Toll-Like Receptors in Systemic Autoimmune Disease

描述(由申请人提供)： 系统性红斑狼疮(SLE)是一种威胁生命的慢性自身免疫性疾病，目前在美国每年有多达200万人受到影响。治疗系统性红斑狼疮患者的治疗选择包括类固醇、细胞毒性药物和抗疟疾药物。虽然这些疗法可以降低疾病的严重性，但它们往往有有害的副作用，限制了它们的推广使用。更好地了解引发疾病发生的因素可以促进专门针对自身反应效应细胞的药物的开发，而不会出现与当前治疗方案相关的衰弱副作用和一般免疫抑制。这一建议是基于最近的研究，这些研究发现了一种新的途径，涉及自身反应性B细胞和(自身)抗原呈递的树突状细胞的激活。我们的团队已经证明，含有染色质的免疫复合物(染色质-IC)被BCR或FcGammaR结合到一个内部隔室，在那里它们通过MyD88依赖的Toll样受体9(TLR9)途径激活细胞。因此，抑制TLR9通路可以特异性地阻止全身性自身免疫性疾病的发生和/或进展，而不会干扰对外来蛋白的免疫反应。为了利用这一潜在的治疗机会，有必要进一步描述这一双受体范例的机制和普遍适用性。通过结合具有不同研究背景的项目调查人员的研究努力-B细胞调节(Marshak-Rothstein)、抗原摄取和囊泡运输(Corley)、染色质重塑(Viglianti)、树突状细胞激活(Rifkin)和自身免疫病的转基因模型(Shlomchik)-来解决以下问题：(A)B细胞和树突状细胞染色质-IC参与的独特功能后果是什么(项目1和2)？(B)染色质结构的哪些方面决定了该系统的免疫原性(项目1)？(C)染色质IC是如何处理的，TLR9如何影响这些事件的持久性和部位(项目1)；(D)TLR9以外的TLR是否介导了对非染色质相关自身抗原的反应(项目2、3)？(E)TLRs在全身性自身免疫中的体内作用是什么(项目3)？最后(F)是否可以用阻断TLR9信号通路的药物在治疗上针对这一途径(项目1，2)？这些研究的结果应该提供重要的见解，将促进非侵入性疗法的发展，以治疗系统性自身免疫性疾病，如系统性红斑狼疮。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a chronic life-threatening autoimmune disorder that currently afflicts up to 2,000,000 individuals within the United States each year. Therapeutic options for treating patients with SLE include agents such as steroids, cytotoxic drugs, and anti-malarials. Although these therapies can reduce disease severity, they often have deleterious side effects that limit their extended use. A better understanding of the factors that trigger disease onset could facilitate the development of drugs that specifically target the autoreactive effector cells without the debilitating side effects and general immunosuppression associated with curent treatment protocols. This proposal is based on recent studies that identify a novel pathway involved in the activation of both autoreactive B cells and (auto)antigen presenting dendritic cells. Our group has shown that chromatin-containing immune complexes (chromatin- IC), bound by either the BCR or an FcgammaR, are delivered to an internal compartment where they activate the cells via a MyD88-dependent Toll-like receptor 9 (TLR9) pathway. Thus, inhibition of the TLR9 pathway may specifically block the development and/or progression of systemic autoimmune disease without interfering with immune responses to foreign proteins. To take advantage of this potential therapeutic opportunity, it will be necessary to further delineate the mechanism and general applicability of this dual receptor paradigm. The goal can best be met by combining the research endeavors of program investigators with diverse research backgrounds - B cell regulation (Marshak-Rothstein), antigen uptake and vesicle trafficking (Corley), chromatin remodeling (Viglianti), dendritic cell activation (Rifkin), and transgenic models of autoimmune disease (Shlomchik) - to address the following questions: (a) What are the unique functional consequences of chromatin-IC engagement of B cells and dendritic cells (project 1 and 2)? (b) What aspects of chromatin structure determine immunogenicity in this system (project 1)? (c) How are chromatin-IC processed and how does TLR9 affect the persistence and site of these events (project 1)?; (d) Do TLR other than TLR9 mediate responses to non-chromatin associated autoantigens (project 2, 3,)? (e) What is the in vivo role of TLRs in systemic autoimmunity (project 3)? and finally (f) Can this pathway be specifically targeted therapeutically with agents that block the TLR9 signaling pathway (project 1,2)? The results of these studies should provide important insights that will facilitate the development of non-invasive therapies for the treatment of systemic autoimmune diseases such as SLE.