Human TNFa-Induced Pre-B Cell Bone Marrow Emigrants

人 TNFa 诱导的前 B 细胞骨髓移出

• 批准号: 7105129
• 负责人: MARC C. LEVESQUE
• 金额: $ 19.44万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105129
• 关键词: bone marrow; clinical research; human; osteocytes

DESCRIPTION (provided by applicant): In humans, autoimmune disorders such as rheumatoid arthritis (RA) are characterized by increased inflammatory cytokine production including overproduction of TNFa. Many rheumatic disorders are also characterized by alterations in B cell subsets and autoantibody production. In RA, the administration of agents that neutralize TNFa promotes resolution of clinical symptoms and reductions in rheumatoid factor production. The success of anti-B cell therapies in RA underscores the importance of B cells to the pathogenesis of RA and highlights possible interconnections between the overproduction of TNFa and B cell abnormalities in rheumatic inflammatory diseases. In mice, the administration of inflammatory stimuli such as adjuvants or TNFa, induces the emigration of immature B cells from the bone marrow to the peripheral blood and spleen. These B cell emigrants have the characteristics of immature B cells and contain subpopulations that expand in colony forming assays, and subpopulations that express AID and have somatically mutated immunoglobulin genes despite their development outside germinal centers. Importantly, the administration of adjuvants such as Freund's or pristane to susceptible rodent strains is associated with the development of arthritis and lupus-like symptoms and the development of autoantibodies. B cells with immature phenotypes accumulate in the synovial tissue of RA patients. Therefore, although speculative, we believe that there may be an important relationship between TNFa-induced pre-B cell bone marrow emigrants and the subsequent development of autoimmunity. We also believe that this population of peripheral pre-B cells may represent the precursors for populations of B cells identified in X-linked hyper IgM syndrome patients that contain somatically mutated immunoglobulin genes despite the absence of germinal centers in these patients. Patients with hyper IgM syndrome develop autoantibodies and autoimmune syndromes. Studies on TNFa-induced pre-B cell bone marrow emigrants have not been performed in humans. Therefore, we will determine whether similar populations of pre-B cells can be detected in human peripheral blood and we will characterize these B cells phenotypically and functionally. We believe that B cell populations similar to TNFa-induced pre-B cell bone marrow emigrants in mice will be expanded in human cord blood samples, in peripheral blood in human subjects administered adjuvant, and in patients with RA. We will also determine whether anti-TNFa therapy is associated with reductions in peripheral populations of TNFa- induced pre-B cell bone marrow emigrants in RA patients.

描述（由申请人提供）：在人类中，自身免疫性疾病（例如类风湿关节炎（RA））的特征是炎性细胞因子产生增加，包括TNFA过量产生。许多风湿性疾病的特征也具有B细胞亚群和自身抗体产生的改变。在RA中，中和TNFA的药物的给药促进了临床症状的分辨率和类风湿因子产生的减少。抗B细胞疗法在RA中的成功强调了B细胞对RA发病机理的重要性，并突出了TNFA过量生产和B细胞异常在风湿性炎症性疾病中的可能相互联系。在小鼠中，炎症刺激（如辅助或TNFA）的给药会诱导未成熟的B细胞从骨髓到外周血和脾脏的迁移。这些B细胞移民具有未成熟B细胞的特征，并包含在菌落形成测定中扩展的亚群，以及表达辅助的亚群，尽管它们在生发中心以外发育，但它们尽管它们在生发中心之外发育。重要的是，弗朗德（Freund）或pristane等辅助因素与易感啮齿动物菌株的给药与关节炎和类似狼疮的症状的发展以及自身抗体的发展有关。具有未成熟表型的B细胞积聚在RA患者的滑膜组织中。因此，尽管推测性，但我们认为TNFA诱导的B细胞骨髓移民与随后自身免疫性的发展之间可能存在重要关系。我们还认为，这种外周前B细胞的群体可能代表了在X连锁的超IGM综合征患者中鉴定出的B细胞群体的前体，尽管这些患者没有生发中心，但这些患者含有体外突变的免疫球蛋白基因。高IgM综合征患者患有自身抗体和自身免疫性综合征。人类尚未对TNFA诱导的前B细胞骨髓移民进行研究。因此，我们将确定在人外周血中是否可以检测到类似的前B细胞群体，我们将在表型和功能上表征这些B细胞。我们认为，与TNFA诱导的小鼠前B细胞骨髓移民类似的B细胞群体将在人类的脐带血样本中扩展，在辅助辅助治疗的人类受试者和RA患者中，将扩展。我们还将确定抗TNFA治疗是否与RA患者中TNFA诱导的前B细胞骨髓移民的外周种群减少有关。