Regulation of Persistent Ab Responses by Fc Receptors

Fc 受体对持续抗体反应的调节

基本信息

批准号：
8116781
负责人：
TIMOTHY L MANSER
金额：
$ 11.9万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-29 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8116781
关键词：
Adoptive Transfer Affinity Antibodies Antibody Formation Antigen-Antibody Complex Antigens Apoptosis Apoptotic Autoimmune Diseases Autoimmunity B-Cell Development B-Lymphocytes Binding Bone Marrow Cell Line Cells Chimera organism Chromatin Development Elements Evaluation Fc Receptor Follicular Dendritic Cells Funding Generations Haptens ITAM ITIM Immune Immunoglobulin G Link Maintenance Mature B-Lymphocyte Mediating Memory Memory B-Lymphocyte Mus Nuclear Antigens Outcome Play Predisposition Reaction Receptors, Antigen, B-Cell Regulation Regulatory Pathway Role Signal Pathway Signal Transduction Signal Transduction Inhibitor Stromal Cells Structure of germinal center of lymph node Suggestion Testing Transgenes Tyrosine arsonate autoreactive B cell cell type crosslink insight novel peripheral tolerance receptor response systemic autoimmune disease

项目摘要

DESCRIPTION (provided by applicant): Receptors for the Fc portion of IgG (FcgammaRs) are widely distributed on hematopoetic cells and play an important role in immune regulation by linking antibody-mediated responses with effector and regulatory cell activity. The murine FcgammaR FcgammaRIIB is a low affinity receptor and thus binds IgGs only in the form of immune complexes (ICs). This receptor contains an immunoreceptor tyrosine based inhibitory motif (ITIM) that is a potent inhibitor of signal transduction via receptors with immunoreceptor tyrosine activation motifs, such as the B cell antigen receptor (BCR), when co-crosslinked with the BCR via IC binding. In the previous funding period we discovered that levels of FcgammaRIIB expression are dramatically altered during the germinal center (GC) reaction, being down regulated on GC B cells and upregulated on follicular dendritic cells (FDCs). Moreover, FcgammaRIIB deficient mice display perturbations in the GC response. We also found that homologous cross-linking of FcgammaRIIB on B cell lines results in induction of an apoptotic response, and this does not require the presence of the ITIM motif. Finally, mice with an FcgammaRIIB deficiency on a C57BL/6 background were observed to develop high liters on anti-nuclear antigen antibody, and systemic autoimmune disease. The latter finding is consistent with previous suggestions that dysregulated expression of FcgammaRIIB can contribute to loss of B cell tolerance. These findings have motivated the development of hypotheses asserting that FcgammaRIIB plays a central role in regulating the outcome of the GC reaction. However, the different hypotheses that have been forwarded ascribe widely divergent levels of importance to FcgammaRIIB expression and function on GC B cells versus FDCs, as well as to the 1C trapping, BCR inhibitory, and apoptosis inducing capacities of this receptor. Therefore, in the next funding period we propose to: 1) analyze the GC response, memory B cell development and predisposition to systemic autoimmunity in mice with selective deficiencies of FcgammaRIIB in B cells versus stromal elements including FDCs; 2) perform analogous studies on mice with either complete or selective B cell and FDC deficiencies in the ITIM signaling pathway of FcgammaRIIB; and, 3) utilize a novel VH "knockin" line of mice expressing chromatin/arsonate "dual reactive" BCRs to determine if global or selective FcgammaRIIB deficiencies alter negative selection of autoreactive B cells during the GC response. The results of these studies will provide important new insights into how regulation of the functions and expression of FcgammaRIIB in various cell types are orchestrated towards the normal development of immune memory and maintenance of tolerance, and how perturbations in these regulatory pathways can contribute to the development of autoimmune disease.

描述（由申请人提供）：IgG Fc 部分的受体 (FcgammaR) 广泛分布在造血细胞上，通过将抗体介导的反应与效应细胞和调节细胞活性联系起来，在免疫调节中发挥重要作用。鼠 FcgammaR FcgammaRIIB 是一种低亲和力受体，因此仅以免疫复合物 (IC) 的形式结合 IgG。该受体包含基于免疫受体酪氨酸的抑制基序 (ITIM)，当通过 IC 结合与 BCR 共交联时，它是通过具有免疫受体酪氨酸激活基序的受体（例如 B 细胞抗原受体 (BCR)）进行信号转导的有效抑制剂。在之前的资助期间，我们发现 FcgammaRIIB 表达水平在生发中心 (GC) 反应期间发生显着改变，在 GC B 细胞上下调，在滤泡树突细胞 (FDC) 上上调。此外，FcgammaRIIB 缺陷小鼠的 GC 反应表现出扰动。我们还发现 FcgammaRIIB 在 B 细胞系上的同源交联会导致细胞凋亡反应的诱导，并且这不需要 ITIM 基序的存在。最后，观察到 C57BL/6 背景下 FcgammaRIIB 缺陷的小鼠出现高水平的抗核抗原抗体和全身性自身免疫性疾病。后一个发现与之前的建议一致，即 FcgammaRIIB 表达失调可能导致 B 细胞耐受性丧失。这些发现推动了假设的发展，这些假设断言 FcgammaRIIB 在调节 GC 反应的结果中发挥着核心作用。然而，已提出的不同假设对 GC B 细胞上的 FcgammaRIIB 表达和功能与 FDC 的重要性以及该受体的 1C 捕获、BCR 抑制和细胞凋亡诱导能力的重要性有很大不同。因此，在下一个资助期内，我们建议：1) 分析 B 细胞与基质成分（包括 FDC）选择性缺乏 FcgammaRIIB 的小鼠的 GC 反应、记忆 B 细胞发育和系统性自身免疫倾向； 2) 对 FcgammaRIIB 的 ITIM 信号通路中完全或选择性 B 细胞和 FDC 缺陷的小鼠进行类似研究； 3) 利用表达染色质/胂酸“双反应性”BCR 的新型 VH“敲入”小鼠系来确定全局或选择性 FcgammaRIIB 缺陷是否会改变 GC 反应期间自身反应性 B 细胞的阴性选择。这些研究的结果将为了解如何协调各种细胞类型中 FcgammaRIIB 的功能和表达的调节以促进免疫记忆的正常发展和耐受性的维持，以及这些调节途径的扰动如何促进免疫记忆的发展提供重要的新见解。自身免疫性疾病。