IgM Fc receptor in CLL

CLL 中的 IgM Fc 受体

• 批准号: 8431808
• 负责人: Hiromi Kubagawa
• 金额: $ 18.31万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-20 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431808
• 关键词: Antibodies; Antigen Receptors; Antigen-Antibody Complex; Antigens; Apoptosis; Apoptotic; Autoantibodies; B-Lymphocytes; Binding; Biochemical; Biological Assay; Biology; Blocking Antibodies; Cell Survival; Cell physiology; Cell surface; Cells; Cessation of life; Characteristics; Chronic; Chronic Lymphocytic Leukemia; Clinical; Cloning; Complementary DNA; Conflict (Psychology); Confounding Factors (Epidemiology); Cytoplasmic Tail; Data; Databases; Development; Diagnostic; Disease; Effectiveness; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Fc Receptor; Fluorochrome; Fostering; Future; Generations; Genes; Glycoproteins; Goals; Health; Hematologic Neoplasms; IgM Fc receptor; Immune; Immunoglobulin G; Immunoglobulin M; Individual; Knowledge; Label; Lead; Leukemic Cell; Ligation; Literature; Mediating; Membrane; Mission; Monoclonal Antibodies; Mus; Mutation; Nature; Outcome; Pathogenesis; Patient Care; Patients; Pilot Projects; Play; Preventive Intervention; Prognostic Marker; Public Health; Publishing; RNA Splicing; Receptors, Antigen, B-Cell; Regulation; Research; Research Personnel; Resistance; Role; Serum; Signal Transduction; Surface; T-Cell Activation; T-Lymphocyte; TNFRSF6 gene; Testing; Therapeutic; Therapeutic Intervention; Time; Transcript; United States National Institutes of Health; Work; anti-IgM; base; cell type; clinically relevant; clinically significant; cost effective; improved; innovation; leukemia; novel; outcome forecast; prognostic; receptor; receptor expression; therapeutic target; tool; variable region gene

DESCRIPTION (provided by applicant): The long-term goals of our studies are to develop an improved understanding of the disease sub-sets in chronic lymphocytic leukemia (CLL) and thereby propel the development of improved prognostic tools and identification of therapeutic targets. The objectives of this application are to determine the clinical relevance of the enhanced expression of the Fc receptor for IgM (Fc¿R) by CLL B cells and to explore the role of Fc¿R signaling in promoting CLL-cell survival. The over-expression of Fc¿R by CLL cells has been suspected for some time, but the lack of direct assays has been a major barrier to unambiguous analysis. Our recent functional cloning of the FCMR cDNA and subsequent generation of receptor-specific mAbs are enabling rapid clarification of the expression of the Fc¿R and its functional roles. Based on our preliminary data and the available literature concerning CLL, we have formulated the central hypothesis that: the enhanced Fc¿R expression by CLL B cells is a result of chronic antigenic stimulation and the ensuing IgM/antigen immune complexes lead to co-ligation of Fc¿R and the IgM B cell receptor (BCR) on CLL cells, thereby providing a survival signal. Our approach is in Aim 1, to define the potential clinical relevance of the enhanced expression of both membrane-bound and soluble forms of Fc¿R in patients with CLL. The working hypotheses are: (i) Both cell surface and serum levels of Fc¿R predict the mutation status of the Ig heavy chain V region gene and the clinical progression in CLL; and (ii) The soluble form of Fc¿R detected in CLL patients' sera, which is encoded by an alternatively spliced transcript, is produced by CLL B cells and modulates CLL B-cell function as a decoy receptor or by interacting with the membrane IgM. The cell surface and serum levels of Fc¿R in patients with CLL and normal individuals will be quantified using a unique panel of monoclonal antibodies for flow cytometric analyses and a newly developed enzyme-linked immunosorbent assay. In parallel, transcript levels will be analyzed using real time quantitative PCR. In Aim 2, the role of Fc¿R in survival of CLL B cells will be explored. The effects of co-ligation of Fc¿R and surface IgM on CLL cell survival will be determined, as well as whether the highly-expressed Fc¿R interacts with membrane IgM on the same CLL cells. The study is technically innovative as it utilizes IgM antibodies for cross-linkage of the B-cell receptor and the Fc¿R along with Fc¿R -blocking antibodies, and is conceptually innovative as it is expected to provide the first demonstration of a survival function of Fc¿R for CLL B cells as a consequence of interaction with IgM/antigen immune complexes. The clinical significance lies in the expected definition of surface and soluble Fc¿R as reliable markers for predicting the prognosis and disease activity of CLL, which will form the basis for subsequent rapid development of a robust cost-effective prognostic test for CLL patients. Evidence supporting the central hypothesis will greatly improve the understanding of the pathogenesis of CLL and justify the future exploration of the effectiveness of targeting Fc¿R in CLL.

描述（由应用程序提供）：我们研究的长期目标是对慢性淋巴细胞性白血病（CLL）中疾病子群的了解得到改进，从而推动了改进的预后工具的发展以及对治疗靶标的识别。该应用的目标是确定CLL B细胞增强FC受体对IgM（FC¿R）增强表达的临床相关性，并探索FC r信号传导在促进CLL细胞存活中的作用。怀疑CLL细胞对FCCOR的过表达已有一段时间了，但是缺乏直接测定是明确分析的主要障碍。我们最近对FCMR cDNA的功能克隆以及随后的受体特异性mAb的产生，可以快速阐明Fc。r及其功能作用的表达。 Based on our preliminary data and the available literature concerning CLL, we have formulated the central hypothesis that: the enhanced Fc¿ R expression by CLL B cells is a result of chronic antigenic stimulation and the ensuring IgM/antigen immune complexes lead to co-ligation of Fc¿ R and the IgM B cell receptor (BCR) on CLL cells, thereby providing a survival signal.我们的方法是AIM 1，以定义CLL患者中膜结合和固体形式的FC r表达增强的潜在临床相关性。工作假设是：（i）FC。的细胞表面和血清水平都可以预测Ig重链V区域基因的突变状态和CLL的临床进展； （ii）在CLL患者的血清中检测到的FCTO的固体形式，由CLL B细胞编码，由CLL B细胞产生，并调节CLL B细胞作为诱饵接收器或与膜IgM相互作用。使用独特的单克隆抗体，用于流式细胞仪分析和新开发的酶连接的免疫吸附测定法，将对具有CLL和正常个体患者的FCT的细胞表面和血清水平进行定量。同时，将使用实时定量PCR分析转录水平。在AIM 2中，将探讨FcTOR在CLL B细胞存活中的作用。将确定FC波和表面IgM对CLL细胞存活的影响，以及高表达的FCW与同一CLL细胞上的膜IgM相互作用。这项研究在技术上具有创新性，因为它利用IgM抗体用于B细胞接收器的交叉链接和FCCOR以及FcTOR块抗体，并且在概念上是创新的，因为它预计将首先证明Cll B细胞的FC b细胞的生存功能，这是与Igm/Antects相互作用的结果。临床意义在于对表面和固体FC的预期定义作为预测CLL预后和疾病活性的可靠标记，这将构成随后快速开发CLL患者的稳健成本有效预后测试的基础。支持中心假设的证据将大大提高对CLL发病机理的理解，并证明对靶向FC r在CLL中的有效性的未来探索是合理的。

项目成果

Is Toso/IgM Fc receptor (FcμR) expressed by innate immune cells?

• DOI: 10.1073/pnas.1304904110
• 发表时间: 2013-07-09
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Honjo, Kazuhito;Kubagawa, Yoshiki;Kubagawa, Hiromi
• 通讯作者: Kubagawa, Hiromi