1897

Paul Ehrlich, in a seminal paper, established the first practical method for standardization of diphtheria toxin and antitoxin, and also proposed the side chain theory of antibody formation (the affinities of chemicals, nutrients, or antitoxins for target biologicals). Three tenets of side-chain theory: 1. antibodies were normal cell receptors ready, on a best-fit basis, to bind antigen; 2. antibody specificity resided in chemical complementarity; and 3. antigen-antibody binding was a chemical and irreversible process (Tauber & Chernyak, 163-164; Bäumler, 62-67; Silverstein, 64-66. 94-97). According to Ehrlich’s side-chain theory, “the antibodies represent the side chains of the cell protoplasm produced in excess and therefore rejected. These side chains or antibodies were thus bound to have a specific affinity with the toxin” (Bäumler, 66). The cell shed the excess side chains in the blood in the manner of secretory gland cells, but the released side chains possessed one group of atoms capable of linking with toxins; hence they could be regarded as antitoxins (82); “When, however, large amounts or repeated doses of toxin were administered, then the cell would overcompensate for the loss of these side-chain receptors, producing so many that some would be released into the blood” [Silverstein, 65]). Ehrlich believed the causes of immunity were not confined to hapten (linking) action and phagocytosis, but included athrepsia – a model of passive immunity in which antigens died when they were incapable of absorbing their essential nutrient from the host: “. . . microorganisms can only be pathogenic for a certain animal if they find in it possibilities of nutrition” (Tauber & Chernyak, 168). “In summary, both Ehrlich and Metchnikoff recognized the dynamic struggle between host and pathogen, but the former viewed the issue in passive terms, whereas the latter was ever conscious of an active response. . . . The failure then to formalize the question of immune specificity is the central lacuna of Metchnikoff’s later defense of the phagocytosis theory” (171).