Clonal deletion and anergy are believed by many immunologists to be the fundamental mechanisms responsible for self tolerance. Nevertheless, as Irun Cohen and Douglas Young point out, such notions of nonreactivity cannot explain certain key features of immune behaviour: the immunological dominance of microbial antigens that mimic self, the uniformity of autoimmune diseases and the prevalence of natural autoimmunity among the healthy. The theory of the immunological homunculus is presented here as a unifying principle.

The healthy immune system is tolerant to the molecules comprising the body in which it resides. Why this should be so is obvious; how it is so is obscure. The demonstration of negative selection of T cells during their differentiation in the thymus I provides experimental support for the venerable idea that the source of self tolerance is the cleansing filter of clonal deletion 2. Some will argue that healthy individuals have lymphocytes that recognize self antigens but most would agree that self antigens are poor immunogens. To state the idea in operational terms, the closer a molecule is to self, the less immunogenic it should be. It is surprising, therefore, to find that among the major antigens recognized during a wide variety of bacterial and parasitic diseases many belong to conserved protein families sharing extensive sequence identity with the host's molecules.