the 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: 7193897
• 负责人: Kaihong Su
• 金额: $ 7.01万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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/7193897
• 关键词: Address; Antibodies; Antigen-Antibody Complex; Autoimmune Diseases; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; Biology; CD32 Antigens; Cell Lineage; Cells; Classification; Condition; Data; Dendritic Cells; Disease; Drug or chemical Tissue Distribution; Endothelial Cells; Equilibrium; FCGR2B gene; Family; Fc Receptor; Genes; Granulocyte-Macrophage Colony-Stimulating Factor; Haplotypes; Homeostasis; Human; Immune; Immune response; Immunoglobulin G; Immunoglobulins; Immunologic Receptors; Individual; Infection; Interferon Type I; Interleukin-3; Interleukin-4; Intravenous; Knowledge; Lead; Leukocytes; Light; Lupus; Lymphoid; Maintenance; Mediating; Modeling; Molecular; Monoclonal Antibodies; Mus; Myelogenous; Myeloid Cells; Natural Killer Cells; Nuclear Extract; Pathogenesis; Patients; Placenta; Play; Population; Printing; Proteins; Receptors, Antigen, B-Cell; Regulation; Regulatory Element; Role; Serum; Staining method; Stains; Systemic Lupus Erythematosus; Therapeutic; Tissues; Transcription Factor 3; Tyrosine; Variant; base; cytokine; foot; genetic variant; macrophage; mast cell; monocyte; neutrophil; novel; promoter; receptor; response; transcription factor; 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，以提供对感染和肿瘤的平衡免疫应答。Fc γ RIIb（CD32B）是唯一具有基于酪氨酸的抑制基序（ITIM）的Fc受体，并且在鼠模型中维持免疫稳态中起关键作用。然而，在人中，高度同源的Fc γ RIIa的存在和特异性单克隆抗体的缺乏极大地阻碍了在正常和疾病条件下Fc γ RIIb生物学的研究。我们最近开发了一种Fc γ RIIb特异性mAb 4F5，并发现在淋巴和骨髓系细胞中Fc γ RIIb表达的差异调节以及活动性SLE中B淋巴细胞中Fc γ RIIb的失调。基于这些观察结果和从鼠模型获得的知识，我们假设Fc γ RIIb表达以组织特异性方式调节，并且Fc γ RIIb的失调可能有助于人类狼疮的发病机制。该提案的具体目的是1）检查Fc γ RIIb在淋巴和骨髓谱系白细胞和循环内皮细胞（CEC）中与其天然遗传变体相关的和通过离体刺激物的表达和调节谱。2)通过对FCGR2B基因调控元件和组织特异性转录因子的分析，阐明FcgammaRllb组织特异性调控的分子机制。3)通过分析SLE循环髓系细胞和内皮细胞中Fc γ Rll B b的调节，并与SLE B淋巴细胞中Fc γ Rll B b的失调进行比较，探讨SLE中Fc γ Rll B b的潜在组织特异性失调。将对观察到的SLE B淋巴细胞中Fc γ Rll B b失调的分子机制进行剖析。研究Fc γ RIIb的组织特异性调节及在SLE中的异常调节，不仅有助于阐明SLE免疫稳态维持的机制，而且为以Fc γ RIIb为靶点治疗自身免疫性疾病提供了新的思路。