A two-step hypothesis for the appearance of autoimmune disease.

Two phenomena are likely to be central to an understanding of how autoimmune disease comes about--immunological tolerance and ignorance. Yet ignorance, the state where antigen and lymphocyte have never come together in such a way as to induce either tolerance or an immune response, is often ignored in recent discussion. This article reviews evidence that has led to the suggestion that most autoimmune disease arises from termination of ignorance. Termination could come about in a number of ways. Self-antigens may be made available to the immune system by infective or physical tissue damage or by a defect in the phagocytic removal of apoptotic cells. Moreover, infectious agents may bring an end to ignorance by mimicry or by their ability to induce co-stimulatory activity as a consequence of inflammation. Since loss of ignorance could be a relatively common occurrence it is suggested that a back-up would be essential. This could be a role for regulatory T cells, possibly those expressing both CD4 and CD25. Two steps may thus be necessary for the appearance of autoimmune disease--loss of ignorance followed by failure of regulatory T cells to control anti-self effector T cells.