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: 7268102
• 负责人: MARC C. LEVESQUE
• 金额: $ 22.72万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268102
• 关键词: Human; TNFa; Induced; Pre; Cell

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，自身免疫性疾病如类风湿性关节炎（RA）的特征在于增加的炎性细胞因子产生，包括TNF α的过度产生。许多风湿性疾病的特征还在于B细胞亚群和自身抗体产生的改变。在RA中，给予中和TNF α的药物可促进临床症状的缓解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发病机制的重要性，并突出了风湿性炎性疾病中TNF α过度产生和B细胞异常之间可能的相互联系。在小鼠中，给予炎性刺激物如佐剂或TNF α诱导未成熟B细胞从骨髓迁移到外周血和脾脏。这些B细胞移出物具有未成熟B细胞的特征，并含有在集落形成测定中扩增的亚群，以及表达AID并具有体细胞突变的免疫球蛋白基因的亚群，尽管它们在生殖中心外发育。重要的是，将佐剂如弗氏佐剂或降植烷给予敏感的啮齿动物品系与关节炎和狼疮样症状的发展以及自身抗体的发展相关。具有不成熟表型的B细胞在RA患者的滑膜组织中积聚。因此，尽管是推测性的，但我们相信TNF α诱导的前B细胞骨髓迁移和随后的自身免疫发展之间可能存在重要的关系。我们还认为，外周前B细胞群可能代表了X连锁高IgM综合征患者中鉴定的B细胞群的前体细胞，这些患者含有体细胞突变的免疫球蛋白基因，尽管这些患者缺乏生殖中心。高IgM综合征患者发展自身抗体和自身免疫综合征。尚未在人体中进行TNF α诱导的前B细胞骨髓迁移研究。因此，我们将确定是否可以在人外周血中检测到相似的前B细胞群体，并将表征这些B细胞的表型和功能。我们相信，类似于小鼠中TNF α诱导的前B细胞骨髓迁移的B细胞群将在人脐带血样品、给予佐剂的人受试者的外周血和RA患者中扩增。我们还将确定抗TNF α治疗是否与RA患者中TNF α诱导的前B细胞骨髓移行物的外周群体减少相关。