Mechanisms controlling ABC differentiation and function in SLE

SLE 中 ABC 分化和功能的控制机制

• 批准号: 10364120
• 负责人: ALESSANDRA B PERNIS
• 金额: $ 56.96万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364120
• 关键词: 2019-nCoV; Affect; African American; Age; Antiviral Response; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; B cell differentiation; B-Lymphocyte Subsets; B-Lymphocytes; C57BL/6 Mouse; COVID-19 pandemic; Cell Lineage; Cell physiology; Cells; Cellular biology; Characteristics; Child; Clinical; Data; Development; Disease; Effector Cell; Epigenetic Process; Estrogens; Exhibits; Family; Family member; Female; Gene Expression Profile; Genes; Genetic; Genetic study; Gonadal Steroid Hormones; HIV; Homologous Gene; Human; ITGAX gene; Immune response; Immunity; Interferon Type II; Interferons; Knockout Mice; Link; Lupus; Lupus Nephritis; Molecular; Molecular Genetics; Mus; Mutation; Myelogenous; Pathogenesis; Patients; Peripheral; Phenotype; Plants; Plasma Cells; Plasmablast; Play; Population; Predisposition; Production; Proteins; Regulation; Risk Factors; Role; Sex Bias; Sex Differences; Signal Transduction; Structure of germinal center of lymph node; Susceptibility Gene; Syndrome; System; Systemic Lupus Erythematosus; T-bet protein; TLR7 gene; Therapeutic; Translating; Up-Regulation; Virus; Virus Diseases; Woman; X Chromosome; X Inactivation; autoimmune pathogenesis; cytokine; early onset; genetic approach; genetic risk factor; genetic signature; genome-wide; immunoregulation; interest; male; monocyte; new therapeutic target; novel; response; sex; sexual dimorphism; systemic autoimmune disease; systemic autoimmunity; vaccination outcome

ABSTRACT Abnormalities in B cell subsets play a key role in SLE, a disease that, in addition to AutoAb production and multi-organ involvement, often includes upregulation of interferon stimulated genes (ISGs). One of the hallmarks of SLE is that it preferentially affects women. Both sex hormones and the X chromosome (where TLR7 is located) have been implicated in the heightened susceptibility of women to SLE and to other autoimmune disorders. Understanding the molecular mechanisms that underlie the sex-bias that accompanies SLE pathogenesis will thus provide critical information into the development of autoimmunity and help uncover novel therapeutic targets. While expansion of germinal center (GC) B cells and plasmablasts/plasma cells (PB/PC) has long been associated with SLE, recent studies have implicated a novel B cell subset, termed Age/Autoimmune-associated B cells (ABCs), in lupus pathogenesis. In addition to classical B cell markers, ABCs also express CD11c and the transcription factor T-bet. Formation of ABCs is promoted by a combination of signals that includes TLR7 or TLR9 engagement and cytokines like IFN-g and IL-21. Aberrant accumulation of ABCs is observed both in murine lupus and in SLE patients where they are major producers of autoAbs and correlate with disease activity and clinical manifestations. Our lab has had a long-standing interest in dissecting the regulation and function of IRF family members, which have emerged as key controllers of B cell responses. While identifying IRF-interacting proteins, we isolated a protein termed Def6. Def6 and its only other homologue, SWAP-70, play an important immunoregulatory role in humans and mice. Def6 is a genetic risk factor for human SLE and biallelic mutations in Def6 result in early-onset systemic autoimmunity. Furthermore, in C57BL/6 mice, the concomitant lack of Def6 and SWAP-70 (Double-knockout mice=DKOs) leads to the spontaneous development of SLE, which, similarly to humans, preferentially affects female mice. Lupus development in DKO mice is accompanied by a marked accumulation of ABCs, which is controlled by IRF5. We have recently found that, as compared to ABCs from DKO males, ABCs from DKO females expand to a greater extent, express an ISG signature, and readily produce autoAbs upon TLR7 stimulation. Furthermore, in comparison with DKO males, DKO females accumulate greater numbers of GC B cells and PB/PCs that contain CD11c+ subsets. Dysregulating TLR7 expression in DKO males results in a marked expansion of ABCs and other B cell effector lineages including CD11c-expressing B cell subsets and promotes autoAb production and disease development in DKO males. Taken together these data suggest that sexual dimorphism underlies several aspects of ABC biology in autoimmune settings. In this proposal we will investigate the hypothesis that sex- specific mechanisms control the function and differentiation of ABCs as well as characterize the developmental relationships between ABCs and other effector B cell lineages.

抽象的 B细胞子集的异常在SLE中起关键作用，这种疾病除了自动产生和 多器官介入，通常包括干扰素刺激基因（ISG）的上调。中的一个 SLE的标志是它优先影响女性。性激素和X染色体都 TLR7的位置已与女性对SLE和其他人的敏感性增强有关 自身免疫性疾病。了解是基于性别偏见的分子机制 因此，伴随SLE发病机理将为自身免疫发展提供关键信息 并帮助发现新颖的治疗靶标。而生发中心（GC）B细胞的扩展和 浆膜/浆细胞（PB/PC）长期与SLE相关，最近的研究暗示了 新型B细胞子群，称为年龄/自身免疫相关的B细胞（ABC），在狼疮发病机理中。此外 对于经典B细胞标记，ABC还表达CD11C和转录因子T-BET。 ABC的形成 通过包括TLR7或TLR9参与度以及IFN-G等细胞因子在内的信号组合促进 和IL-21。在鼠狼疮和SLE患者中都观察到ABC的异常积累 他们是自动动伤动能的主要生产国，与疾病活动和临床表现相关。我们的实验室 一直有兴趣剖析IRF家庭成员的法规和功能，这 已成为B细胞反应的关键控制器。在识别IRF相互作用蛋白时，我们分离了 称为DEF6的蛋白质。 DEF6及其唯一的其他同源物Swap-70发挥重要的免疫调节作用 在人类和小鼠中的作用。 DEF6是人类SLE和双重突变的遗传危险因素 在早期发作的系统性自身免疫性中。此外，在C57BL/6小鼠中，伴随的缺乏DEF6和 Swap-70（双敲击小鼠= DKO）导致SLE的自发发展，同样 对于人类，优先影响雌性小鼠。 DKO小鼠的狼疮发育伴随着 ABC的明显积累，由IRF5控制。我们最近发现，与 来自DKO雄性的ABC，来自DKO女性的ABC在更大程度上扩展，表达ISG签名， 并在TLR7刺激时很容易产生自动动作。此外，与DKO男性相比 女性积累了更多包含CD11C+子集的GC B细胞和PB/PC。 DKO雄性中TLR7表达失调导致ABC和其他B细胞的显着膨胀 效应子谱系包括表达CD11C的B细胞子集并促进自动产生和疾病 DKO男性的发展。综合这些数据表明，性二态性是几个的基础 自身免疫环境中ABC生物学的各个方面。在此提案中，我们将调查性别的假设 特定机制控制ABC的功能和差异，并表征 ABC与其他效应B细胞谱系之间的发展关系。