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: 6508161
• 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/6508161
• 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（由申请人提供）：边缘区（MZ）B 细胞与小鼠的 SLE 样自身免疫有关，因此可能对人类 SLE 的诱导很重要。该提议基于以下假设：MZ B 的几个方面。细胞（即 C3dg 结合 CD21 的驻留水平、它们与 BAFF 的接近度和敏感性，以及它们对 Toll 样受体 (TLR) 结合 DNA 的接近度和可能的敏感性重要的是，后者表征了自身反应性 B 细胞与自身抗原 (Ag) 的相互作用，并且 C3dg 包被的凋亡细胞表达细胞内分子作为表面 Ag。该应用的长期目标是阐明 MZ 环境中的刺激和人类 MZ B 细胞表面受体表达有助于增强已发现的自身反应性 B 细胞的激活的机制。使用来自人脾脏的分离的 lgM+lgD-CD27+ MZ B 细胞和 lgM+lgD+CD27- 滤泡 (FO) B 细胞，我们将： (a) 比较 IL-4 和 BAFF 在促进 MZ 和FO B 细胞活力和防止 BCR 触发的细胞凋亡，(b) 比较 MZ 和 FO B 细胞的 BAFF 和 IL-4 受体密度，(c) 与一系列亲和力多样化的抗 BCR:葡聚糖缀合物 ¿ CD21 结合位点，确定 BCR 与 CD21 :CD19 共刺激复合物连接的程度 (i) 在限制 BCR 结合的条件下增强 BAFF 依赖性 MZ 和 FO B 细胞增殖，以及 (ii) 与 BAFF 和 TLR9 结合 CpG DNA 协作增强 MZ 或 FO B 细胞分化的基序，(d) 探索同型 CD27:CD7O 相互作用在上述激活后促进 MZ B 细胞分化中的作用(e) 检查在 BAFF 和微生物 DNA 基序存在的情况下与 C3dg 包被的凋亡细胞一起培养时，正常个体 MZ 中的自身反应性 B 细胞是否被触发分泌自身抗体。阐明 MZ 环境中预期的刺激，特别是微生物感染期间的刺激，是否可以在限制 BCR 参与的条件下协同促进人类 B 细胞的激活，这样的见解应该建议采用免疫干预疗法来阻止激活。 SLE 中的自身反应性 B 细胞。