alpha v integrin regulation of B cell tolerance

B 细胞耐受的 α v 整合素调节

• 批准号: 10294130
• 负责人: Adam Lacy-Hulbert
• 金额: $ 20万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-16 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294130
• 关键词: Affect; Affinity; American; Animal Model; Antigens; Apoptotic; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Autophagocytosis; B cell differentiation; B-Cell Activation; B-Cell Development; B-Lymphocytes; CD19 gene; Cell Death; Cell Proliferation; Cells; Chronic; Complex; DNA; Data; Development; Endosomes; Etiology; Excision; Exposure to; Frequencies; Genetic; Goals; Grant; Homologous Gene; Immune Tolerance; Immune response; Immune signaling; Immune system; Immunoglobulin Class Switching; Inflammation; Inflammatory; Integrin alphaV; Integrins; Interferon-beta; Interferons; Kidney; Knock-out; Knockout Mice; Ligands; Link; Mediating; Mission; Modeling; Mouse Strains; Mus; Nucleic Acids; Organ; Pathway interactions; Patients; Pattern recognition receptor; Peripheral; Plasma Cells; Production; RNA; Receptor Signaling; Regulation; Regulatory Pathway; Research; Rheumatoid Arthritis; Role; Signal Transduction; Skin; Systemic Lupus Erythematosus; Testing; Toll-like receptors; Transgenic Mice; Translating; United States National Institutes of Health; Work; autoreactive B cell; autoreactivity; base; chronic inflammatory disease; design; experimental study; immunoregulation; in vivo; innovation; insight; lupus-like; mouse model; novel; novel therapeutic intervention; peripheral tolerance; recruit; response; trafficking

PROJECT SUMMARY There is a fundamental need to understand how the immune system discriminates self-antigens and regulates potentially harmful autoimmune responses. Increasing evidence from genetics and functional studies indicate that innate immune signaling in response to products caused by cell death is a major etiological factor in autoimmune and chronic inflammatory disease. Our long-term goal is to better understand how immune tolerance to antigens derived from apoptotic cells and other self-antigens is maintained and how this can break down in autoimmune diseases. The objective in this application is to understand how av integrins and components of the autophagy pathway contribute to B cell tolerance. Our central hypothesis is that av- mediated activation of autophagy components regulates TLR signaling in B cells, limiting cell proliferation, differentiation and production of autoantibodies. The rationale for this grant is that the proposed work will define the role of av-mediated autophagy in B cell tolerance, and develop better models for autoimmune disease. Furthermore, this work has the potential to translate into new therapeutic approaches through the use of existing compounds that target av and autophagy. Based on strong preliminary data, our hypothesis will be tested in three specific aims: (1) Determine how av regulates development of autoreactive B cells and lupus- like autoimmunity in mice. av-knockout mice crossed with an autoreactive BCR heavy chain transgenic mouse strain will be used to follow development of autoreactive B cells, and understand how av regulates tolerance and response to self-antigen. (2) Determine how av-mediated regulation of type I-IFNs regulates B cell tolerance. We will test how increased type I IFN production by B cells and plasmacyotid DCs contribute to B cell activation. (3) Test the hypothesis that non-canonical autophagy regulates B cell TLR signaling to promote tolerance. We will analyze the role of Rubicon in autoreactive B cell activation, and evaluate a potential new component of non-canonical autophagy, Atg16l2 Our approach is innovative as it focuses on a novel role for integrins and autophagy components in regulating immune signaling in B cells. The proposed work is significant because it will establish a new paradigm for B cell recognition of potential self-antigens in immune tolerance and provide a mechanism by which this occurs. Ultimately this has the potential to change our understanding of how immune tolerance is maintained and how autoreactive B cells may escape control to promote autoimmunity.

项目摘要 有一个基本的需要了解免疫系统如何区分自身抗原和调节 潜在有害的自身免疫反应。越来越多的遗传学和功能研究证据表明， 先天免疫信号对细胞死亡引起的产物的反应是免疫缺陷的主要致病因素。 自身免疫性和慢性炎症性疾病。我们的长期目标是更好地了解免疫 对来自凋亡细胞和其他自身抗原的抗原的耐受性得以维持，以及这种耐受性如何破坏 降低自身免疫性疾病的发病率本申请的目的是了解av整联蛋白和 自噬途径的组分有助于B细胞耐受性。我们的中心假设是， 介导的自噬组分的活化调节B细胞中的TLR信号传导，限制细胞增殖， 分化和自身抗体的产生。这项赠款的理由是，拟议的工作将 确定av介导的自噬在B细胞耐受中的作用，并开发更好的自身免疫模型 疾病此外，这项工作有可能通过使用 针对AV和自噬的现有化合物。基于强有力的初步数据，我们的假设将是 在三个特定目标中进行测试：（1）确定av如何调节自身反应性B细胞和狼疮的发展- 比如小鼠的自身免疫。av基因敲除小鼠与自身反应性BCR重链转基因小鼠杂交 菌株将用于跟踪自身反应性B细胞发育，并了解av如何调节耐受性 和对自身抗原的反应(2)确定av介导的I型干扰素调节如何调节B细胞 宽容我们将测试B细胞和浆细胞DC增加的I型IFN产生如何对B产生贡献 细胞激活(3)检验非经典自噬调节B细胞TLR信号传导以促进 宽容我们将分析Rubicon在自身反应性B细胞活化中的作用，并评估一种潜在的新的 我们的方法是创新的，因为它专注于一个新的作用， 整合素和自噬组分在调节B细胞中的免疫信号传导中的作用。拟议的工作是 意义重大，因为它将建立免疫中B细胞识别潜在自身抗原的新范例 容忍并提供一种机制，通过这种机制发生。最终，这有可能改变我们的 了解免疫耐受是如何维持的，以及自身反应性B细胞如何逃脱控制， 促进自身免疫。