The common sense of the self-nonself discrimination.

The vertebrate immune system was evolutionarily selected to express a large random somatically generated paratopic repertoire coupled to effector mechanisms invented, in large measure, by non-vertebrates. The self-nonself discrimination is determined by Decision 1, the sorting of this repertoire into those specificities (anti-self) which, if expressed, would debilitate the host and those specificities (anti-nonself) which, if not expressed, would result in the death of the host by infection. Decision 1, the sorting of the repertoire, is mediated by a somatic learning process operating epitope-by-epitope that deletes anti-self specificities leaving the residue as anti-nonself. The activation of anti-nonself is the first step on entry into Decision 2, which optimizes the choice and magnitude of the effector class that rids the pathogen without significantly debilitating the host. The principles governing Decision 1, the self-nonself discrimination are analyzed here.