Organ-specific Autoimmunity Induced by Lymphopenia

In 1973 two groups reported the induction of organ-specific autoimmune diseases by T cell deprivation. Penhale and co-workers found that autoimmune thyroiditis could be induced in 5-week-old Wistar rats by thymectomy and repeated low-dose irradiation. On the other hand, Nishizuka and colleagues made the fascinating observation that autoimmune thyroiditis spontaneously developed in mice following thymectomy alone, so long as the thymectomy was carried out in the neonatal period. Subsequently, neonatal thymectomy was shown to induce a wide variety of organ-specific autoimmune diseases in mice, with different strains showing differences in disease susceptibility. The overlap in autoimmune diseases in this mouse model is reminiscent of the overlap observed in the endocrine organ/stomach cluster of organ-specific autoimmune diseases of humans. From 1975 onwards a number of other manipulations of the immune system have been shown to induce organ-specific autoimmune diseases in rodents. A common characteristic of these manipulations is either a deficit of T cells or reduction of the TCR repertoire, in other words functional T cell lymphopenia. The range of autoimmune diseases induced by these manipulations is most impressive and includes diabetes, thyroiditis, gastritis, orchitis, oophoritis, prostatitis, and coagulating adenitis. Many of these diseases are rare in laboratory strains of rats and mice. Evidence that the autoimmune diseases are due to specific immune responses is supported by the presence of infiltrating lymphocytes in the target organ, circulating tissue-specific autoantibodies, and the ability of splenocytes from diseased animals to transfer disease to naive immunodeficient recipients. The target autoantigens in autoimmune gastritis have been defined and are identical to antigens involved in the corresponding human autoimmune disease. A critical question in understanding autoimmunity is how the causative autoimmune response is initiated. These lymphopenia induced models of autoimmunity do not rely on immunisation with autoantigen in adjuvant but rather on perturbation of the immune system where the natural tissue autoantigens, rather than a surrogate model antigen, are immunologically targeted. Thus they provide a powerful avenue to study the basis for the loss of tolerance to peripheral antigens and development of destructive autoimmune lesions. These experimental models are useful for the study of human autoimmune diseases because they are simi