An integrated view of immunological tolerance

I summarize how diverse mechanisms may contribute to self-tolerance, and how an appreciation of their interdependence is necessary to understand how they collectively provide the imperfect degree of tolerance achieved. I suggest that the Quorum Hypothesis of Lymphocyte Activation incorporates one means of achieving peripheral tolerance. This hypothesis posits that the activation of all lymphocytes requires their antigen-mediated interaction with other lymphocytes, whereas single lymphocytes are inactivated by antigen. Mature lymphocytes, specific for a peripheral self-antigen, are eliminated as generated, one or a very few at a time, due to the first presence of the antigen early in development and continuously thereafter. There are limits to the circumstances under which this mechanism leads to tolerance. For example, if most self-specific lymphocytes were not eliminated by the mechanism of central tolerance, the emigration of anti-self lymphocytes, from primary lymphoid organs, would occur at so high a rate that the quorum mechanism would fail to eliminate but lead to their activation. Evolutionary considerations lead me to suggest that the thymic expression of certain self-antigens, via such transcription factors as the autoimmune response element, allows more rapid immune responses against invaders without resulting in autoimmunity. This is clearly evolutionarily advantageous. It has been proposed that novel self-antigens may be expressed at certain stages of life, such as adolescence. I discuss how tolerance to 'adolescent antigens' may be achieved, and to a special class of 'newly arising self-antigens', namely idiotypic epitopes of the antigen-specific receptors of B and T lymphocytes.