Immunol Rev. incontrovertible evidence that cross-reacting antibodies or autoreactive cells mediate the typical pathologic changes associated with human Chagas disease. The data and views backing and questioning the autoimmunity hypothesis for Chagas disease are summarized in this review. The last time the clinical, pathological, epidemiological, immunological, biological cycle, vector biology, and other aspects of infection (Chagas disease [CD] or American trypanosomiosis) were all CY3 condensed and compiled in comprehensive book form was in 1979 (14). Since then, reviews and books have sporadically updated the available information on the clinical (116), pathological (116), and immunological (13, 17, 68, 72) aspects of infection, as well as progress in chemotherapeutic approaches (61), experimental vaccination (64), and our knowledge of parasite invasion requirements (19). The mechanisms underlying the pathology associated with the various forms of CD have been subjects of active research and sometimes polemic discussions. The latter is not unexpected for a disease that presents itself in cardiac, digestive, nervous, and even asymptomatic forms and is caused by a multifaceted parasite displaying variable tissue tropisms Rabbit polyclonal to EPHA4 and degrees of virulence. Over the years, several hypotheses have been advanced to explain the development of pathologic changes in CD. Of these, the autoimmunity hypothesis is covered in detail in this review while the others are succinctly described in Nonautoimmune hypotheses for the production of chronic chagasic tissue lesions below. The evidence suggesting a role for autoimmune events in the pathogenesis of CD is presented, interjecting where applicable the pitfalls CY3 noted and criticisms raised by skeptics. In addition, and whenever possible, approaches that may help clarify uncertainties or resolve disagreements are suggested. Over nearly a quarter century, numerous reviews and articles have recorded the evolution of the discussion and controversy surrounding the notion of autoimmunity as a determining factor in the pathologic findings of CD (2, 16, 27, 34, 37, 51, 54, 62, 63, 89, 106, 109, 119). Being the sequel of a review CY3 on autoimmunity in CD published by the author in 1986 (63), the present assessment focuses on the more recent literature. Far from engaging in an ineffectual attempt to try to cover exhaustively the entire pertinent literature, this review addresses only the main current trends of thought. Before tackling the core topics, and for the benefit of readers for whom this may be a new field, it would be appropriate to summarize the implications of the autoimmunity theory for the millions of individuals who suffer from some form of CD or may acquire it. If autoimmunity elicited by cross-reactive antigens were responsible for CD, efforts to develop effective chemotherapy would be worthless and meaningless, since drugs that kill would not arrest an immune response maintained through continuous stimulation by host tissue antigens. Immunosuppressants used to control autoimmunity have been shown consistently to exacerbate human and experimental infections (15, 21, 49, 75, 90, 112) and therefore could not be counted on to control autoimmunity in this case. In addition, and if autoimmunity were a true reflection of immunological cross-reactivity between and host tissue antigens, attempts to develop an effective anti-vaccine would be severely hampered by the need to demonstrate that the selected antigens do not elicit anti-host tissue immune responses. Reliance on negative results is generally poor, and health authorities would be reluctant to use a lack of demonstrable cross-reactivity as a basis for the critical decision about putting millions of people at risk of.