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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（由申请方提供）：IgG Fc部分的受体（Fc γ R）广泛分布于造血细胞上，通过将抗体介导的应答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Fc γ R Fc γ RIIB是低亲和力受体，因此仅以免疫复合物（IC）的形式结合IgG。该受体含有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，ITIM是通过具有免疫受体酪氨酸活化基序的受体（如B细胞抗原受体（BCR））的信号转导的有效抑制剂。在之前的资助期，我们发现在生发中心（GC）反应期间Fc γ RIIB表达水平显著改变，在GC B细胞上下调，在滤泡树突细胞（FDC）上上调。此外，Fc γ RIIB缺陷型小鼠显示GC应答的扰动。我们还发现Fc γ RIIB在B细胞系上的同源交联导致诱导凋亡应答，并且这不需要存在ITIM基序。最后，观察到在C57 BL/6背景下具有Fc γ RIIB缺陷的小鼠产生高的抗核抗原抗体和全身性自身免疫疾病。后一发现与先前的建议一致，即Fc γ RIIB的表达失调可导致B细胞耐受性的丧失。这些发现激发了断言Fc γ RIIB在调节GC反应的结果中起核心作用的假说的发展。然而，已经提出的不同假设归因于Fc γ RIIB在GC B细胞与FDC上的表达和功能的重要性水平大相径庭，以及该受体的1C捕获、BCR抑制和凋亡诱导能力。因此，在下一个资助期内，我们建议：1）分析在B细胞相对于包括FDC的基质成分中具有Fc γ RIIB选择性缺陷的小鼠中的GC应答、记忆B细胞发育和全身性自身免疫的易感性; 2）对在Fc γ RIIB的ITIM信号传导途径中具有完全或选择性B细胞和FDC缺陷的小鼠进行类似研究;和3）利用表达染色质/胂酸盐“双重反应性”BCR的小鼠的新VH“敲入”系来确定整体或选择性Fc γ RIIB缺陷是否改变GC应答期间自身反应性B细胞的阴性选择。这些研究的结果将提供重要的新见解，以了解在各种细胞类型中Fc γ RIIB的功能和表达的调节如何协调免疫记忆的正常发展和耐受性的维持，以及这些调节途径中的扰动如何有助于自身免疫性疾病的发展。