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：
9899730
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 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899730
关键词：
Address Antibodies Antigen Presentation Antigens Autoantibodies Autoantigens 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 Dangerousness 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 Immunoglobulin Somatic Hypermutation Ligation Mediating Membrane Modeling Mus Mutate Nucleic Acid Binding Nucleic Acids PTPRC gene Pathogenesis Pathogenicity Patients Play Population Process Production Property Protein Tyrosine Phosphatase Receptor Signaling Receptors, Antigen, B-Cell Reporter Role Signal Pathway Signal Transduction Specificity Study models Systemic Lupus Erythematosus T-Lymphocyte Therapeutic Intervention Time To autoantigen antigen binding autoreactive B cell autoreactivity central tolerance genetic approach in vivo lupus prone mice mouse model new therapeutic target novel peripheral tolerance prevent receptor recruit response systemic autoimmune disease systemic autoimmunity 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：“剖析 IgM 和 IgD BCR 在耐受性和自身免疫方面的独特功能” 典型的自身免疫性疾病系统性红斑狼疮 (SLE) 的特点是抗核自身抗体（ANA）不仅作为疾病的关键生物标志物，而且发挥着核心作用令人惊讶的是，尽管存在中央耐受机制，例如受体编辑和删除。骨髓发育过程中存在自身反应性 B 细胞，但高达 30% 的成熟人类 B 细胞仍具有自身反应性 B 细胞一定程度的 ANA 反应性，这表明额外的外周耐受机制必须保持这种状态。我们最近鉴定了一种新型荧光报告小鼠品系， Nur77-eGFP，对体内抗原依赖性 B 细胞受体 (BCR) 信号敏感。来自这些小鼠的荧光幼稚 B 细胞已识别内源性抗原，并且富含 ANA- 因此，Nur77-eGFP 报告基因可识别多种正常细胞库中的 ANA 反应性 B 细胞，使我们能够追踪和分离此类细胞。我们已经证明这些 ANA 反应性 B 细胞下调。 IgM 同种型 BCR 的表达，导致对 IgM 刺激的反应减弱。细胞独特地表达第二种 BCR 同种型 IgD，与 IgM 具有相同的表位结合域。 ANA 反应性 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。尽管 IgD 表达较高，但每种 BCR 同种型都能够对自身抗原产生自身免疫反应吗？与此相反，介导 B 细胞发育和对模型抗原免疫的反应。明显冗余，我们有新的初步数据表明 B 细胞缺乏 IgM 且仅表达 IgD 在 SLE 小鼠模型中，它们完全无法促进自身抗体的产生。最近的研究表明，IgM（而非 IgD）对单价抗原具有独特的敏感性。 SLE 中的核酸相关自身抗原被认为是膜相关的和多价的这表明 IgM 的其他独特特性可能对自身抗体的产生很重要。提议我们打算确定 IgM 和 IgD 差异调节 B 细胞的机制为此，我们将利用缺乏 IgM 或 IgD 的小鼠来进行研究。探索单独表达每种同种型的 B 细胞如何被招募来分泌两种致病性自身抗体具有不同疾病机制的系统性自身免疫模型（Lyn-/- 和 BAFF Tg）（2）我们将。确定 IgM 和 IgD BCR 如何运输至内体区室以通过以下方式招募共刺激信号 TLRs7/9 并通过 MHCII 将抗原呈递给 T 细胞 (3) 我们将探讨 IgM 的差异偶联方式。 B 细胞刺激性和抑制性共受体的 IgD 和 IgD 改变下游信号传导并有助于 B 细胞这些研究将共同确定 IgM 下调如何限制 B 细胞对自身的反应。该耐受检查点可能代表治疗干预的新目标。在 SLE 和其他自身抗体介导的疾病患者中建立免疫稳态。