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，其外分泌组织受损，导致泪液丢失 和唾液原发性干燥综合征（primarySS，pSS）是一种累及涎腺和泪腺组织的疾病，可导致多种严重的全身性疾病 表现。自身免疫的特点是丧失对自身的耐受性，而自身抗体是这一点的指示 无法清除自身反应性B细胞。虽然IgG自身抗体明显介导病理，但我们对IgG自身抗体的理解是， IgM在SS疾病中的作用令人惊讶地有限。目前，SS的治疗仅是姑息性的; 没有针对疾病病因学的疗法。我们的中心假设是自身反应IgM 在特定的先天性B细胞亚群中，这种IgM减弱了SS的发病机制。我们的目标是建立 IgM+唾液B细胞的来源，并确定是否富集了特异性IgM+ B细胞亚群， 自体反应性此外，我们将评估调节IgM水平的受体（FcμR）的表达，并确定是否 IgM在SS中主要是致病性或保护性的。我们将检测pSS小鼠的自身反应性IgM+ B细胞， 模型我们还将pSS小鼠的血清IgM转移到缺乏B细胞的SS动物中，并评估SS样唾液 腺体疾病的表现。这个建议的基本原理是IgM在许多自身免疫性疾病中具有保护作用。 疾病一些研究表明IgM+ B细胞在SS中失调，并且在pSS中鉴定出自身反应性IgM 小鼠模型和患者。目前，B细胞耗竭疗法正在SS患者中进行测试，并且许多这样的治疗方法已经被证实是有效的。 治疗显著降低IgM水平。虽然这是一种很有前途的新疗法，但IgM抗体的后果 这种疾病的长期减少还没有得到很好的理解。我们将通过完成以下两项来验证我们的假设： 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)到 探讨IgM在pSS中的调节作用。这项研究是创新的，因为它将研究一类 抗体（IgM）尚未在SS中深入研究。IgM的特异性以及它是否主要 致病性或保护性目前尚不清楚。IgM在健康和疾病中的重要性是众所周知的， 和IgM+ B细胞可能对免疫调节和病理生理学有深远的影响， 自身免疫，鉴于最近发现的人IgM+ B1，记忆和浆细胞。这项工作将提供 与IgM在SS和其他自身免疫性疾病中的调节和作用相关的新知识， 特征在于IgM失调，如系统性红斑狼疮和类风湿性关节炎。该提案 意义重大，因为具有全身性疾病表现的pSS患者的IgM水平往往升高。 然而，目前尚不清楚哪种B细胞亚群产生这种IgM，以及SS中的IgM自身抗体是否与IgM相关。 致病性或作为补偿性保护机制的一部分出现。因此，鉴定B细胞是重要的 在SS患者中负责自身反应性IgM产生的亚群，并确定IgM是否在SS患者中具有保护性。 SS疾病的背景。维持甚至扩增分泌IgM的B细胞的治疗可以改善 疾病，并可能代表一种新的方法来管理SS患者。

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.