire of 10 billion antibodies, each having a slightly different shape". Thus, whenever a non-self molecule appears in the human body, one of these antibodies will have an accurate enough shape to bind to that molecule. This idea is known as clonal selection theory. At the time, many leading scientists including Linus Pauling and James Watson completely rejected the idea, but repeated experimentation intended to disprove the theory actually served to build up a large body of evidence supporting Burnet and Jerne's theory. The biggest weakness in Burnet's theory was that he had no explanation for how the body selected for immune cells that only identified non-self. In 1961, Jacques Miller published a paper offering an explanation. Miller was a PhD student at the Chester Beatty Research Institute in London. His discovery centered on the thymus. The thymus had long been regarded as nothing more than a repository for dead cells. Miller didn't buy this hypothesis. By removing the thymus of leukemic mice early in life, he found that the mice had a drastically weakened immune system. Taking inspiration from Medawar's skin transplant work, he performed a series of skin-graft experiments that showed that these immunocompromised mice didn't reject skin grafts from non-genetically identical mice. Miller then hypothesized that the thymus was essential in the construction and maintenance of the immune system. At this point Burnet came back into the picture, extending the hypothesis to specify that the dead cells found in the thymus are not any old immune cells, but instead the cells that are activated by self molecules. In other words, any cell that binds to and hence "recognizes" a self molecule is killed before exiting the thymus. These cells were later found to be one of the three types of Lymphocytes, the T-cells (named for their origin, the thymus).

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