Autoimmunity in Rag Deficiency: A Nexus of Immunodeficiency and Dysregulation

描述（由申请人提供）：免疫介导的疾病构成重大的健康负担，这些疾病的复杂性阻碍了靶向治疗的发展。具有特异性遗传缺陷的原发性免疫缺陷（PID）的自身免疫表现可以为自身免疫性疾病提供一个简化的模型，并允许对特定分子在建立耐受性方面的作用进行仔细检查，并可能确定治疗免疫介导疾病的新策略。在这些模型中发现的自身抗体或细胞因子特征和特定的生物标志物可以指导未来的干预措施。我们试图在rag1亚型突变的小鼠模型和重组酶激活基因（RAG）缺陷患者中评估B细胞失调的机制和自身免疫的其他触发因素。在具有致病性RAG突变的患者中，RAG活性的损害各不相同，并且与临床和免疫表型的关联比以前认为的更广泛。其范围从严重感染和早期死亡（SCID， Omenn综合征）到与自身免疫相关的迟发性肉芽肿疾病的细微表现（从轻度细胞减少到局部破坏性血管炎）。我们在rag1低变形小鼠模型上发表的数据表明，受体编辑受损（中枢B细胞耐受性的破坏）和继发于淋巴细胞减少的B细胞激活因子（BAFF）水平的增加可能有助于外周自身反应性B细胞的拯救（外周耐受性的破坏）。此外，我们的初步数据显示，模拟病毒感染的TLR刺激可以进一步增加自身抗体库的滴度和多样性。这些机制在B细胞失调中的相对重要性尚不清楚。在使用或不使用抗BAFF单克隆自身抗体的情况下，评估B细胞成熟不同阶段的自身反应性B细胞库，将使我们能够比较ragg缺陷小鼠中中枢和外周耐受机制破坏的相对重要性。TLR刺激实验，模拟慢性病毒感染，可以确定自身免疫扩增的其他特定触发因素。本提案的中心目标是在小鼠模型和具有RAG突变的人类中获得B细胞介导的自身免疫的详细知识。了解这些情况下B细胞失调的发病机制不仅对受影响患者的治疗有意义，而且可能为多种自身免疫性疾病的共同机制提供见解。

DESCRIPTION (provided by applicant): Immune mediated diseases pose a significant health burden, and the complexity of these conditions hinder development of targeted therapies. Autoimmune manifestations in primary immune deficiencies (PID) with specific genetic defect can provide a simplified model for autoimmune diseases and allow close examination of the role of specific molecules to establish tolerance and may identify novel strategies for treating immune-mediated diseases. Autoantibody or cytokine signatures and specific biomarkers identified in these models can guide future interventions. We seek to evaluate mechanisms of B cell dysregulation and additional triggers of autoimmunity in a distinct murine model with a rag1 hypomorphic mutation and among patients with Recombinase Activating gene (RAG) defects. Among patients with pathogenic RAG mutations, impairment of RAG activity varies and is associated with clinical and immunological phenotypes broader than previously considered. These range from severe infections and early mortality (SCID, Omenn syndrome) to subtle presentation with late onset granulomatous disease associated with autoimmunity (from mild cytopenias to localized destructive vasculitis). Our published data on a rag1 hypomorph murine model indicated impaired receptor editing (a disruption of central B cell tolerance) and increased levels of B cell activating factor (BAFF) secondary to lymphopenia that might contribute to the rescue of self-reactive B cell in the periphery (a disruption of peripheral tolerance). In addition our preliminary data shows that TLR stimulation mimicking viral infections can further increased the titer and diversity of the autoantibody repertoire. The relative importance of these mechanisms in B cell dysregulation is unclear. Evaluating the autoreactive B cell repertoire at distinct stages of B cell maturation with or without the use of anti- BAFF monoclonal autoantibodies would allow us to compare the relative importance of the disruption in central versus peripheral tolerance mechanisms in RAG-deficient mice. TLR stimulation experiments, mimicking chronic viral infections, may identify additional specific triggers for amplification of autoimmunity. The central goal of this proposal is to achieve detailed knowledge of B cell mediated autoimmunity both in a murine model as well as among humans with RAG mutations. Understanding the pathogenesis of B cell dysregulation in these conditions not only has implications for the treatment of the affected patients, but may also provide insights into mechanisms common to multiple autoimmune diseases.