Control of B cell differentiation by IFNg induced transcription factors

在美国，高达20%的个体接受自身免疫性和/或慢性炎症性疾病的治疗。 自身免疫性疾病，如风湿性关节炎（RA）和系统性红斑狼疮（SLE）， 严重的痛苦，并对医疗保健系统造成巨大的财政负担。尽管 尽管新疗法的发布，许多个体仍然对治疗难治。因此，仍有很大的未解决问题。 需要开发新的药物，可以用来治疗自身免疫性患者。尽管我们知道B细胞， B系抗体（Ab）分泌细胞（ASCs）和炎性细胞因子都在驱动免疫应答中发挥重要作用。 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理解， B细胞向ASC谱系的定型以及B细胞是否仅通过其 抗体的产生或炎症效应B细胞是否也有助于免疫或免疫病理学。我们 鉴定了在SLE亚组中扩增的循环T-bethi前ASC（DN 2细胞）的独特群体， RA患者。我们发现，这些细胞，这也被观察到在其他自身免疫性和慢性 炎症环境，与增加的全身性炎性细胞因子，致病性自身抗体和 疾病严重程度。我们将炎性细胞因子IFNg鉴定为T-bethi前ASC亚群的关键诱导物。我们 进一步显示IFNg信号显著增强小鼠和人ASC的发育， 确定了两个IFN诱导的转录因子（TF），T-bet和IRF 1，在 IFN-γ诱导的ASC发展。在本申请中，我们正在测试我们的中心假设，即IFNg诱导两个 在B细胞中相互排斥或竞争的细胞命运程序-一种产生精氨酸的效应细胞命运和一种产生精氨酸的效应细胞命运， ASC分化命运-以及来自TLR和其他细胞因子（如IL-2）的信号整合， T-bet抑制炎性命运并促进IRF 1介导的向ASC的分化。立即 该提案的目的是（i）确定IFNg信号如何与TLR、IL-2和IL-21协同作用以促进 人ASC发育和（ii）确定IRF 1和T-bet之间的平衡是否调节人ASC发育。 保护性或破坏性免疫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情况。我们的长期目标是利用我们对B细胞命运的了解 决策被编程，以确定可以防止形成，维持或 潜在致病性B细胞亚群的功能。这项研究意义重大，因为我们将首次 在分子水平上定义IFNg如何有助于人类B细胞命运决定以及两种TF如何诱导 通过IFNg，T-bet和IRF 1，合作促进急性感染和慢性感染环境中的ASC发展 自身免疫性疾病我们希望这些旨在揭示IFN-γ如何诱导TF的研究 调节B细胞的命运决定，可能有一天会导致疾病治疗的新策略，如SLE和RA， 由炎性细胞因子和致病性抗体引起或加重。 !

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. !