Dissecting unique functions of IgM and IgD BCRs in tolerance and autoimmunity

剖析 IgM 和 IgD BCR 在耐受和自身免疫中的独特功能

基本信息

批准号：
9193713
负责人：
JULIE ZIKHERMAN
金额：
$ 34.87万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9193713
关键词：
Address Antibodies Antigen Presentation Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Responses Autoimmunity B cell repertoire B-Cell Activation B-Cell Development B-Lymphocytes Binding Biochemical Genetics Biological Markers Bone Marrow CD22 gene Cells Characteristics Coupled Coupling Data Development Disease Down-Regulation Epitopes Germ Lines Goals Health Homeostasis Human Immune Immune Tolerance Immune response Immunization Immunoglobulin Class Switching Immunoglobulin D Immunoglobulin M Ligation Mediating Membrane Modeling Mus Mutate Mutation Nuclear Nucleic Acid Binding Nucleic Acids PTPRC gene Pathogenesis Patients Play Population Process Production Property Protein Tyrosine Phosphatase Receptor Signaling Receptors, Antigen, B-Cell Recruitment Activity Reporter Role Signal Pathway Signal Transduction Specificity Systemic Lupus Erythematosus T-Lymphocyte Therapeutic Intervention Time antigen binding autoreactive B cell autoreactivity central tolerance genetic approach in vivo lupus prone mice mouse model novel peripheral tolerance prevent receptor response trafficking

项目摘要

Project Summary: “Dissecting unique functions of IgM and IgD BCRs in tolerance and autoimmunity” The prototypical autoimmune disease systemic lupus erythematosus (SLE) is characterized by anti- nuclear autoantibodies (ANAs) that serve not only as critical biomarkers of disease, but also play a central role in pathogenesis. Surprisingly, despite central tolerance mechanisms such as receptor editing and deletion of autoreactive B cells during bone marrow development, up to 30% of mature human B cells nevertheless harbor some degree of ANA-reactivity. This suggests that additional peripheral tolerance mechanisms must keep such potentially dangerous clones in check. We have recently characterized a novel fluorescent reporter mouse line, Nur77-eGFP, that is sensitive to antigen-dependent B cell receptor (BCR) signaling in vivo. The most highly fluorescent naïve B cells from these mice have recognized endogenous antigen, and are enriched for ANA- reactivity. The Nur77-eGFP reporter thus identifies ANA-reactive B cells in a diverse, normal repertoire, enabling us to track and isolate such cells. We have shown that these ANA-reactive B cells down-regulate expression of the IgM isotype BCR, resulting in dampened responses to IgM stimulation. However, naïve B cells uniquely express a second BCR isotype, IgD, with the same epitope-binding domain as IgM. In contrast to IgM, IgD expression and signaling in ANA-reactive B cells are unperturbed. How does IgM downregulation limit autoimmune responses to self-antigens despite high IgD expression? Each BCR isotype alone is capable of mediating B cell development and responses to immunization with model antigens. In contrast to such apparent redundancy, we have new preliminary data to show that B cells lacking IgM and expressing only IgD are completely prevented from contributing to autoantibody production in a mouse model of SLE. It has recently been shown that IgM, but not IgD, is uniquely sensitive to monovalent antigens. However, relevant nucleic acid-associated autoantigens in SLE are thought to be membrane associated and multivalent suggesting that other distinctive properties of IgM may be important for autoantibody production. In this proposal we intend to identify the mechanisms by which IgM and IgD differentially regulate B cells in the context of health and disease. To do so: (1) We will take advantage of mice deficient for either IgM or IgD to explore how B cells expressing each isotype alone are recruited to secrete pathogenic autoantibodies in two models of systemic autoimmunity with distinct disease mechanisms (Lyn-/- and BAFF Tg). (2) We will determine how the IgM and IgD BCRs traffic to endosomal compartments to recruit costimulatory signals via TLRs7/9 and via MHCII presentation of antigen to T cells. (3) We will explore how differential coupling of IgM and IgD to B cell stimulatory and inhibitory co-receptors alters downstream signaling and contributes to B cell tolerance. Together these studies will define how IgM down-modulation limits B cell responses to self- antigens. This tolerance checkpoint may represent a novel target for therapeutic intervention to re- establish immune homeostasis in patients with SLE and other autoantibody-mediated diseases.

项目摘要：“在耐受性和自身免疫性中剖析IGM和IGD BCR的独特功能” 原型自身免疫性疾病全身性红斑狼疮（SLE）的特征是核自身抗体（ANA）不仅是疾病的关键生物标志物，而且还起着核心作用在发病机理中。令人惊讶的是，任务中心容忍机制，例如接收器编辑和删除骨髓发育过程中的自动反应性B细胞，多达30％的成熟人类B细胞仍然藏有某种程度的ANA反应性。这表明额外的外围耐受性机制必须保持这样检查潜在的危险克隆。我们最近表征了一种新型的荧光记者小鼠系列， NUR77-EGFP，对体内抗原依赖性B细胞受体（BCR）信号敏感。最高的这些小鼠的荧光幼稚的B细胞已识别出内源性抗原，并富含Ana- 反应性。因此使我们能够跟踪和分离此类细胞。我们已经表明这些ANA反应性B细胞下调 IgM同种型BCR的表达，导致对IgM刺激的响应减弱。但是，天真b 细胞独特地表达第二个BCR同种型IgD，具有与IgM相同的表位结合域。与 ANA反应B细胞中的IgM，IgD表达和信号传导不受干扰。 IgM下调如何限制对自我抗原的自身免疫反应希望高IgD表达吗？每个BCR同种型都有能力用模型抗原介导B细胞的发育和对免疫的反应。与此相反明显的冗余，我们有新的初步数据，以表明缺乏IgM的B细胞仅表示IgD 完全阻止在SLE的小鼠模型中贡献自身抗体的产生。它有最近显示，IgM而不是IgD对单价抗原具有独特的敏感。但是，相关 SLE中与核酸相关的自身抗原被认为是膜相关的和多价的表明IgM的其他独特特性对于自身抗体的产生可能很重要。在这个提案我们打算确定IgM和IgD对B细胞中B细胞不同调节B细胞的机制健康与疾病的背景。为此：（1）我们将利用缺乏IGM或IGD的小鼠探索如何仅募集单独表达每种同种型的B细胞在两个中招募到秘密的致病自身抗体具有不同疾病机制（Lyn - / - 和Baff TG）的全身自身免疫模型。（2）我们会的确定IgM和IgD BCR如何通过招募共同刺激信号的内体隔室的流量 TLRS7/9以及通过MHCII向T细胞的抗原表示。（3）我们将探讨IgM的差异耦合 IgD到B细胞刺激和抑制性共受体会改变下游信号，并有助于B细胞宽容。这些研究一起将定义IgM下调如何限制B细胞对自我的反应抗原。该耐受性检查点可能代表了治疗干预的新目标在患有SLE和其他自身抗体介导的疾病的患者中建立免疫稳态。