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功能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，SLE的发病机制仍不清楚。我们发现，IL-6家族成员之一的肿瘤抑制素M （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缺乏的小鼠进行了表征，以了解SLE的原因。组织学分析显示，肺和脾脏出现炎症，活化的T细胞浸润肺。此外，在osm缺陷的雄性小鼠中观察到后肢关节炎。这些结果表明，osm缺陷小鼠自发发展为SLE，并伴有多器官炎症。为了解决OSM和自身免疫之间的关系，我们检查了OSM缺陷小鼠的胸腺，发现胸腺发育不全和胸腺结构改变。在T细胞正常发育的同时，osm缺陷胸腺中检测到大量凋亡的胸腺细胞。在osm缺陷小鼠中，具有强吞噬活性的独特胸腺巨噬细胞的发育受到损害，这表明来自胸腺的自身抗原可能是自身抗体产生的原因。由于树突状细胞（dc）的失调，osm缺陷小鼠的外周免疫应答中Th1应答增强，表明Th1极化与肾小球肾炎的发展相关。为了进一步分析DC激活的异常，我们试图通过使用osm缺陷DC的微阵列分析来确定参与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.