The scurfy mouse : a potential model of thymic education

Gene mutations in laboratory mice have provided numerous model systems for the study of disease processes. The initial description of the X-linked recessive mutation, scurfy (sƒ), noted severe runting, exfoliative dermatitis, and early death at roughly three to four weeks of age. We sought to clarify the pathogenesis of the scurfy syndrome via complete morphologic evaluation followed by in-depth analysis of the most consistently affected organ system(s). In addition to the previously described scaly skin and reddened genital papilla, gross morphologic lesions included marked splenomegaly, hepatomegaly, enlarged lymph nodes, and variable thickening of the ears. The characteristic microscopic lesion was a lymphohistiocytic proliferation that effaced lymph node architecture, thickened the dermis, expanded the splenic white pulp, and formed nodular portal infiltrates in the liver. Scurfy males had a consistently severe, Coombs'-positive anemia, polyclonal increases in serum IgG, and leukocytosis with atypical mononuclear cells. Since the morphologic lesions suggested a disease primarily affecting the lymphoid system, we attempted to modify the scurfy phenotype by in vivo immunologic manipulations. Neonatal thymectomy of sƒ/Y mice increased lifespan and ameliorated the histologic lesions, but did not prevent death. Mice bred to be scurfy (sƒ/Y) and nude (nu/nu; athymic) were viable, fertile, and free of lesions associated with the scurfy phenotype. Bone marrow from scurfy males could reconstitute lethally-irradiated, H-2 compatible animals but did not transmit disease. Morphologic lesions similar to those of sƒfY mice were seen in H-2 compatible nude mice that received sƒfY thymic grafts. These lesions resembled those described in subacute graft versus host (GVH) disease. No lesions resulted from transplantation of sƒ/Y thymuses into H-2 incompatible nude mice. Our data indicates that the scurfy mutation causes a lymphoproliferative disease mediated by T cells, and that these T cells can be generated in a sƒ/Y thymic environment, but not in a normal (+/Y) thymus. Coupled with the observation that sƒ/Y T cells produce disease only in H-2 compatible hosts, these findings suggest that scurfy disease results from a defective thymic education of T cells.