THYMIC EPITHELIAL DEFECTS AND PREDISPOSITION TO AUTOIMMUNE-DISEASE INBB RATS

We report an association between thymic epithelial defects and predisp osition to autoimmunity. Diabetes-prone (DP) BB rats develop spontaneo us hyperglycemia and are deficient in T cell subsets expressing the RT 6 alloantigen. Diabetes resistant (DR) BB rats become diabetic if depl eted of RTG(+) T cells. The inciting immune system defects are unknown . We made the following observations: 1) Regions of thymic cortex and medulla devoid of thymic epithelium exist in DP-BB, DR-BB, and Lewis r ats, all of which are susceptible to autoimmune disorders. Such defect s were absent in eight normal rat strains. 2) Thymic epithelial defect s are absent at birth, but present in BB rats at 4 weeks of age. 3) Th e genetic predisposition to thymic epithelial defects is an autosomal dominant trait. 4) Tbe observation of thymic defects in (DP x WF)F-1 r ats led to the prediction that such animals, which never develop spont aneous autoimmunity, might be susceptible to its induction. Following depletion of RT6(+) T cells we observed diabetes in 91%, and thyroidit is in 43%, of treated F-1 animals (n = 23). Pancreatic insulitis was u niformly present. Because thymic epithelium participates ill the posit ive and negative selection of developing thymocytes, we propose that t hymic epithelial defects may play an important role in the predisposit ion of BB mts to autoimmunity.