Mountz J D, Zhou T, Bluethmann H, Wu J, Edwards C K
Department of Medicine, University of Alabama at Birmingham.
Int Rev Immunol. 1994;11(4):321-42. doi: 10.3109/08830189409051178.
Although autoreactive T cells are thought to play a prominent role in autoimmune disease in MRL-lpr/lpr mice, it has been difficult to directly determine if autoreactive T cells escape from the thymus and react with self-antigens in the periphery. Defective expression of the Fas apoptosis antigen in MRL-lpr/lpr mice results from the insertion of the ETn retrotransposon. The fas defect can be partially corrected in CD2-fas transgenic mice in which the expression of fas is corrected in T cells. To identify a possible defect in clonal deletion or clonal anergy induction of auto-specific T cells, we have studied C57BL/6-lpr/lpr transgenic mice that express TcR genes that recognize a known self-antigen, the male H-Y antigen. In addition, we have analyzed clonal deletion and tolerance induction after neonatal tolerance induction and superantigen-induced arthritis with the class II MHC reactive superantigen staphylococcal enterotoxin B (SEB) in V beta 8 TcR transgenic and non-transgenic MRL-lpr/lpr mice. Neonatal tolerance induction to SEB was normal in lpr/lpr mice. However, over time a loss of tolerance (thymic or peripheral) was observed in lpr/lpr mice but not in +/+ TcR transgenic mice. This defect in lpr/lpr mice was thymic-dependent and was due to increased CD28/CTLA4 signaling. These results suggest that an apoptosis defect involving both thymocytes and peripheral lymphoid cells leads to autoimmune disease in lpr/lpr mice. The challenge in the future will be to determine the role of defective apoptosis in other autoimmune diseases.
尽管自身反应性T细胞被认为在MRL-lpr/lpr小鼠的自身免疫疾病中起重要作用，但一直难以直接确定自身反应性T细胞是否从胸腺逃逸并在外周与自身抗原发生反应。MRL-lpr/lpr小鼠中Fas凋亡抗原的表达缺陷是由ETn逆转座子的插入导致的。在CD2-fas转基因小鼠中，Fas缺陷可得到部分纠正，其中Fas在T细胞中的表达得以纠正。为了确定自身特异性T细胞的克隆清除或克隆无能诱导中可能存在的缺陷，我们研究了表达识别已知自身抗原——雄性H-Y抗原的TcR基因的C57BL/6-lpr/lpr转基因小鼠。此外，我们还分析了在Vβ8 TcR转基因和非转基因MRL-lpr/lpr小鼠中，新生期耐受诱导以及用II类MHC反应性超抗原葡萄球菌肠毒素B（SEB）诱导超抗原性关节炎后克隆清除和耐受诱导情况。lpr/lpr小鼠对SEB的新生期耐受诱导正常。然而，随着时间的推移，在lpr/lpr小鼠中观察到耐受（胸腺或外周）丧失，而在+/+ TcR转基因小鼠中未观察到。lpr/lpr小鼠中的这种缺陷是胸腺依赖性的，并且是由于CD28/CTLA4信号传导增加所致。这些结果表明，涉及胸腺细胞和外周淋巴细胞的凋亡缺陷导致了lpr/lpr小鼠的自身免疫疾病。未来的挑战将是确定缺陷性凋亡在其他自身免疫疾病中的作用。
