Autoimmunity in Rag Deficiency: A Nexus of Immunodeficiency and Dysregulation

拉格缺陷中的自身免疫：免疫缺陷和失调的关系

• 批准号: 8536725
• 负责人: Jolan Eszter Walter
• 金额: $ 13.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-28 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536725
• 关键词: Affect; Agonist; American; Animal Model; Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell repertoire; B-Lymphocytes; Biological Markers; Bone Marrow; Cell Maturation; Cell Survival; Cells; Characteristics; Chronic; Clinical; Cloning; Data; Defect; Development; Disease; Disease model; Dose; Emigrant; Event; Family; Future; Gap Junctions; Gene Expression Profiling; Gene Mutation; Generations; Genes; Genetic; Goals; Granulomatous; Health; Heterogeneity; Human; Immune; Immunoglobulin Genes; Immunologic Deficiency Syndromes; Impairment; Individual; Infection; Intervention; Knowledge; Lead; Lupus; Lymphopenia; Mediating; Modeling; Molecular; Monoclonal Antibodies; Mus; Mutant Strains Mice; Mutation; Nature; Pathogenesis; Pathway interactions; Patients; Peripheral; Phenotype; Publishing; Rag1 Mouse; Receptors, Antigen, B-Cell; Relative (related person); Residual state; Roche brand of rituximab; Role; Sampling; Secondary to; Sorting - Cell Movement; Spleen; Staging; Stimulus; Syndrome; T-Lymphocyte; TLR3 gene; TLR7 gene; Testing; Toll-like receptors; V(D)J Recombination; Vasculitis; Viral; Virus Diseases; anergy; autoreactive B cell; belimumab; central tolerance; clinical phenotype; congenital immunodeficiency; cytokine; cytopenia; design; early onset; gene function; insight; mortality; mouse model; novel strategies; peripheral tolerance; receptor; recombinase; research study; screening; tool

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.

描述（由申请人提供）：免疫介导的疾病造成重大的健康负担，并且这些病症的复杂性阻碍了靶向治疗的开发。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。这些模型中确定的自身抗体或细胞因子特征以及特定生物标志物可以指导未来的干预措施。我们试图在具有 rag1 低等态突变的独特小鼠模型以及重组酶激活基因 (RAG) 缺陷的患者中评估 B 细胞失调的机制和其他自身免疫触发因素。在携带致病性 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相关性比之前认为的更广泛。这些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的微妙表现（从轻度血细胞减少到局部破坏性血管炎）。我们发表的关于 rag1 亚型体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），并且继发于淋巴细胞减少症的 B 细胞激活因子 (BAFF) 水平升高，这可能有助于拯救外周自身反应性 B 细胞（外周耐受性破坏）。此外，我们的初步数据表明，模仿病毒感染的 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 RAG 缺陷小鼠中中枢与外周耐受机制破坏的相对重要性。模拟慢性病毒感染的 TLR 刺激实验可能会识别自身免疫放大的其他特定触发因素。该提案的中心目标是在小鼠模型以及具有 RAG 突变的人类中详细了解 B 细胞介导的自身免疫。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具有影响，而且还可能为了解多种自身免疫性疾病的常见机制提供见解。