Analysis of the role of IgM in Sjogrens syndrome

项目摘要 干燥综合征(SS)是一种自身免疫性疾病，外分泌组织受损，导致泪水丢失 还有唾液。原发SS(PSS)累及唾液和泪腺组织，导致多种严重的全身疾病 表现形式。自身免疫的特征是对自身的耐受性丧失，自身抗体就是这种情况的征兆。 未能消除自我反应的B细胞。虽然免疫球蛋白自身抗体明显地介导了病理，但我们对 令人惊讶的是，IgM在SS疾病中的作用是有限的。目前，对SS的治疗只是姑息治疗； 目前还没有针对疾病病因的治疗方法。我们的中心假设是，自身反应性IgM集中在 在特定的先天类B细胞亚群中，这种IgM可以减轻SS的发病。我们的目标是建立 检测唾液中IgM+B细胞的来源，并确定特定的IgM+B细胞亚群是否被浓缩 自身反应性。此外，我们将评估调节免疫球蛋白水平的受体(FcμR)的表达，并确定是否 在SS中，IgM主要是致病或保护性的。我们将检测PSS小鼠的自身反应性IgM+B细胞 模特。我们还将把PSS小鼠的血清IgM转移到缺乏B细胞的SS动物身上，并评估类似SS的唾液 腺病表现。这一建议理由是，IgM在许多自身免疫中具有保护性作用 疾病。多项研究表明，在SS中，IgM+B细胞调节失调，在PSS中发现有自身反应性的IgM 小鼠模型和患者。目前，B细胞去除疗法正在SS患者和许多此类患者中进行测试 治疗可显著降低IgM水平。虽然这是一种很有希望的新疗法，但IgM的后果 这种疾病的长期减少还没有很好的了解。我们将通过完成两个测试来验证我们的假设 具体目的：(1)利用PSS小鼠模型评价自身反应性IgM的来源和特异性。(2)至 检测IgM在PSS中的调节和作用。这项研究具有创新性，因为它将考察一类 在SS中尚未深入研究的抗体(IgM)。免疫球蛋白M的特异性以及它是否主要是 致病或保护性目前尚不清楚。免疫球蛋白M在健康和疾病中的重要性是众所周知的， 而IgM+B细胞可能对慢性粒细胞白血病患者的免疫调节和病理生理有深远的影响 自身免疫，考虑到最近发现的人类IgM+B1、记忆和浆细胞。这项工作将提供 关于IgM在SS和其他自身免疫性疾病中的调节和作用的新知识 以免疫球蛋白M失调为特征，如系统性红斑狼疮和类风湿性关节炎。这项建议 意义重大，因为有全身性疾病表现的PSS患者往往有升高的IgM水平。 然而，目前尚不清楚是哪些B细胞亚群产生了这种IgM，以及SS中的IgM自身抗体是否 致病或作为补偿保护机制的一部分而产生。因此，确定B细胞是很重要的 SS患者产生自身反应性IgM的亚群及其是否具有保护性 SS病的背景。维持甚至扩大分泌IgM的B细胞的治疗可能会改善 这可能代表了一种治疗SS患者的新方法。

Project Summary Sjögren’s syndrome (SS) is an autoimmune disease in which exocrine tissue is damaged, resulting in loss of tears and saliva. Primary SS (pSS) affects salivary and lacrimal tissue and results in many serious systemic disease manifestations. Autoimmunity is characterized by loss of tolerance to self, and autoantibodies are indicative of this failure to eliminate self-reactive B cells. While IgG autoantibodies clearly mediate pathology, our understanding of the role of IgM in the context of SS disease is surprisingly limited. Currently, treatments for SS are only palliative; there are no therapies that target disease etiology. Our central hypothesis is that self-reactive IgM is concentrated in specific innate-like B cell subsets and this IgM attenuates SS pathogenesis. Our objectives are to establish the source of IgM+ salivary B cells and to determine whether specific IgM+ B cell subsets are enriched for autoreactivity. Moreover, we will assess expression of a receptor that regulates IgM levels (FcμR) and determine if IgM is primarily pathogenic or protective in SS. We will examine autoreactive IgM+ B cells from a pSS murine model. We will also transfer serum IgM from pSS mice to SS animals lacking B cells and assess SS-like salivary gland disease manifestations. The rationale for this proposal is that IgM is protective in many autoimmune diseases. Several studies show IgM+ B cells are dysregulated in SS and self-reactive IgM is identified in pSS mouse models and patients. Currently, B cell depletion therapies are being tested in SS patients and many such therapies reduce IgM levels significantly. While this is a promising new treatment, the consequences of IgM reduction long-term in this disease are not well understood. We will test our hypothesis by completion of two specific aims: (1) To evaluate the source and specificity of autoreactive IgM using a pSS mouse model. (2) To examine the regulation and function of IgM in pSS. This study is innovative because it will examine a class of antibody (IgM) that has not been studied in depth in SS. The specificity of IgM and whether it is primarily pathogenic or protective is unclear at present. The importance of IgM in health and disease is well established, and IgM+ B cells likely have a profound impact on immune regulation and pathophysiology in patients with autoimmunity, given the recent discovery of human IgM+ B1, memory, and plasma cells. This work will provide new knowledge related to the regulation and role of IgM in SS, and other autoimmune disease that are characterized by IgM dysregulation, such as systemic lupus erythematosus and rheumatoid arthritis. The proposal is significant because pSS patients with systemic disease manifestations tend to have elevated IgM levels. However, it is unclear at present which B cell subsets produce this IgM, and whether IgM autoantibodies in SS are pathogenic or arise as part of a compensatory protective mechanism. Thus, it is important to identify the B cells subsets responsible for autoreactive IgM production in SS patients and to determine whether IgM is protective in the context of SS disease. Therapeutics that maintain or even expand IgM-secreting B cells may ameliorate disease, and may represent a novel approach for management of SS patients.