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The earliest reference to antibodies was from Emil von Behring along with Kitasato Shibasaburo in 1890 who found the presence of a neutralizing substance in the blood that could counter infections. They developed the serum against diphtheria. This they did by transferring serum produced from animals immunized against diphtheria to animals suffering from it. This serum could cure the infected animals. Behring was awarded the Nobel Prize for this work in 1901.
In 1900 Paul Ehrlich hypothesized that there are side chain receptors on cells that bind to a given pathogen. He speculated that this interaction induces the cell exhibiting the receptor to multiply and produce more copies of the same receptor. This theory, called the selective theory was not proven for next five decades.
Between 1901-1920, Landsteiner demonstrated the ABO blood group system (Rh antibody was found in in 1940). In the 1920s, Michael Heidelberger and Oswald Avery observed that antigens could be precipitated by antibodies and went on to show that antibodies were made of protein.
The chemical nature of antibodies was still not known. The biochemical properties of antigen-antibody binding interactions were examined in more detail in the late 1930s by John Marrack. In the next few decades that followed it could be shown that the protective serum could neutralize and precipitate toxins, and clump bacteria. The biomolecule responsible for these actions was termed antitoxin, precipitin and agglutinin.
It was not known that all the three substances were one entity. This was later shown by Elvin A. Kabat in 1939. Kabat in 1938 had also shown heterogeneity of antibodies through ultracentrifugation studies of horses' sera.
Thereafter cell-mediated immunity was found and recognized as different from humoral immunity in 1942 when Merrill Chase successfully transferred immunity against tuberculosis between pigs by transferring white blood cells.
The next major advance was in the 1940s, when Linus Pauling confirmed the lock-and-key theory proposed by Ehrlich by showing that the interactions between antibodies and antigens depended more on their shape than their chemical composition.
In 1948 Astrid Fagraeus in her doctoral thesis demonstrated that plasma B cells are specifically involved in antibody production. James Gowans in 1959 showed that lymphocytes had a role in mediating both cell-mediated and humoral responses.
Jerne, Talmage and Burnet in the late 1950’s found the clonal selection theory. This proved all the elements of Ehrlich's hypothesis except that the specific receptors that could neutralize the agent were soluble and free and not membrane bound. This was further proven by Sir Gustav Nossal who showed that one clone of B cell always produces only one antibody.
In the 1960’s Edelman, Porter, and Hilschmann elucidated the primary and secondary structure of antibodies. They also found that Bence-Jones proteins were immunoglobulin L-chains. Thomas Tomasi discovered secretory antibody(IgA) and David Rowe and John Fahey identified IgD, and IgE was identified by Kikishige Ishizaka and Teruki Ishizaka as a class of antibodies involved in allergic reactions. In 1974 the role of MHC in antigen presentation was demonstrated by Rolf Zinkernagel and Peter C. Doherty.
In 1975, Kohler and Milstein found the key to monoclonal antibodies. These were the magic bullets that were derived from the progeny of a single immune cell. These were pure and available in potentially unlimited quantities.
Several have been found which recognise human cancers and some of these have been tested in clinical trials. In 1976 Susumu Tonegawa cloned the first antibody gene.