AUTOIMMUNE ORCHITIS

Abstract

The various models of EAO have contributed to a general view that orchitis is a T-cell-mediated disease regulated by local, genetic, and immunologic factors. T cells of the CD4 + phenotype are responsible not only for inducing disease but also for suppressing it. The immunoregulatory role of T cells bearing high levels of CD5 has been suggested by several studies and deserves more detailed analysis. That T cells with receptors for testicular antigens can be activated by immunization implies that such cells are not deleted during ontogeny in the thymus, nor are they terminally anergic (unresponsive). Because novel immunogenic antigens exist in the testis outside the blood-testis barrier there must be local or systemic regulation to prevent a response to these antigens. There is abundant evidence for both modes of regulation, and the complete picture is undoubtedly complex. When orchitis occurs spontaneously in animals, it appears to have a strong genetic component. Its etiology and genetic predisposition in men is poorly understood because in most cases the antigen(s) providing the initial insult is unknown. Analysis of the antigens recognized by serum antibodies from men with orchitis reveals little because disease is likely to be well advanced before it is recognized, so the antibodies could well be the result of disease and unrelated to its cause. The local immunosuppressive environment of the testis is likely to prevent serious autoimmune response in the case of mild testicular trauma (such as that induced by biopsy); however, no studies have attempted to correlate the degree of testicular trauma with the incidence of orchitis. Molecular mimicry is another mechanism likely to be involved in the etiology of orchitis. A bacterial or viral antigen could carry an epitope shared by a testicular antigen. Protective immune response to the pathogen would lead to activation of lymphocytes recognizing this shared epitope. This is equivalent to extra testicular immunization. Once the afferent limb of the immune response is activated, the local protective mechanisms of the testis would be unable to prevent an inflammatory response in the testis leading to damage of the seminiferous epithelium and aspermatogenesis. It is likely that molecular mimicry or trauma will produce orchitis only in genetically susceptible men. These speculations are supported by the evidence gained from the experimental models of autoimmune orchitis. Further studies of autoimmune orchitis will likely focus on identifying the antigens inducing disease in the various models. It is highly likely that more than one antigen will prove to be effective. Systemic immunoregulation of the response to testicular antigens will be another focus of study. The mechanisms responsible for local immunoregulation in the testis, especially the role of testicular macrophages and local antigen presentation, demand much more study. The genes controlling susceptibility to EAO in mice are being identified and characterized. It will be interesting to determine whether these genes also can be associated with human orchitis. Results of studies of autoimmune orchitis not only contribute to our understanding and eventual treatment of this disease, but also contribute to our understanding of all organ-specific autoimmune diseases.