Role of L2pB1 Cells on Central Immune Tolerance in Systemic Lupus Erythematosus

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，目前尚无有效的治疗方法。SLE的主要临床表现是产生多种影响多器官系统的自身抗体。尽管几乎所有的免疫成分都可能参与SLE发展的不同阶段，但产生抗体的B细胞一直是罪魁祸首。一些旨在消耗B细胞的治疗干预措施已经在临床试验中。最近，利妥昔单抗（一种消耗性抗cd20单克隆抗体）的II/III期临床试验未能证明其治疗SLE患者的临床疗效。与其他有争议的B细胞消耗试验一起，在未来的治疗设计中迫切需要更好地了解SLE中的B细胞免疫学。研究表明，B细胞在自身免疫性疾病中并不总是致病的。在一些动物模型中，消耗B细胞不仅不能缓解症状，而且还阻碍了疾病的迅速恢复。也有人报道，B细胞甚至可以通过各种机制抑制自身免疫。然而，这种“抑制性”或调节性B细胞的真实身份仍然难以捉摸。我们的初步数据表明B1 B细胞具有以前未知的调节功能。此外，我们发现了一个新的B1 B细胞亚群，它在识别SLE相关自身抗原时具有高度的自身反应性和混杂性，并且可以在小鼠狼疮和人类自身免疫性患者中检测到。在小鼠狼疮模型中，我们已经证明这种B细胞亚群在外周血中升高，最重要的是浸润到胸腺。基于我们的初步结果，我们假设在SLE中，胸腺中B1细胞的增加可能反映了免疫系统加强中枢耐受性的反馈努力，这可能被压倒性的炎症环境破坏，对抗B1 B细胞的调节功能。在这项RO3资助中，我们建议获得关于B1 B细胞新亚群的体外和体内调节功能的初步数据，特别是它对健康和SLE小鼠胸腺T细胞发育的影响。该研究结果将允许我们申请RO1拨款支持，以进一步研究B细胞的调节臂以及“Breg”本身如何在SLE中受到调节。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a complex autoimmune disease with no effective cure. The major clinical manifestation of SLE is the production of a variety of autoantibodies affecting multiple organ systems. Although almost all immune components could be involved at different stages of SLE development, antibody-producing B cells have been the focus of blame. Several therapeutic interventions aimed to deplete B cells have been under clinical trials. Recently, the phase II/III clinical trial of Rituximab, a depleting anti-CD20 monoclonal antibody, failed to demonstrate clinical efficacy in treating SLE patients. Together with other controversial B cell- depleting trials, a better understanding of B cell immunology in SLE is urgently needed for future therapeutics design. Studies have shown that B cells are not always pathogenic in autoimmune diseases. In some animal models, depleting B cells not only failed to alleviate symptoms, but also prevented prompt recovery from diseases. Others have reported that B cells can even suppress autoimmunity through various mechanisms. However, the true identity of such "suppressive" or regulatory B cells is still elusive. Our preliminary data suggested that B1 B cells have previously unknown regulatory functions. Moreover, we found a new subpopulation of B1 B cells that is highly auto-reactive with promiscuity in recognition SLE related autoantigens and can be detected in both murine lupus and human autoimmune patients. In the murine lupus model, we have shown that this B cell subset is elevated in the peripheral blood and most importantly infiltrates into the thymus. Based on our preliminary results, we hypothesize that in SLE the increase of B1 cells in the thymus may reflect a feedback effort of the immune system to reinforce central tolerance, which might be breached by the overwhelming inflammatory environment that counters the regulatory functions of B1 B cells. In this RO3 grant, we propose to obtain preliminary data on the in vitro and in vivo regulatory functions of the novel subpopulation of B1 B cells, particularly, its effects on thymic T cell development in healthy and SLE mice. The results of the study will allow us to apply for RO1 grant support for further investigation of the regulatory arm of B cells and how "Breg" themselves are regulated in SLE. PUBLIC HEALTH RELEVANCE: Project narrative Although B cells are thought to contribute to systemic lupus erythematosus (SLE) by producing self-attacking antibodies that leads to multi-organ failure, recent clinical studies suggest that pan-depletion of B cells may not be the optimal solution. We believe that not all B cells are villains in autoimmune diseases, and particularly we suspect a novel subset of B1 B cells could be the "guardian angels" that may be called upon during systemic autoimmune crisis like SLE and can enter the thymus to re-establish central immune tolerance. Our study will provide new knowledge for redesigning future immune therapy for SLE.