ACE: Autoimmunity Center of Excellence (ACE) at Stanford

描述(由申请人提供)：斯坦福ACE的广泛和长期目标是在ACE网络中为ACE试验开发、实施和传播多路机械分析方面的领导者。这项提议将开发4项创造性和新颖的机械学研究技术，可以转移到我们的人类免疫监测中心(HIMC，ACE Core B)。作为原则证明，我们建议研究系统性红斑狼疮(SLE)、类风湿性关节炎(RA)和系统性幼年特发性关节炎(SJIA)中的B细胞和抗体。然而，我们的新技术可以用于研究任何自身免疫性疾病，以及包括单核细胞和T淋巴细胞在内的多种细胞类型。这种灵活性应该使斯坦福ACE有别于所有其他ACE网站。大多数自身免疫性疾病与用于辅助诊断和预测的血清自身抗体有关。关于对自我的反应的性质，该领域仍然存在一些关键问题。自身反应性B和T细胞会致病吗？自身抗体和免疫复合体(IC)是直接致病的吗？如果是这样，哪些抗原会导致疾病？斯坦福大学ACE提案的主要目标是检验一种假设，即ICs的一个子集在成人和儿童风湿病中是致病的，其致病机制(S)包括细胞因子、先天免疫受体(FC受体、Toll样受体，TLR)以及由JAK/STAT、NFKB、RORS、NFAT、IRRs和其他转录调节因子介导的信号通路。我们将利用来自SLE、RA和SJIA患者的丰富的特征良好的血液样本。我们将通过进一步开发创造性的新技术来检验这一假设，这些新技术包括蛋白质和多肽阵列、B细胞受体测序、细胞周期图和一种名为ATAC-Seq的表观基因组分析。我们将向HIMC(ACE Core B)和其他ACE站点传播检测结果，并将(i.)在ACE供资期间，将这些技术扩大应用于更多的人类自身免疫性疾病，(2)与其他ACE调查人员就其基础科学项目进行合作，以及(Iii)将所有4种分析和核心纳入ACE共享研究议程，作为临床试验的机械性核心分析。

DESCRIPTION (provided by applicant): The Broad, Long Term Objective of the Stanford ACE is to serve as the leader within the ACE network in the development, implementation, and dissemination of multiplexed mechanistic assays for ACE trials. This proposal will develop 4 creative and novel techniques for mechanistic studies that can be transferred to our Human Immune Monitoring Center (HIMC, ACE Core B). As proof-of-principle, we propose to study B cells and antibodies in Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and Systemic Juvenile Idiopathic Arthritis (SJIA). Nevertheless, our new techniques can be used to study any autoimmune disease, and many cell types including monocytes and T lymphocytes. This flexibility should set the Stanford ACE apart from all other ACE sites. Most autoimmune diseases are associated with serum autoantibodies used to assist with diagnosis and prognostication. Critical questions remain in the field regarding the nature of the response to self. Do autoreactive B and T cells cause disease? Are autoantibodies and immune complexes (ICs) directly pathogenic, and if so which antigens drive disease? The overarching goal of the Stanford ACE proposal is to test the hypothesis that a subset of ICs are pathogenic in adult and pediatric rheumatic diseases, and that the mechanism(s) underlying their pathogenicity include cytokines, innate immune receptors (Fc receptors, Toll Like Receptors, TLRs), and signaling pathways mediated by JAK/STAT, NFKB, RORs, NFAT, IRFs, and other transcriptional regulators. We will take advantage of a rich repository of well characterized blood samples derived from patients with SLE, RA, and SJIA. We will test the hypothesis through further development of creative new technologies including protein and peptide arrays, B cell receptor sequencing, CyTOF, and an epigenomic assay called ATAC-Seq. We will disseminate assays to HIMC (ACE Core B) and other ACE sites, and will (i.) expand application of the technologies to additional human autoimmune diseases during the ACE funding period, (ii.) collaborate with other ACE investigators on their basic science projects, and (iii.) incorporate all 4 assays and Cores into the ACE Shared Research Agenda as mechanistic core assays for clinical trials.