Project 4

抗体分泌细胞是系统性红斑狼疮病原性自身抗体的来源 红斑狼疮(SLE)。尽管有充分的证据证明 系统性红斑狼疮ASC的发生及其与活动期疾病的相关性 它们的多样性、产生机制和监管计划。我们之前的研究 记录了人类ASC在表型、功能和分子上的巨大异质性，并具有 提供了关于不同B细胞前体对产生的贡献的原创性见解 致病性ASC。具体地说，我们描述了激活的幼稚B细胞对 重症系统性红斑狼疮和COVID19通过滤泡外分化感染的病原性ASC 最初的单细胞(SC)，研究提供了血液和骨髓SLE B细胞和 ASC和路线图，以破译ASC多样性在疾病中的致病和治疗意义 人类疾病。在本项目中，我们将测试总体假设，以实现 初级和记忆反应中的保护功能健康的免疫系统已经进化 决定多发性骨髓瘤强度、动力学和寿命的特化分化途径 ASC种群。这种精确的调控在系统性红斑狼疮中由于内在程序而被颠覆 (表观遗传)和外部线索(微环境)，由局部的组织特定因素决定 和全身反应(分别为肾炎和骨髓)。一个核心推论是，不同的 ASC人群对针对单独B细胞前体的治疗将具有不同的敏感性 以及它们的ASC后代。这些假设将以与其他假设协同的方式加以解决 PPG项目和核心B通过3个目标：1)SLE ASC的异质性、起源和命运；2) 系统性红斑狼疮组织特异性和全身性ASC的分子调控；3)利用B细胞 以靶向疗法探索人类ASC的起源、寿命和功能。我们的研究将 极大地提高了我们对人类ASC生物学及其在SLE中的失调的认识。这个 所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 系统性红斑狼疮和多种抗体介导的疾病及其优化保护的调节策略 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.