One of the greatest enigmas facing early immunologists was the specificity of the antibody molecule for foreign material, or antigen (the general term for a substance that binds with a specific antibody). Around 1900, Jules Bordet at the Pasteur Institute expanded the concept of immunity by demonstrating specific immune reactivity to nonpathogenic substances, such as red blood cells from other species. Serum from an animal inoculated previously with material that did not cause infection would react with this material in a specific manner, and this reactivity could be passed to other animals by transferring serum from the first. The work of Karl Landsteiner and those who followed him showed that injecting an animal with almost any organic chemical could induce production of antibodies that would bind specifically to the chemical. These studies demonstrated that antibodies have a capacity for an almost unlimited range of reactivity, including responses to compounds that had only recently been synthesized in the laboratory and had not previously existed in nature. In addition, it was shown that molecules differing in the smallest detail could be distinguished by their reactivity with different antibodies. Two major theories were proposed to account for this specificity: the selective theory and the instructional theory.
The earliest conception of the selective theory dates to Paul Ehrlich in 1900. In an attempt to explain the origin of serum antibody, Ehrlich proposed that cells in the blood expressed a variety of receptors, which he called "side-chain receptors," that could react with infectious agents and inactivate them. Borrowing a concept used by Emil Fischer in 1894 to explain the interaction between an enzyme and its substrate, Ehrlich proposed that binding of the receptor to an infectious agent was like the fit between a lock and key. Ehrlich suggested that interaction between an infectious agent and a cell-bound receptor would induce the cell to produce and release more receptors with the same specificity. According to Ehrlich's theory, the specificity of the receptor was determined before its exposure to antigen, and the antigen selected the appropriate receptor. Ultimately all aspects of Ehrlich's theory would be proven correct with the minor exception that the "receptor" exists as both a soluble antibody molecule and as a cell-bound receptor; it is the soluble form that is secreted rather than the bound form released.
In the 1930s and 1940s, the selective theory was challenged by various instructional theories, in which antigen played a central role in determining the specificity of the antibody molecule. According to the instructional theories, a particular antigen would serve as a template around which antibody would fold. The antibody molecule would thereby assume a configuration complementary to that of the antigen template. This concept was first postulated by Friedrich Breinl and Felix Haurowitz about 1930 and redefined in the 1940s in terms of protein folding by Linus Pauling. The instructional theories were formally disproved in the 1960s, by which time information was emerging about the structure of DNA, RNA, and protein that would offer new insights into the vexing problem of how an individual could make antibodies against almost anything.
In the 1950s, selective theories resurfaced as a result of new experimental data and, through the insights of Niels Jerne, David Talmadge, and F. Macfarlane Burnet, were refined into a theory that came to be known as the clonal-selection theory. According to this theory, an individual lymphocyte expresses membrane receptors that are specific for a distinct antigen. This unique receptor specificity is determined before the lymphocyte is exposed to the antigen. Binding of antigen to its specific receptor activates the cell, causing it to proliferate into a clone of cells that have the same immunologic specificity as the parent cell. The clonal-selection theory has been further refined and is now accepted as the underlying paradigm of modern immunology.
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