The Natural-Selection Theory of Antibody Formation

Abstract

An immense amount of experimental data related to the problem of antibody formation has accumulated. Theories offering a basic interpretation of these observations have, in contrast, been few. The theory formulated in the present paper, though highly speculative, attempts to provide a framework for the interpretation of the main features of antibody appearance in response to the injection of antigen into an animal. Two views concerning the mechanism of antibody formation are at present most widely favored. One is the "antigen-template" theory, developed by Breinl [1], Haurowitz [1,2], Mudd [3], Alexander [4], and Pauling [5]. This theory assumes that antibodies can be produced only by cells in which the antigen is present. The specific affinity of an antibody molecule toward the antigen is due to a complementarity in structure derived from the folding of part of the polypeptide chain of a globulin molecule in direct contact with a determinant or haptenic region of the antigen. The antigen thus serves as a template in the final stage of formation of a globulin molecule. The other view tries to establish a similarity between antibody formation and adaptive enzyme formation and allows for the continued production of antibody after the antigen has disappeared from the body. This is the "modified-enzyme" theory, formulated by Burnet [6,7] and Fenner [7]. They propose that the introduction of an antigen into cells, containing enzymes directed toward the disposal of effete cells and cellular debris from the organism itself, induces the formation of "enzymic units" adapted toward the destruction of the antigen. A renewed contact with the antigen stimulates the replication of these enzymic units. Circulating antibody molecules are partial replicas of the modified enzymic units, carrying specificity but lacking enzymic action. The "natural-selection" theory, proposed in the present paper, may be stated as follows: The role of the antigen is neither that of a template nor that of an enzyme modifier. The antigen is solely a selective carrier of spontaneously circulating antibody to a system of cells which can reproduce this antibody. Globulin molecules are continuously being synthesized in an enormous variety of different configurations. Among the population of circulating globulin molecules there will, spontaneously, be fractions possessing affinity toward any antigen to which the animal can respond. These are the so-called "natural" antibodies. The introduction of an antigen into the blood or into the lymph leads to the selective attachment to the antigen surface of those globulin molecules which happen to have a complementary configuration. The antigen carrying these molecules may then be engulfed by a phagocytic cell. When the globulin molecules thus brought into a cell have been dissociated from the surface of the antigen, the antigen has accomplished its role and can be eliminated.

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