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

• 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
• 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

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.

项目总结：“解剖IgM和IgD bcr在耐受性和自身免疫中的独特功能”