Abstract

Attempts to determine the underlying causes of autoimmune disease have, in many cases, been hampered by a lack of knowledge of the target antigens. The characterisation of human and animal red blood cell (RBC) autoantigens in autoimmune hemolytic anemia (AIHA) has provided an opportunity to study the control of specific autoimmune responses of unequivocal pathogenic relevance. The results reveal that censorship of the autoimmune T and B cell repertoire by deletion and anergy is very incomplete in healthy individuals, even for widely distributed, abundant self-antigens on RBC . There is strong evidence that autoaggression by surviving T cells is normally held in check by other mechanisms, including failure to display the epitopes that they recognise, and active immunoregulation. A number of hypotheses have been put forward to explain how such mechanisms can be overcome in autoimmune disease, and, taking advantage of the well-characterised RBC autoimmune responses, these possibilities can be tested in examples of AIHA in different species. In particular, studies of AIHA have shed light on the role of cross-reactivity or molecular mimicry between self and foreign antigens, defects in regulation, and aberrant antigen presentation in the loss of self-tolerance, and on the links between autoimmunity and cancer. These findings are relevant to the understanding of other autoimmune diseases, and to the rational design of effective, targeted therapies for this group of conditions.