Autoimmunity in Rag Deficiency: A Nexus of Immunodeficiency and Dysregulation

描述（由申请人提供）：免疫介导的疾病造成了重大的健康负担，这些疾病的复杂性阻碍了靶向治疗的发展。具有特定遗传缺陷的原发性免疫缺陷（PID）中的自身免疫表现可以为自身免疫性疾病提供简化的模型，并允许仔细检查特定分子的作用以建立耐受性，并可能确定治疗免疫介导疾病的新策略。在这些模型中鉴定的自身抗体或细胞因子特征和特异性生物标志物可以指导未来的干预。我们试图评估B细胞失调的机制，并在一个不同的小鼠模型与rag1亚型突变和患者中的自身免疫性的额外触发因子中与RAG酶激活基因（RAG）缺陷。在致病性RAG突变的患者中，RAG活性受损各不相同，并且与临床和免疫表型的相关性比以前认为的更广泛。这些疾病的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性疾病（从轻度血细胞减少到局部破坏性血管炎）的轻微表现。我们发表的关于rag1亚型小鼠模型的数据表明受体编辑受损（中枢B细胞耐受性破坏）和继发于淋巴细胞减少症的B细胞活化因子（BAFF）水平升高，这可能有助于拯救外周中的自身反应性B细胞（外周耐受性破坏）。此外，我们的初步数据显示，TLR刺激模拟病毒感染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B细胞成熟的不同阶段，使用或不使用抗BAFF单克隆自身抗体评估自身反应性B细胞库将允许我们比较在RAC缺陷小鼠中中枢耐受机制与外周耐受机制中破坏的相对重要性。TLR刺激实验，模仿慢性病毒感染，可能会发现额外的特定触发放大自身免疫。该建议的中心目标是在鼠模型以及RAG突变的人中获得B细胞介导的自身免疫的详细知识。了解这些疾病中B细胞失调的发病机制不仅对受影响患者的治疗有意义，而且还可以提供对多种自身免疫性疾病共同机制的见解。 公共卫生相关性：自身反应性抗体和自身免疫表现越来越被认为是原发性免疫缺陷的一个关键特征，特别是在基因功能部分丧失（亚型突变）的患者中。在这些患者中，临床和免疫学表型比之前想象的更广泛，可能包括自反应细胞的存在或自身免疫的临床表现，从轻微疾病到破坏性自身免疫并发症。产生和表征的小鼠模型与亚型突变提供了一个独特的机会，调查中断的中央和外周耐受机制，和继发性触发（如病毒感染），导致自身免疫性原发性免疫缺陷。

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. PUBLIC HEALTH RELEVANCE: Self-reactive antibodies and autoimmune manifestations are increasingly recognized as a key feature of primary immunodeficiencies, especially among patients with partial loss of gene function (hypomorphic mutations). Among these patients the clinical and immunological phenotype is broader than previously thought and may include the presence of self-reactive cells or clinical manifestations of autoimmunity ranging from mild disease to destructive autoimmune complications. The generation and characterization of mouse models with hypomorphic mutations provide a unique opportunity to investigate the disruption of central and peripheral tolerance mechanisms, and secondary triggers (such as viral infections) that lead to autoimmunity in primary immunodeficiencies.