Analysis of the role of IgM in Sjogrens syndrome

IgM在干燥综合征中的作用分析

• 批准号: 9507227
• 负责人: Jill Marie Kramer
• 金额: $ 15.95万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-16 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9507227
• 关键词: Abnormal Cell; Address; Affect; Animals; Antibodies; Attenuated; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell therapy; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Cells; Characteristics; Clinical; Data; Development; Diagnosis; Disease; Early Diagnosis; Etiology; Event; Failure; Functional disorder; Funding; Future; Genetic Transcription; Goals; Health; Human; Immune; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Inbred NOD Mice; Individual; Inflammation; Investigation; Knockout Mice; Knowledge; Lymphoid Tissue; Mediating; Memory; Modeling; Mus; Oral; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Peripheral; Peritoneum; Plasma Cells; Population; Production; Proteins; Public Health; Regulation; Research; Rheumatoid Arthritis; Role; Saliva; Salivary; Salivary Gland Diseases; Salivary Glands; Sampling; Serum; Signal Transduction; Sjogren' s Syndrome; Source; Specificity; Spleen; Symptoms; Systemic Lupus Erythematosus; Systemic disease; Testing; Therapeutic; Tissues; Work; autoreactivity; curative treatments; experimental study; immunoregulation; improved; in vivo; innovation; lacrimal; mouse model; new therapeutic target; next generation sequencing; novel; novel strategies; novel therapeutics; palliative; prevent; receptor; receptor expression; salivary cell; targeted treatment

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.

项目摘要 Sjögren's综合征（SS）是一种自身免疫性疾病，外分泌组织受损，导致泪水丧失 和唾液。原发性SS（PSS）影响唾液和泪组织，并导致许多严重的全身性疾病 表现。自身免疫的特征是失去对自我的宽容，自身抗体表明了这一点 无法消除自反应的B细胞。虽然IgG自身抗体显然介导了病理学，但我们对 IgM在SS疾病背景下的作用令人惊讶地受到限制。目前，SS的治疗只是姑息治疗。 没有针对疾病病因的疗法。我们的中心假设是自我反应性IgM集中 在特定的先天B细胞子集中，该IgM减弱了SS发病机理。我们的目标是建立 IgM+唾液B细胞的来源，并确定特定的IgM+ B细胞是否富含 自动反应性。此外，我们将评估调节IgM水平（FCμR）的接收器的表达，并确定是否 IgM是原发性致病性或在SS中受保护的。我们将检查来自PSS鼠的自动反应性IgM+ B细胞 模型。我们还将将血清IgM从PSS小鼠转移到缺乏B细胞的SS动物并评估SS样唾液 腺体疾病表现。该提议的理由是IGM受到许多自身免疫性的保护 疾病。几项研究表明，IgM+ B细胞在SS中失调，PSS中鉴定出自反应性IgM 小鼠模型和患者。目前，B细胞部署疗法正在SS患者中进行测试 疗法大大降低了IgM水平。虽然这是一种有希望的新待遇，但IgM的后果 长期降低这种疾病尚不清楚。我们将通过完成两个来检验我们的假设 具体目的：（1）使用PSS鼠标模型评估自动反应性IGM的源和特异性。 （2）至 检查PSS中IgM的调节和功能。这项研究具有创新性，因为它将检查一类 在SS中尚未深入研究的抗体（IgM）。 IgM的特异性及其是否为主要 目前尚不清楚致病性或保护性。 IgM在健康和疾病中的重要性已经确定， IgM+ B细胞可能对患者的免疫调节和病理生理学产生深远影响 鉴于最近发现人IgM+ B1，记忆和浆细胞的自身免疫性。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有关的新知识 以IgM失调为特征，例如全身性红斑狼疮和类风湿关节炎。提案 很重要，因为患有全身性疾病表现的PSS患者往往具有升高的IgM水平。 但是，目前尚不清楚B细胞子集产生此IgM，以及SS中的IgM自身抗体是否为 致病性或作为补偿保护机制的一部分而产生。那很重要的是要识别B细胞 负责SS患者自动反应性IgM产生的子集，并确定IGM是否受到保护 SS疾病的背景。维持甚至扩展分泌IgM的B细胞的治疗剂可能会改善 疾病，可能代表了一种新型的SS患者治疗方法。