Control of B cell differentiation by IFNg induced transcription factors

在美国，多达20%的人接受了自身免疫性和/或慢性炎症性疾病的治疗。 自身免疫性疾病，如类风湿性关节炎(RA)和系统性红斑狼疮(SLE) 造成重大痛苦，并对卫生保健系统造成巨大的财政负担。尽管 随着新疗法的发布，许多人仍然对治疗难以抗拒。因此，仍然有很大的未满足 需要开发可用于治疗自身免疫患者的新药。虽然我们知道B细胞， B系抗体(Ab)、分泌细胞(ASCs)和炎症细胞因子都在推动 临床疾病，我们仍然缺乏对急性或慢性炎症信号如何启动的基本了解 B细胞对ASC谱系的承诺以及B细胞是否仅通过其自身的 抗体的产生或炎性效应B细胞是否也对免疫或免疫病理有贡献。我们 确定了一组独特的循环T-bethi前ASCs(DN2细胞)，这些细胞在SLE的子集中扩增 和类风湿关节炎患者。我们发现，这些细胞也在其他自身免疫和慢性疾病中观察到 炎症环境与全身炎性细胞因子、致病性自身抗体和 疾病的严重性。我们确定炎性细胞因子IFNG是T-bethi前ASC亚群的关键诱因。我们 进一步表明，IFNG信号显著促进了小鼠和人类ASCs的发育，并 确定了两个IFNG诱导的转录因子，T-bet和IRF1，在 IFNG诱导ASC的发生。在这个应用程序中，我们正在测试我们的中心假设，即IFNG推导出两个 B细胞中相互排斥或竞争的细胞命运程序-产生细胞因子的效应细胞命运和 ASC分化命运-以及来自TLRs和其他细胞因子(如IL-2)信号的整合 T-bet抑制炎症命运，促进IRF1介导的ASCs分化。最直接的 这项建议的目标是：(I)确定IFNG信号如何与TLR、IL-2和IL-21协同促进 以及(Ii)确定IRF1和T-bet之间的平衡是否调节 保护性或损伤性免疫B细胞介导的体液和炎症反应的发展 病毒感染和自身免疫的设置。我们的长期目标是利用我们所了解到的B细胞如何 决策被编程为确定干预措施，可以防止形成、维护或 潜在致病B细胞亚群的功能。这项研究意义重大，因为我们将第一次 在分子水平上确定干扰素对人类B细胞命运的影响，以及两种转化因子如何诱导 通过IFNG、T-BET和IRF1，在急性传染病和慢性疾病的背景下合作促进ASC的发展 自身免疫性疾病。我们预计，这些旨在揭示IFNG如何诱导TF的研究 调节B细胞命运的决定，有朝一日可能会导致治疗疾病的新策略，如SLE和RA， 由炎性细胞因子和致病抗体引起或加重。 好了！

Up to 20% of all individuals in the US are treated for an autoimmune and/or chronic inflammatory disease. Autoimmune diseases like Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are responsible for significant suffering and represent an enormous financial burden to the health care system. Despite the release of new therapies, many individuals remain refractory to treatment. Thus, there is still a very large unmet need to develop new medicines that can be used to treat autoimmune patients. Although we know that B cells, B lineage antibody (Ab) secreting cells (ASCs) and inflammatory cytokines all play important roles in driving clinical disease, we still lack a fundamental understanding of how acute or chronic inflammatory signals initiate commitment of B cells into the ASC lineage and whether B cells contribute to pathology only through their production of Abs or whether inflammatory effector B cells also contribute to immunity or immunopathology. We identified a unique population of circulating T-bethi pre-ASCs (DN2 cells) that are expanded in a subset of SLE and RA patients. We showed that these cells, which have also been observed in other autoimmune and chronic inflammatory settings, are associated with increased systemic inflammatory cytokines, pathogenic autoAbs and disease severity. We identified the inflammatory cytokine IFNg as key inducer of the T-bethi pre-ASC subset. We further showed that IFNg signals significantly enhance development of both mouse and human ASCs and determined that two IFNg-induced transcription factors (TFs), T-bet and IRF1, play important but distinct roles in IFNg-induced ASC development. In this application we are testing our central hypothesis that IFNg induces two mutually exclusive or competing cell fate programs in B cells – a cytokine-producing effector cell fate and an ASC differentiation fate – and that integration of signals from TLRs and other cytokines, like IL-2, cooperate with T-bet to repress the inflammatory fate and promote IRF1-mediated differentiation into ASCs. The immediate objectives of this proposal are to (i) determine how IFNg signals synergize with TLR, IL-2 and IL-21 to promote human ASC development and (ii) determine whether the balance between IRF1 and T-bet regulates the development of protective or damaging immune B cell mediated humoral and inflammatory responses in the setting of viral infection and autoimmunity. Our long-term goal is to use what we learn about how B cell fate decisions are programmed to identify interventions that can be that can prevent the formation, maintenance or function of potentially pathogenic B cell subsets. This research is significant because we will for the first time define at a molecular level how IFNg contributes to human B cell fate decisions and how two of the TFs induced by IFNg, T-bet and IRF1, cooperate to facilitate ASC development in the settings of acute infectious and chronic autoimmune disease. We expect that these studies, which are designed to reveal how IFNg-induced TFs modulate B cell fate decisions, may someday lead to new strategies for treatment of diseases, like SLE and RA, that are caused or exacerbated by inflammatory cytokines and pathogenic Abs. !