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（FCGAMMAR）的受体被广泛分布在造血细胞上，并通过将抗体介导的反应与效应子和调节细胞活性联系起来在免疫调节中起重要作用。鼠FCGAMMAR FCGAMMARIIB是一种低亲和力受体，因此仅以免疫复合物（ICS）的形式结合IgG。该受体含有一种免疫感受器酪氨酸基抑制基序（ITIM），该基序是一种有效的抑制剂，该抑制剂是通过受体通过IC结合与BCR共链接的，该受体通过具有免疫感受器酪氨酸活化基序（例如B细胞抗原受体（BCR））的受体进行了信号转导的抑制剂。在上一个资金期间，我们发现在生发中心（GC）反应期间，Fcgammariib表达的水平发生了巨大变化，对GC B细胞的调节下调并在卵泡树突状细胞（FDC）上上调。此外，Fcgammariib缺乏小鼠在GC响应中显示扰动。我们还发现，fcgammariiB在B细胞系上的同源交联导致凋亡反应的诱导，这不需要ITIM基序的存在。最后，观察到在C57BL/6背景上具有fcgammariib缺乏症的小鼠在抗核抗原抗体和全身性自身免疫性疾病上会产生高升。后一个发现与以前的建议一致，即Fcgammariib的表达失调可能导致B细胞耐受性丧失。这些发现激发了假设的发展，断言Fcgammariib在调节GC反应的结果中起着核心作用。然而，已转发的不同假设归因于FCMAMARIIB对GC B细胞的表达和功能与FDC与FDC相比，以及1C捕获，BCR抑制性和凋亡诱导该受体能力的作用。因此，在下一个资金期间，我们建议：1）分析GC响应，记忆B细胞的发育和易感性的小鼠全身自身免疫性，其在B细胞中具有fcgammariib的选择性缺陷，在B细胞中与包括FDC在内的基质元素相对于基质元素； 2）对Fcgammariib的ITIM信号通路中的完整或选择性B细胞和FDC缺陷进行类似研究； 3）使用表达染色质/纵火症“双反应性” BCR的小鼠的新型VH“敲击蛋白”系来确定在GC响应期间自动反应性B细胞的阴性选择是否改变了全球或选择性的FCGAMMARIIB缺陷。这些研究的结果将提供重要的新见解，以了解各种细胞类型中FcgammariiB的调节和表达如何策划免疫记忆和耐受性的正常发展，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。