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，自身免疫性疾病如类风湿关节炎（RA）的特征是炎症细胞因子的产生增加，包括TNFa的过量产生。许多风湿病也以B细胞亚群和自身抗体产生的改变为特征。在类风湿性关节炎中，给予中和TNFa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细胞治疗在类风湿关节炎中的成功强调了B细胞在类风湿关节炎发病机制中的重要性，并强调了类风湿炎症疾病中TNFa的过量产生和B细胞异常之间可能存在的相互联系。在小鼠中，给予炎症刺激，如佐剂或TNFa，诱导未成熟B细胞从骨髓向外周血和脾脏迁移。这些B细胞移入者具有未成熟B细胞的特征，包含在集落形成试验中扩展的亚群，以及表达AID和具有免疫球蛋白基因突变的亚群，尽管它们在生发中心外发育。重要的是，对易感的啮齿动物品系使用诸如弗氏或普里斯坦等佐剂与关节炎和狼疮样症状的发展以及自身抗体的产生有关。具有不成熟表型的B细胞积聚在RA患者的滑膜组织中。因此，尽管是推测性的，但我们认为tnfa诱导的前b细胞骨髓迁移与随后的自身免疫发展之间可能存在重要关系。我们还认为，这种外周前B细胞群可能代表了在x连锁高IgM综合征患者中发现的B细胞群的前体，尽管这些患者缺乏生发中心，但这些患者含有体细胞突变的免疫球蛋白基因。高IgM综合征患者出现自身抗体和自身免疫综合征。tnfa诱导的前b细胞骨髓迁移的研究尚未在人类中进行。因此，我们将确定是否可以在人外周血中检测到类似的前B细胞群，并将对这些B细胞进行表型和功能表征。我们相信，与tnfa诱导的小鼠骨髓前B细胞迁移相似的B细胞群将在人类脐带血样本、接受佐剂治疗的人类受试者外周血和RA患者中扩增。我们还将确定抗TNFa治疗是否与RA患者外周血TNFa诱导的前b细胞骨髓移植物减少有关。