Regulatory B10 Cells in Autoimmune Arthritis

B淋巴细胞是体液免疫的中枢介质。B细胞功能异常也是导致 多种自身免疫性疾病，包括类风湿性关节炎(RA)。此外，我们和其他人有 最近发现，在适应性CD4+T细胞过程中，B细胞也具有关键的负调节功能 可抑制细胞和体液免疫反应的反应，以及 自身免疫力。这种意想不到的观察在一定程度上是因为发现了一种有效的 调节性B细胞亚群显著减弱Th1免疫反应和自身免疫 老鼠。这种调节性B细胞亚群是唯一的CD1d+CD5+，产生IL-10。并代表1-2%的 野生型小鼠的脾B细胞总数和人类循环B细胞的1%。我们称这个子集为B10 强调它们是产生IL-10的主要B细胞群，如果不是排他性的话 并将它们与可能也存在的其他监管子集区分开来。内的B10单元号 在自身免疫和增龄的小鼠中，组织显著增加。在这项提案中，我们假设 抗原特异性调节B10细胞影响小鼠和人类的自身免疫性疾病。我们 我将检验这一假设，并研究B10细胞的生成、功能和作用机制 小鼠胶原性关节炎(CIA)模型及RA患者的B细胞。在四年内 为了达到特定目的，拟议的研究将确定B10亚群调节免疫的程度 自身免疫过程中的反应，决定B10细胞是否可以被操纵用于治疗 在正常人和慢性病患者中对这种独特的B细胞亚群进行鉴定和鉴定 自身免疫力。具体目标1将在之前、期间和之后识别和表征B10细胞亚群 CIA诱导；特异性目标2将描述CIA过程中B10细胞的功能；特异性目标3将发展 B10细胞过继治疗的体内临床前小鼠模型；和特定目标4将识别和 描述人类自身免疫性疾病期间的B10亚群。这些相互重叠的研究将 显著扩展我们对B10细胞如何调节正常和异常免疫的知识 在两个物种中都有反应。

B lymphocytes are central mediators of humoral immunity. Aberrant B cell function also contributes to multiple autoimmune diseases, including rheumatoid arthritis (RA). In addition, we and others have recently found that B cells also serve critical negative regulatory functions during adaptive CD4+ T cell responses that can dampen both cellular and humoral immune responses, and the development of autoimmunity. This unexpected observation is explained in part by the identification of a potent regulatory B cell subset that dramatically attenuates Th1 immune responses and autoimmunity in mice. This regulatory B cell subset is uniquely CD1d+CD5+, produces IL-10. and represents 1-2% of total spleen B cells in wild type mice and <1% of circulating human B cells. We call this subset B10 cells to emphasize that they are the predominant, if not exclusive, B cell population that produces IL-10 and to distinguish them from other regulatory subsets that may also exist. B10 cell numbers within tissues increase significantly in mice with autoimmunity and age. In this proposal, we hypothesize that antigen-specific regulatory B10 cells influence autoimmune disease in both mice and humans. We will test this hypothesis and examine B10 cell generation, function, and mechanisms of action using the mouse collagen-induced arthritis (CIA) model of RA and B cells from patients with RA. In four specific aims, the proposed studies will identify the extent that the B10 subset modulates immune responses during autoimmunity, determine whether B10 cells can be manipulated for therapeutic benefit, and identify and characterize this unique B cell subset in normal humans and patients with autoimmunity. Specific Aim 1 will identify and characterize the B10 cell subset before, during and after CIA induction; Specific Aim 2 will characterize B10 cell function during CIA; Specific Aim 3 will develop an in vivo preclinical mouse model for B10 cell adoptive therapy; and Specific Aim 4 will identify and characterize the B10 subset during human autoimmune disease. These overlapping studies will significantly expand our knowledge of how B10 cells regulate both normal and abnormal immune responses in both species.