Project 4

抗体分泌细胞（ASC）是系统性狼疮中致病性自身抗体的来源 红斑狼疮（SLE）。尽管有充分的证据证明， SLE中ASC的产生及其与活动性疾病的相关性，关于 它们的多样性、生成机制和监管程序。我们以前的研究 在人类ASC中记录了巨大的表型、功能和分子异质性， 提供了关于不同B细胞前体对产生 致病性ASC具体地说，我们描述了活化的幼稚B细胞对 通过滤泡外分化在严重SLE和COVID 19感染中的致病性ASC。 初始单细胞（SC）研究提供了血液和骨髓SLE B细胞的初始图谱， ASC和路线图，以破译致病性和治疗的影响，ASC的多样性， 人类疾病在这个项目中，我们将测试过度假设，为了实现 在初级和记忆反应中的保护功能一个健康的免疫系统已经进化出来 决定多种分化强度、动力学和寿命的专门分化途径 ASC人群。这种精确的调节在SLE中由于内在程序而被破坏 （表观遗传）和外在线索（微环境），由局部组织特异性因素决定 和全身反应（分别为肾炎和BM）。一个核心推论是， ASC群体对靶向单独B细胞前体的治疗具有不同的敏感性 和他们的ASC后代这些假设将在一个协同的方式与其他 PPG项目和核心B通过3个目的：1）SLE ASC的异质性、起源和结局; 2） SLE中组织特异性和全身致病性ASC的分子调控; 3）使用B细胞 靶向治疗以探索人类ASC的起源、寿命和功能。我们的研究将 大大提高了我们对人类ASC生物学及其在SLE中调节异常的认识。的 获得的信息还将提高我们设计更安全，更有效的治疗方法的能力， SLE和多种抗体介导的疾病以及优化保护性的调节策略 疫苗反应。

Antibody Secreting Cells (ASC), are the source of pathogenic autoantibodies in Systemic Lupus Erythematosus (SLE). Despite ample evidence documenting profound abnormalities in the generation of ASC in SLE and their correlation with active disease, little is still known regarding their diversity, mechanisms of generation and regulatory programs. Our previous studies document great phenotypic, functional, and molecular heterogeneity in human ASC and have provided original insight into the contribution of different B cell precursors to the generation of pathogenic ASC. Specifically, we described a large contribution of activated naïve B cells to pathogenic ASC in severe SLE and COVID19 infection through extra-follicular differentiation. Initial single cell (SC), studies provide an initial atlas of blood and bone marrow SLE B cell and ASC and a roadmap to decipher the pathogenic and therapeutic implications of ASC diversity in human disease. In this Project we will test the over-arching hypothesis that in order to fulfill protective functions in primary and memory responses a healthy immune system has evolved specialized differentiation pathways that determine the intensity, kinetics and longevity of diverse ASC populations. Such precise regulation is subverted in SLE owing to intrinsic programs (epigenetic) and extrinsic cues (microenvironment), determined by tissue-specific factors for local and systemic responses (nephritis and BM , respectively). A central corollary is that the different ASC populations will be differentially sensitive to therapies targeting separate B cell precursor and their ASC progeny. These postulates will be addressed in a synergistic fashion with the other PPG projects and Core B through 3 Aims: 1) Heterogeneity, origin, and fate of SLE ASC; 2) Molecular Regulation of tissue-specific and systemic pathogenic ASC in SLE; and 3) Using B cell targeting therapies to probe the origin, longevity and function of human ASC. Our studies will greatly enhance our knowledge of human ASC biology and their dysregulation in SLE. The information gained will also improve our ability to design safer and more effective therapies for SLE and multiple antibody-mediated diseases and modulatory strategies to optimize protective vaccine responses.