alpha v integrin regulation of B cell tolerance

B 细胞耐受的 α v 整合素调节

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要有根本需要了解免疫系统如何区分自我抗原和调节潜在有害的自身免疫反应。来自遗传学和功能研究的越来越多的证据表明对细胞死亡引起的产物响应的先天免疫信号传导是一个主要的病因学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力对源自凋亡细胞和其他自我抗原衍生的抗原的耐受性保持不变，以及如何破裂自身免疫性疾病。本应用程序的目的是了解AV整合素和自噬途径的成分有助于B细胞耐受性。我们的中心假设是介导的自噬成分的激活调节B细胞中TLR信号传导，从而限制了细胞增殖，自身抗体的分化和生产。这笔赠款的理由是拟议的工作将定义AV介导的自噬在B细胞耐受性中的作用，并为自身免疫开发更好的模型疾病。此外，这项工作有可能通过使用转化为新的治疗方法靶向AV和自噬的现有化合物。基于强大的初步数据，我们的假设将是在三个特定目的中进行了测试：（1）确定AV如何调节自动反应性B细胞和狼疮的发展像小鼠的自身免疫性。 AV-KNOCKOUT小鼠与自动反应性BCR重链转基因小鼠交叉应变将用于遵循自动反应性B细胞的开发，并了解AV如何调节公差和对自我抗原的反应。（2）确定AV介导的I型IFN的调节如何调节B细胞宽容。我们将测试B细胞和浆细胞DC产生I型IFN的增加如何有助于B 细胞激活。（3）检验以下假设：非典型自噬调节B细胞TLR信号传导促进宽容。我们将分析Rubicon在自动反应性B细胞激活中的作用，并评估潜在的新非典型自噬的组成部分，ATG16L2我们的方法是创新的，因为它着重于新颖的作用整联蛋白和自噬成分在调节B细胞中免疫信号传导方面。拟议的工作是意义重大，因为它将建立一个新的范式，以识别免疫中潜在自我抗原的潜在自我抗原耐受性并提供了这种发生的机制。最终，这有可能改变我们的了解如何维持免疫耐受性以及自动反应性B细胞如何逃脱控制促进自身免疫性。