Studies on autommune diseases in OSM deficient mice

系统性红斑狼疮(SLE)是一种典型的由免疫紊乱引起的系统性自身免疫性疾病，具有多种临床表型。然而，系统性红斑狼疮的发生机制仍不清楚。我们发现IL-6家族成员OSM缺乏的小鼠表现出血清自身抗体水平升高和肾小球肾炎，我们对OSM缺乏的小鼠进行了特征分析，以了解SLE的病因。组织学检查发现肺、脾组织有炎症反应，活化的T细胞渗入肺内。此外，在OSM基因缺陷的雄性小鼠中还观察到了后爪关节炎。这些结果表明，OSM缺陷小鼠自发发展为SLE，并伴有多个器官的炎症。为了解决OSM与自身免疫的关系，我们检查了OSM缺陷小鼠的胸腺，发现胸腺发育不良和胸腺结构改变。在T细胞正常发育的同时，在OSM缺陷的胸腺中检测到大量的凋亡胸腺细胞。在OSM缺陷的小鼠中，具有强烈吞噬活性的独特的胸腺巨噬细胞的发育受到损害，提示胸腺来源的自身抗原可能是产生自身抗体的原因之一。OSM缺陷小鼠外周免疫应答中的Th1应答由于树突状细胞(DC)调节失调而增强，提示Th1极化与肾小球肾炎的发生有关。为了进一步分析DC激活的异常，我们试图通过利用OSM缺陷的DC进行基因芯片分析来确定参与DC调节的因素。目前，我们正在研究一些候选基因的功能。

Systemic lupus erythematosus (SLE) is a typical systemic autoimmune disease caused by immunological disorders and exhibits various clinical phenotypes. However, the mechanism of SLE development still remains unclear. We found that mice deficient for Oncostatin M (OSM), a member of IL-6 family, exhibit increased serum autoantibody levels and glomerulonephritis, we characterized OSM deficient mice to understand a cause of SLE. Histological analysis revealed that inflammation was observed in the lung and spleen and activated T cells infiltrated into the lung. Furthermore, arthritis of hind paw was observed in OSM-deficient male mice. These results indicated that OSM-deficient mice spontaneously develop SLE with inflammation in multiple organs. To address the relationship between OSM and autoimmunity, we examined the thymus of OSM-deficient mice and found thymic hypoplasia and altered thymic architecture. While T cells developed normally, numerous apoptotic thymocytes were detected in OSM-deficient thymus. Development of unique thymic macrophages with strong phagocytic activity was impaired in OSM-deficient mice, suggesting that autoantigens derived from thymus may be a cause of autoantibody production. Th1 response in peripheral immune response against LPS was augmented in OSM-deficient mice due to dysregulation of dendritic cells (DCs), indicating correlation of Th1 polarization and development of glomerulonephritis. To further analyze the abnormality of DC activation, we tried to identify factors involved in DC regulation by microarray analysis using OSM-deficient DCs. Currently, we are investigating functions of some candidate genes.