Editor's note: Citation Classics Commentaries were written by the authors of some of studies that were the most highly cited papers between 1961 and 1975. The essays were originally published between 1977 and 1993 in Current Contents, a publication of the Institute for Scientific Information (ISI), now Thomson Scientific. (ISI was founded by Eugene Garfield, also the founder of The Scientist.)
In this essay, Jean Dausset recalls experiments in which he mixed blood derivatives from different patients and observed clumping of white blood cells. Dausset correctly hypothesized that certain human leukocyte antigens (HLAs) stimulated this immune response. He called the first group Mac, which has since become known as HLA-A2. Further work showed that these antigens formed part of the human major histocompatibility complex, a key component of the immune system. Dausset received the Nobel Prize for Medicine in 1980, and four years later he used the award money to establish the Human Polymorphism Study Center (CEPH), later renamed the Foundation Jean Dausset-CEPH, where he continues to work today. His original findings were published in a 1958 paper, which became the third most cited paper ever published in Acta Haematologica .
Reference » J. Dausset, "Iso-leuco-anticorps," Acta Haematol, 20:156-66, 1958.
Image reprinted with permission from S. Karger AG
In 1952, when only the red blood cell groups were known, I mixed on a glass plate the serum of an agranulocytic woman with the bone marrow of another individual. I observed a massive macroscopic agglutination. I soon understood that it was not due to autoantibodies but to alloantibodies (at that time called isoantibodies).
This paper gathered together all the work that had been done since 1952, in collaboration with Gilbert Malinvaud, Hélène Brécy, and later, Jacques and Monique Colombani
During this time, we organized the systematic detection of leucoantibodies in the sera of polytransfused patients tested against a panel of leucocytes from volunteers. The agglutinations were sometimes obvious and sometimes weak; there were no computers at that time and our results were exposed on a large poster on the laboratory wall.
We almost lost hope of ever making sense of it. However, we noticed that the leucocytes from three panel donors were less often agglutinated than others. This gave us the idea that they lacked a certain antigen that is otherwise frequent in the population. Six sera did not agglutinate these three individuals, but agglutinated 11 others, thus dividing the population into two groups: one bearing the Mac antigen (not a Scottish name, but the initials of the surnames of the three nonagglutinated individuals) and the other without this antigen.
Formal proof was obtained when we observed that among the patients systematically transfused with Mac-positive blood, only the Mac-negative recipients developed an anti-Mac antibody.
These leucocyte antigens are genetically determined, since the pattern of agglutination with a battery of antileucocyte sera was strictly identical in monozygotic twins and different in dizygotic twins. Lastly, we demonstrated that leucocyte antibodies were responsible for the transfusion reactions.
This work was the starting point of an extraordinary biological adventure and is the reason why this paper has been highly cited. Two laboratories followed in our footsteps: J.J. Van Rood soon afterward described a supertypic antigen, 4a4b (Bw4,Bw6); Rose Payne with W. Bodmer described the first two alleles, LA1 and LA2 (LA2 being identical to Mac).
B. Amos, R. Ceppellini, F. Kissmeyer-Nielsen, P. Terasaki, and R. Walford joined the game, and numerous scientific communities rapidly followed. A unique collaborative research study was undertaken and has continued ever since. Thanks to ambitious international workshops that allow the exchange of reagents and information, the extraordinary skein of the human HLA complex was unraveled.
Starting with the first serological data, it has been possible, in the space of 20 years, to decipher the biological composition and function of these molecules, protruding like antennae from the surface of our cells. We are now beginning to study the genes that govern these cells and can expect still more marvels to come.
Jean Dausset, Saint Louis Hospital, Paris, Jan. 19, 1983.