Co-stimuli for Human Marginal Zone B Cell Activation

人类边缘区 B 细胞激活的共刺激

• 批准号: 6629463
• 负责人: Patricia K. Mongini
• 金额: $ 26.25万
• 依托单位: HOSPITAL FOR JOINT DISEASES ORTHO INST
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629463
• 关键词: B cell receptor; B lymphocyte; CD antigens; antibody formation; autoantibody; autoantigens; autoimmune disorder; cell differentiation; clinical research; cytokine receptors; human subject; interleukin 4; leukocyte activation /transformation; receptor binding; receptor expression; spleen; toll like receptor; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Marginal zone (MZ) B cells have been implicated in SLE-like autoimmunity in mice and thus may be important in the induction of SLE in man. This proposal is based on the hypothesis that several facets of MZ B cells (i.e. heightened levels of C3dg-binding CD21, their proximity and sensitivity to BAFF, and their proximity and possible sensitivity to Toll-like receptor (TLR)-binding DNA from micro-organisms) may augment the capacity of MZ B cells to respond to weak BCR stimuli. Importantly, the latter characterizes the interaction of autoreactive B cells with self antigen (Ag), and C3dg-coated apoptotic cells expressing intracellular molecules as surface Ag are likely prevalent within the MZ. The application's long-term objectives are to illuminate the mechanisms by which stimuli within the MZ environment and human MZ B cell surface receptor expression contribute to the enhanced activation of autoreactive B cells which are found within the MZ. Using isolated lgM+lgD-CD27+ MZ B cells and lgM+lgD+CD27- follicular (FO) B cells from human spleens, we will: (a) compare the efficacy of IL-4 and BAFF at promoting MZ and FO B cell viability and preventing BCR-triggered apoptosis, (b) compare MZ and FO B cells for density of receptors for BAFF and IL-4, (c) with a series of affinity-diverse anti-BCR:dextran conjugates ¿ CD21 binding sites, determine the degree to which BCR ligation with the CD21 :CD19 costimulatory complex (i) augments BAFF-dependent MZ and FO B cell proliferation under conditions of limiting BCR engagement and (ii) collaborates with BAFF and TLR9-binding CpG DNA motifs to enhance MZ or FO B cell differentiation, (d) explore the role of homotypic CD27:CD7O interactions in promoting the differentiation of MZ B cells upon activation by the above stimuli, and (e) examine whether autoreactive B cells in the MZ of normal individuals are triggered to secrete autoantibody when cultured with C3dg-coated apoptotic cells in the presence of BAFF and microbial DNA motifs. The above functional studies with defined in vitro stimuli should elucidate whether stimuli expected in the MZ environment, particularly during microbial infection, can collaborate in promoting the activation of human B cells under conditions of limiting BCR engagement. Such insights should suggest immunologic intervention therapies for blocking the activation of autoreactive B cells in SLE.

描述（由适用提供）：在小鼠的SLE样自身免疫中实现了边缘区（MZ）B细胞，因此对于人类的SLE诱导可能很重要。该建议基于以下假设：MZ B细胞的几个方面（即C3DG结合CD21的水平升高，它们对BAFF的近端和敏感性以及它们的接近性和可能对TOLL样受体（TLR）的敏感性（TLR）的敏感性（Micro-Oranism）可能会增强MZ BCR的能力。重要的是，后者表征了自动反应性B细胞与自抗原（Ag）和表达细胞内分子的C3DG涂层细胞的相互作用，因为表面Ag可能在MZ中普遍存在。该应用的长期目标是阐明在MZ环境中刺激和人类MZ B细胞表面受体表达的机制，有助于增强自动反应性B细胞的激活，而自动反应性B细胞在MZ中发现。使用人脾脏中的孤立的LGM+LGD-CD27+MZ B细胞和LGM+LGM+LGD+CD27-卵泡（FO）B细胞，我们将：（a）比较IL-4和BAFF在促进MZ和FO B细胞的稳定性和BCR触发apoptise（B frigger for b fector）中的效率（a） IL-4，（c）具有一系列亲和力多样性的抗BCR：葡萄糖结合CD21结合位点，确定BCR与CD21：CD19 c​​odimulatoration Complecter（I）增强BAFF依赖的MZ和FO B细胞在limiting BCR与BCR参与的条件下（ii）合作C.-Bind coff caft and（II）合作caft and（I）的cd21：cd19的程度增加 enhance MZ or FO B cell differentiation, (d) explore the role of homotypic CD27:CD7O interactions in promoting the differentiation of MZ B cells upon activation by the above stimuli, and (e) examination whether autoreactive B cells in the MZ of normal individuals are triggered to secret autoantibody when cultured with C3dg-coated apoptotic cells in the presence of BAFF and microbial DNA motifs.上述具有定义的体外刺激的功能研究应阐明在MZ环境中的预期，特别是在微生物感染期间是否可以在限制BCR参与条件下促进人B细胞的激活。这种见解应建议免疫干预疗法，以阻止SLE中自动反应性B细胞的激活。