Tissue-Specific Expression and Regulation of the Inhibitory lgG Fc Receptor

抑制性 IgG Fc 受体的组织特异性表达和调节

• 批准号: 7644404
• 负责人: Kaihong Su
• 金额: $ 7.28万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7644404
• 关键词: Alleles; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; BLyS receptor; Biology; CD32 Antigens; Cell Lineage; Cells; Cellular biology; Dendritic Cells; Disease; Down-Regulation; Endothelial Cells; Equilibrium; Exhibits; FCGR2B gene; FCGR2C gene; Family; Fc Receptor; Flow Cytometry; Genes; Genetic; Genetic Polymorphism; Genotype; Haplotypes; Homeostasis; Human; Hyperactive behavior; ITIM; Immune; Immune response; Immunoglobulin G; Immunoglobulins; In Vitro; Individual; Infection; Knowledge; Lead; Leukocytes; Light; Lupus; Lymphoid; Maintenance; Mediating; Memory B-Lymphocyte; Modeling; Molecular; Monoclonal Antibodies; Mus; Myelogenous; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Plasma Cells; Play; Predisposition; Principal Investigator; Production; Proteins; Pseudogenes; Reagent; Regulation; Regulatory Element; Reverse Transcriptase Polymerase Chain Reaction; Role; Serum; Small Interfering RNA; Systemic Lupus Erythematosus; TALL-1 protein; Testing; Therapeutic; Tissues; Transcription Factor 3; Tyrosine; base; bis(3-bis(4-chlorophenyl)methyl-4-dimethylaminophenyl)amine; cell type; cytokine; genetic variant; macrophage; mast cell; member; monocyte; mouse model; peripheral blood; programs; promoter; receptor; receptor expression; restoration; tumor

DESCRIPTION (provided by applicant): The IgG Fc receptor family is comprised of both activating and inhibitory receptors to provide a balanced immune response to infections and tumors. FcgammaRllb (CD32B) is the only Fc receptor harboring a tyrosine-based inhibitory motif (ITIM) and plays a critical role in the maintenance of immune homeostasis in murine models. However, in humans, the existence of highly homologous FcgammaRlla and the lack of specific monoclonal antibodies have greatly hampered study of FcgammaRllb biology under both normal and disease conditions. We have recently developed an FcgammaRllb-specific mAb 4F5 and found a differential regulation of FcgammaRllb expression in lymphoid and myeloid-lineage cells and a dysregulation of FcgammaRllb in B lymphocytes in active SLE. Based on these observations and knowledge obtained from murine models, we hypothesize that FcgammaRllb expression is regulated in a tissue-specific manner and dysregulation of FcgammaRllb may contribute to the pathogenesis of human lupus. The specific aims of this proposal are to 1) Examine the expression and regulation profile of FcgammaRllb in lymphoid and myeloid-lineage leukocytes and circulating endothelial cells (CECs) related to its natural genetic variants and by ex vivo stimulants. 2) Elucidate the molecular mechanisms underlying the tissuespecific regulation of FcgammaRllb by characterizing the regulatory elements in FCGR2B gene and the tissue-specific transcription factors. 3) Explore the potential tissue-specific dysregulation of FcgammaRllb in SLE by analyzing the regulation of FcgammaRllb in SLE circulating myeloid and endothelial cells and comparing with the dysregulation of FcgammaRllb in SLE B lymphocytes. The molecular mechanism for the observed dysregulation of FcgammaRllb in SLE B lymphocytes will be dissected. Studies of the tissue-specific regulation of FcgammaRllb and the dysregulation of FcgammaRllb in SLE may not only shed light on the mechanism for the maintenance of immune homeostasis, but also may provide new knowledge for targeting FcgammaRllb in the therapeutics of autoimmune diseases.

描述（由申请人提供）： IgG Fc 受体家族由激活性和抑制性受体组成，可为感染和肿瘤提供平衡的免疫反应。 FcgammaRllb (CD32B) 是唯一带有基于酪氨酸的抑制基序 (ITIM) 的 Fc 受体，在维持小鼠模型中的免疫稳态中发挥着关键作用。然而，在人类中，高度同源的FcgammaRIIa的存在和特异性单克隆抗体的缺乏极大地阻碍了正常和疾病条件下FcgammaRIIb生物学的研究。我们最近开发了一种 FcgammaRllb 特异性 mAb 4F5，并发现活动性 SLE 中淋巴和骨髓系细胞中 FcgammaRllb 表达的差异调节以及 B 淋巴细胞中 FcgammaRllb 的失调。基于从小鼠模型获得的这些观察结果和知识，我们假设 FcgammaRllb 表达以组织特异性方式受到调节，并且 FcgammaRllb 的失调可能导致人类狼疮的发病机制。该提案的具体目标是 1) 检查 FcgammaRllb 在淋巴和髓系白细胞以及循环内皮细胞 (CEC) 中与其自然遗传变异和离体兴奋剂相关的表达和调节概况。 2)通过表征FCGR2B基因的调控元件和组织特异性转录因子，阐明FcgammaRllb组织特异性调控的分子机制。 3)通过分析SLE循环骨髓细胞和内皮细胞中FcgammaRllb的调节并与SLE B淋巴细胞中FcgammaRllb的失调进行比较，探讨SLE中FcgammaRllb潜在的组织特异性失调。将剖析在 SLE B 淋巴细胞中观察到的 FcgammaRIIb 失调的分子机制。对SLE中FcgammaRllb的组织特异性调节和FcgammaRllb失调的研究不仅可以阐明维持免疫稳态的机制，而且还可以为自身免疫性疾病治疗中靶向FcgammaRllb提供新的知识。