Role of CD97 in Xenobiotic-Induced Autoimmunity

CD97 在异生素诱导的自身免疫中的作用

• 批准号: 8300435
• 负责人: Kenneth Michael Pollard
• 金额: $ 28.43万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-11 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300435
• 关键词: Address; Antigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biological Assay; C3 Deficiency; CD28 gene; CD3 Antigens; CD4 Positive T Lymphocytes; CD46 Antigen; CD55 Antigens; CD97 gene; Cells; Complement; Complement Activation; Complementary DNA; Defect; Development; Disease; Environmental Risk Factor; Exposure to; Human; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immunosuppression; In Vitro; Inflammation; Interferons; Interleukin-10; Interleukin-17; Interleukin-2; Interleukin-4; Lead; Lupus; Lymphocyte; Lymphoid Cell; Mediating; Mercury; Modeling; Molecular; Mus; Organ; Patients; Phenotype; Plasmids; Process; Production; Recombinants; Regulation; Regulatory T-Lymphocyte; Role; Silicon Dioxide; Systemic Lupus Erythematosus; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thymus Gland; Xenobiotics; base; cytokine; genetic regulatory protein; in vivo; novel therapeutic intervention; peripheral tolerance; protein function; protein profiling; receptor; research study; response

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. PUBLIC HEALTH RELEVANCE: Studies have shown that stimulation of CD4+ T cells with soluble CD97 can alter the profile of proteins (called cytokines) they secrete from autoimmunity promoting to immuneregulatory. In this application we propose to determine the mechanism by which soluble CD97 modulates T cell activity to suppress development of autoimmunity induced by environmental factors.

描述（由申请人提供）：二氧化硅和汞等外源性物质与人类和小鼠的全身性自身免疫相关。虽然机制研究已经解决了暴露于这些外源性物质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物质诱导的全身性自身免疫发展中的作用。衰变加速因子（Decay Accelerating Factor，CD 55）是一种补体调节蛋白，在获得性免疫应答中起负调节作用。最近的研究表明，CD 55的缺乏加剧了TH 1驱动的器官特异性和全身性自身免疫。此外，在特发性鼠狼疮中T和B细胞上的CD 55减少，并且在鼠汞诱导的自身免疫（mHgIA）中CD 4 + T细胞上特异性减少. CD 55在SLE患者的淋巴细胞上也显示减少。用可溶性形式的CD 55受体CD 97刺激CD 4 + T细胞，导致IL-10的IL-2依赖性表达和自身免疫促进细胞因子IFN-？和IL-17，表明可溶性CD 97（sCD 97）与CD 55的相互作用驱使CD 4 + T细胞远离促炎反应而朝向免疫抑制。这使人想起另一种补体调节蛋白CD 46对调节性IL-10+ CD 4 + T细胞的IL-2依赖性诱导。CD 46的参与使促炎性TH 1细胞向IL-10+免疫调节表型转变。基于CD 46参与和CD 97介导的CD 55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无效的CD 97-CD 55相互作用导致的TH 1向Treg分化缺陷而引起的。(Note：通过CD 46和CD 55活化产生IL-10的机制可能不同，因为一种（CD 46）需要补体，而另一种（CD 55）不需要。如果这一假设是正确的，那么在IL-2的存在下，sCD 97应该介导CD 4 + T细胞的Treg表型的增加和TH 1表型的减少。这将导致减少促炎细胞因子的表达和改善自身免疫。sCD 97在调节外源性自身免疫中的作用将从以下两个方面进行研究：1）sCD 97刺激是否导致具有T调节细胞的细胞因子谱和表型的CD 4 + T细胞？CD 97是否影响外源性自身免疫的表达？实验证实，CD 97调节淋巴细胞的活性和发展的系统性自身免疫性将有助于我们的理解显着的自身免疫性疾病的过程，并在开发新的治疗干预援助。 公共卫生相关性：研究表明，用可溶性CD 97刺激CD 4 + T细胞可以改变它们分泌的蛋白质（称为细胞因子）的谱，从促进自身免疫变为免疫调节。在本申请中，我们提出确定可溶性CD 97调节T细胞活性以抑制由环境因素诱导的自身免疫发展的机制。