Role of CD97 in Xenobiotic-Induced Autoimmunity

描述(申请人提供)：异源物质，如二氧化硅和汞，与人体和小鼠的系统性自身免疫有关。虽然机制研究已经解决了暴露于这些异物引起的免疫功能障碍，但很少有人研究免疫调节在抑制异物诱导的全身自身免疫发展中的作用。衰变加速因子(DAF，CD55)是一种补体调节蛋白，是获得性免疫反应的负调节因子。最近的研究表明，CD55的缺乏加剧了TH1驱动的器官特异性和全身性自身免疫。此外，CD55在特发性小鼠狼疮的T和B细胞上减少，在小鼠汞诱导的自身免疫(MHgIA)中在CD4T细胞上特异性减少。SLE患者淋巴细胞上的CD55也被证明是减少的。CD55受体的可溶性CD97刺激CD4T细胞，可导致IL-2依赖的IL-10表达和自身免疫促进性细胞因子--干扰素？和IL-17提示，可溶性CD97(SCD97)与CD55的相互作用促使CD4T细胞从促炎反应转向免疫抑制。这让人想起了另一种补体调节蛋白CD46对IL-2依赖的调节性IL-10CD4T细胞的诱导。CD46的参与将促炎TH1细胞转换为IL-10免疫调节表型。根据CD46参与和CD97介导的CD55刺激的相似性，我们推测汞和二氧化硅诱导的自身免疫可能是由于CD97-CD55相互作用无效导致TH1向Treg分化的缺陷所致。(注：通过CD46和CD55激活产生IL-10的机制可能不同，因为一个(CD46)需要补充，而另一个(CD55)不需要。)如果这一假设是正确的，那么在IL-2存在的情况下，sCD97应该介导CD4T细胞Treg表型的增加和TH1表型的减少。这应该会导致促炎细胞因子的表达减少，并改善自身免疫。SCD97在调节异种生物诱导的自身免疫中的作用将从以下两个方面进行研究：1)sCD97刺激是否导致具有T调节细胞的细胞因子谱和表型的CD4T细胞？2)CD97是否影响异种诱导的自身免疫的表达？实验证实，CD97调节淋巴样细胞活性和系统自身免疫的发展将有助于我们理解自身免疫性疾病的过程，并有助于开发新的治疗干预措施。

DESCRIPTION (provided by applicant): Xenobiotics such as silica and mercury are associated with systemic autoimmunity in humans and mice. While mechanistic studies have addressed the immune dysfunction resulting from exposure to these xenobiotics little has been done to examine the role of immune regulation in suppressing development of xenobiotic-induced systemic autoimmunity. Decay accelerating factor (DAF, CD55), a complement regulatory protein, functions as a negative regulator of adaptive immune responses. Recent studies have shown that deficiency of CD55 exacerbates TH1-driven organ specific and systemic autoimmunity. Additionally, CD55 is reduced on T and B cells in idiopathic murine lupus and is specifically reduced on CD4+ T cells in murine mercury- induced autoimmunity (mHgIA). CD55 has also been shown to be reduced on lymphocytes of patients with SLE. Stimulation of CD4+ T cells with a soluble form of the CD55 receptor, CD97, results in IL-2 dependent expression of IL-10 and reduction of the autoimmunity promoting cytokines IFN-? and IL-17 suggesting that the interaction of soluble CD97 (sCD97) with CD55 drives CD4+ T cells away from a proinflammatory response towards immunosuppression. This is reminiscent of the IL-2 dependent induction of regulatory IL-10+CD4+ T cells by another complement regulatory protein CD46. Engagement of CD46 switches proinflammatory TH1 cells toward the IL-10+ immunoregulatory phenotype. Based on the similarities between CD46 engagement and CD97 mediated stimulation of CD55 we hypothesize that autoimmunity induced by mercury and silica may arise because of a defect in TH1 to Treg differentiation due to ineffective CD97-CD55 interaction. (Note: The mechanism of IL-10 production via CD46 and CD55 activation is likely different as one (CD46) requires complement and the other (CD55) does not.) If this hypothesis is correct then sCD97, in the presence of IL-2, should mediate increases in the Treg phenotype and reduction of the TH1 phenotype of CD4+ T cells. This should lead to reduced proinflammatory cytokine expression and amelioration of autoimmunity. The role of sCD97 in regulating xenobiotic-induced autoimmunity will be examined in the following two aims: 1) Does sCD97 stimulation result in CD4+ T cells with the cytokine profile and phenotype of T regulatory cells? and 2) Does CD97 influence expression of xenobiotic - induced autoimmunity? Experimental confirmation that CD97 regulates lymphoid cell activity and development of systemic autoimmunity will contribute significantly to our understanding of the autoimmune disease process and aid in the development of novel therapeutic interventions.