Toll-Like Receptors in Systemic Autoimmune Disease

描述（由申请人提供）： 系统性红斑狼疮（SLE）是一种慢性危及生命的自身免疫性疾病，目前在美国每年折磨多达2，000，000人。用于治疗SLE患者的治疗选择包括诸如类固醇、细胞毒性药物和抗疟药的药剂。虽然这些疗法可以降低疾病的严重程度，但它们通常具有限制其长期使用的有害副作用。更好地了解触发疾病发作的因素可以促进特异性靶向自身反应效应细胞的药物的开发，而不会产生与当前治疗方案相关的衰弱副作用和一般免疫抑制。该提议基于最近的研究，该研究鉴定了参与自身反应性B细胞和（自身）抗原呈递树突状细胞的活化的新途径。我们的小组已经表明，由BCR或Fc γ R结合的含染色质的免疫复合物（染色质- IC）被递送到内部隔室，在那里它们通过MyD 88依赖性Toll样受体9（TLR 9）途径激活细胞。因此，TLR 9途径的抑制可以特异性地阻断系统性自身免疫疾病的发展和/或进展，而不干扰对外源蛋白的免疫应答。为了利用这种潜在的治疗机会，有必要进一步阐明这种双重受体模式的机制和普遍适用性。通过将项目研究人员的研究努力与不同的研究背景-- B细胞调节--相结合，可以最好地实现这一目标（Marshak-Rothstein）、抗原摄取和囊泡运输（Corley）、染色质重塑（Viglianti）、树突状细胞活化（Rifkin）和自身免疫性疾病的转基因模型（Shlomchik）-解决以下问题：（a）B细胞和树突细胞的染色质-IC接合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是如何加工的，TLR 9是如何影响这些事件的持续性和位点的（项目1）？(d)TLR而不是TLR 9介导对非染色质相关自身抗原的应答吗（项目2，3，）？(e)TLR在系统性自身免疫中的体内作用是什么（项目3）？最后（f）阻断TLR 9信号通路的药物能否特异性靶向治疗该通路（项目1，2）？这些研究的结果应该提供重要的见解，这将促进非侵入性疗法的发展，用于治疗系统性自身免疫性疾病，如SLE。

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.