Basic Mechanisms and Concepts

Thomas M. Herndon, George C. Tsokos

In 1901, Ehrlich postulated that "organisms possess certain contrivances by means of which the immune reaction [...] is prevented from acting against (its) own elements." Such "contrivances" constitute what in modern terms is designated as "tolerance" and, still in Ehrlich's words,". are of the highest importance for the individual." Several decades later, when autoimmune diseases were described, they were interpreted as the result of a breakdown or failure of the normal tolerance to self, resulting in the development of an autoimmune response. Ehrlich's hypothesis was apparently supported by the definition of pathogenic mechanisms for different diseases considered as autoimmune in which the abnormal anti-self-immune reaction played the main role. In the 1940s, Owen, a British biologist, was involved in ontogeny studies using bovine dizygotic twins, which share the same placenta. Under these circumstances, each animal is exposed to cells expressing the genetic markers of the nonidentical twin during ontogenic development and they become tolerant to each other's antigens.

The first theory concerning tolerance, described by Burnet, Fenner, and Medawar, stated that self-tolerance is achieved by the elimination of autoreactive clones during the differentiation of the immune system. However, the development of autoimmune diseases proved that deletion of these clones was not absolute but that the remaining clones must be silenced or anergized to self-antigens, and that none of these mechanisms is foolproof for all individuals (Tsokos and Virella 2001).

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