ACE: Autoimmunity Center of Excellence (ACE) at Stanford

描述（由申请人提供）：斯坦福大学ACE的广泛、长期目标是在ACE试验的多重机制分析的开发、实施和传播方面充当ACE网络的领导者。该提案将开发4种创新技术用于机制研究，这些技术可以转移到我们的人类免疫监测中心（HIMC，ACE Core B）。作为原理验证，我们建议研究系统性红斑狼疮（SLE）、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，我们的新技术可用于研究任何自身免疫性疾病，以及许多细胞类型，包括单核细胞和T淋巴细胞。这种灵活性应该设置斯坦福大学ACE除了所有其他ACE网站。大多数自身免疫性疾病与血清自身抗体有关，用于辅助诊断和鉴别。关于对自我的反应的性质，关键问题仍然存在于这个领域。自身反应性B和T细胞会导致疾病吗？自身抗体和免疫复合物（IC）是否直接致病，如果是，哪些抗原驱动疾病？斯坦福大学ACE提案的总体目标是检验以下假设：IC的一个子集在成人和儿科风湿性疾病中具有致病性，并且其致病性的潜在机制包括细胞因子、先天免疫受体（Fc受体、Toll样受体、TLR）以及由JAK/STAT、NF κ B、ROR、NFAT、IRF和其他转录调节因子介导的信号传导途径。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库。我们将通过进一步开发创造性的新技术来验证这一假设，包括蛋白质和肽阵列、B细胞受体测序、CyTOF和称为ATAC-Seq的表观基因组测定。我们将向HIMC（ACE核心B）和其他ACE研究中心分发检测试剂盒，并将（i.）在ACE资助期间，将这些技术的应用扩展到其他人类自身免疫性疾病，（ii.）与其他ACE研究人员合作开展基础科学项目，以及（iii.）将所有4种检测试剂盒和核心试剂盒纳入ACE共享研究议程，作为临床试验的机制核心检测试剂盒。

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.