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 break-down or failure of the normal tolerance to self, resulting in the development of an autoim-mune response. Ehrlich’s hypothesis was apparently supported by the definition of pathogenic mechanisms for different diseases considered as autoimmune in which the ab-normal antiself immune reaction played the main role.
The modern understanding of tolerance can be dated to the observations reported by Owen 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 an-imal is exposed to cells expressing the genetic markers of the nonidentical twin during on-togenic development. When the animals are born, they often carry two sets of antigenically distinct red cells in circulation—one of the best examples of natural chimerism. With time, the red cell set acquired from the twin calf will disappear, but the “chimeric” calves will re-main tolerant to each other’s tissues for the rest of their lives. Thus, these experiment seem to prove that there is a critical period during development during which the immune sys-tem becomes tolerant to any antigen it encounters.
Two decades later, Brunt, Medawar, and coworkers developed the first mouse mod-els for the study of tolerance. Mice are born with an incompletely developed immune sys- tem, and these investigators discovered that mice can be rendered tolerant to neonatally in-jected antigens, corroborating and expanding Owen’s observation with chimeric animals.
The first theory concerning tolerance, subscribed to by Burnet, Fenner, and Medawar, is known as the clonal deletion theory of tolerance. In simple terms, this theory stated that self tolerance is achieved by the elimination of autoreactive clones during the differentia-tion of the immune system. However, the development of autoimmune diseases proved that deletion of these clones was not absolute. The remaining autoreactive clones must be si-lenced or anergized, but none of these mechanisms is foolproof for all individuals.