Basic science for the clinician 26: Tolerance--mechanisms and manifestations

Usually the immune system monitors our internal milieu, protecting us from external and internal risks, silently watching over the rest. Pathologic autoimmunity is usually avoided, except in certain animal models and certain immunogenetically predisposed people. On the other hand, "salutary autoimmunity" occurs in the interaction of immune systems with themselves or other immune pathways as part of control or recognition mechanisms, eg, idiotype network, epitope-MHC complex binding with B- or T-cell antigen receptors. There are means by which dangerous autoimmune reactants are eliminated from the repertoire before birth; some of these are described here. However, potentially dangerous autoimmune effectors can be identified in the immunologic repertoire of certain adult animal strains but not damage the animal; these latent autoimmune effector pathways are held in check in adult animals/humans by active suppressive mechanisms.The identification and control of autoimmunity may well be the holy grail of rheumatology. Autoimmunity may also be an active participant in a number of other organ systems and diseases, so lessons learned in immunology may apply broadly throughout medicine. Once a better understanding of the normal processes and aberrancies that lead to disease are had, one can look forward to interventions to reestablish tolerance, perhaps by something as simple as a capsule containing the appropriate self antigen-containing molecules--"oral tolerizing" as a cure for autoimmune diseases! There is much promising evidence in favor of the efficacy of oral tolerance in animal models, but as of yet, human disease has proven a harder nut to crack. Although the concept of oral tolerance is nearing its centennial, there is still much to learn!