Role of CD97 in Xenobiotic-Induced Autoimmunity

描述（由申请人提供）：人类和小鼠的全身自身免疫与诸如二氧化硅和汞之类的外源性药物有关。虽然机制研究已经解决了暴露于这些外源性药物导致的免疫功能障碍，但很少有人研究免疫调节在抑制外源性药物诱导的全身自身免疫发展中的作用。衰减加速因子（DAF, CD55）是一种补体调节蛋白，在适应性免疫应答中起负调节作用。最近的研究表明，CD55缺乏会加剧th1驱动的器官特异性和系统性自身免疫。此外，在特发性小鼠狼疮中，CD55在T细胞和B细胞上减少，在小鼠汞诱导的自身免疫（mHgIA）中，CD55在CD4+ T细胞上特异性减少。CD55也被证明在SLE患者淋巴细胞上减少。CD55受体的可溶性形式CD97刺激CD4+ T细胞，导致IL-2依赖性IL-10的表达和自身免疫促进细胞因子IFN-？和IL-17表明可溶性CD97 （sCD97）与CD55的相互作用驱使CD4+ T细胞从促炎反应转向免疫抑制。这让人想起另一种补体调节蛋白CD46对IL-2依赖性诱导的调节性IL-10+CD4+ T细胞。CD46的参与将促炎TH1细胞转变为IL-10+免疫调节表型。基于CD46参与和CD97介导的CD55刺激之间的相似性，我们假设汞和二氧化硅诱导的自身免疫可能是由于CD97-CD55无效相互作用导致TH1向Treg分化的缺陷。（注：通过CD46和CD55激活产生IL-10的机制可能不同，因为一个（CD46）需要补体，另一个（CD55）不需要。）如果这个假设是正确的，那么在IL-2存在的情况下，sCD97应该介导CD4+ T细胞Treg表型的增加和TH1表型的减少。这将导致促炎细胞因子表达的减少和自身免疫的改善。sCD97在调节外源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刺激是否会导致CD4+ T细胞具有T调节细胞的细胞因子谱和表型？2) CD97是否影响外源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性自身免疫的发展将有助于我们对自身免疫性疾病过程的理解，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.