Autoimmune Drivers and Protectors Team Science (ADAPTS)

项目摘要 系统性红斑狼疮（SLE）是一种异质性的系统性自身免疫性疾病， 发病率和早期死亡率很高，特别是在少数民族人口和育龄妇女中。 当患者达到SLE分类时，大多数患者表现出器官/组织损伤， 侵袭性炎症过程。预防SLE可以降低不可逆器官损伤的风险， 治疗相关毒性，但需要识别和验证疾病的驱动因素和限制因素 在此临床前/早期阶段的进展。我们的研究小组取得了重要进展 来解读临床前自身免疫的各个方面。一些发现包括：自身抗体发生 在临床疾病前数年的连锁亚群中，证明了体液表位扩散和外周 临床前自身免疫转变中的免疫失调，定义自身抗体的免疫内型 阳性健康个体，在SLE疾病之前鉴定活化的B细胞和选择的髓样细胞亚群 爆发，并在SLE疾病发作前建立病毒再激活。 通过我们新成立的ADAPTS联盟，我们将利用12个可用的资源来解决这些差距， 互补的疾病前独特的集合，跨越这个连续体从良性自身免疫到活性 SLE，包括临床资料、问卷信息、生物标本、自身抗体和其他 来自近11,000名参与者的实验数据。一个高风险人群的子集 将遵循自身免疫和临床进展的连续性。这些横截面集合是 增加了纵向过渡队列，包括400多名过渡到SLE的个体， 疾病前样本和临床数据。我们的调查团队成员带来了临床调查的优势， 先天免疫学，无细胞核酸传感，可溶性介质表征，多组学分析， 细胞免疫学、免疫代谢学、系统免疫学、生物信息学等， 合作。基于我们已发表的和新的初步数据，我们的ADAPTS临床和 基础科学家将评估疾病进展的潜在独立或互补机制， 通过检测RNA传感途径、无细胞核酸、年龄相关B细胞的作用， 和自身抗体特征，骨髓细胞亚群，T细胞淋巴细胞减少症和淋巴细胞减少症诱导 增殖，T细胞免疫代谢，以及选择环境（微生物组，病毒组），基因组和 先天性和适应性免疫反应作为SLE疾病的驱动因素。我们还将验证和完善预测 临床SLE疾病发展模型，为未来的预防试验提供信息，并通过以下方式协助该领域： 临床前时期的分子和临床内型鉴定。综合研究的数据 该计划将告知靶向免疫介导的预防试验的开发，细胞/分子的选择， 和路径导向疗法，以及纵向SLE自然史或预防研究的设计。

Project Summary Systemic lupus erythematosus (SLE) is a heterogeneous, systemic autoimmune disease that causes significant morbidity and early mortality, especially in minority populations and in women of child-bearing age. By the time patients reach SLE classification, the majority exhibit organ/tissue damage and ongoing, aggressive inflammatory processes. Preventing SLE would reduce the risk of irreversible organ damage and treatment-related toxicities, but requires identification and validation of drivers and restraints of disease progression during this pre-/early-clinical time period. Our research groups have made important progress toward deciphering aspects of preclinical autoimmunity. A few findings include showing: autoantibodies occur in linked-subsets years before clinical disease, demonstrating humoral epitope spreading and peripheral immune dysregulation in preclinical autoimmune transition, defining immune endotypes of autoantibody positive healthy individuals, identifying activated B cell and select myeloid cell subsets preceding SLE disease flare, and establishing viral reactivation preceding SLE disease onset. Through our newly formed ADAPTS consortium, we will address these gaps with twelve available, complementary pre-disease unique collections that span this continuum from benign autoimmunity to active SLE, which includes clinical data, questionnaire information, biospecimens, autoantibody and other experimental data from nearly 11,000 participants. A subset of the highest-risk individuals earlier in this continuum will be followed for autoimmune and clinical progression. These cross-sectional collections are augmented with longitudinal transitional cohorts which include over 400 individuals who transition to SLE with pre-disease samples and clinical data. Our investigative team members bring strengths in clinical investigation, innate immunology, cell-free nucleic acid sensing, soluble mediator characterization, multi-omic analyses, cellular immunology, immune metabolism, systems immunology, bioinformatics and strong, productive collaborations. Building on our published and new preliminary data, our ADAPTS consortium of clinical and basic scientists will assess potentially independent or complementary mechanisms of disease progression and immune restraint by testing the roles of RNA-sensing pathways, cell-free nucleic acids, age-associated B cells and autoantibody characteristics, myeloid cell subsets, T cell lymphopenia and lymphopenia-induced proliferation, T cell immunometabolism, as well as select environmental (microbiome, virome), genomic and innate and adaptive immune responses as drivers of SLE disease. We will also validate and refine predictive models of clinical SLE disease development to inform future prevention trials and assist the field through molecular and clinical endotype identification of the preclinical time periods. Data from this integrated research program will inform targeted immune-mediated prevention trial development, selection of cellular/molecular and pathway-directed therapies, and the design of longitudinal SLE natural history or prevention studies.