Mechanisms controlling ABC differentiation and function in SLE

SLE 中 ABC 分化和功能的控制机制

• 批准号: 10620619
• 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/10620619
• 关键词: 2019-nCoV; Affect; African American; Age; Alleles; 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; Endosomes; 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; Mus; Mutation; Myelogenous; Organ; 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; interleukin-21; male; monocyte; new therapeutic target; novel; response; restraint; 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.

摘要 B细胞亚群的异常在SLE中起着关键作用，这种疾病除了自身抗体的产生和 多器官受累，通常包括干扰素刺激基因(ISGs)的上调。其中一个 系统性红斑狼疮的特点是它优先影响女性。性激素和X染色体(其中 TLR7)与女性对系统性红斑狼疮和其他疾病的易感性增加有关 自身免疫性疾病。了解导致性别偏见的分子机制 SLE的发病机制将为自身免疫的发展提供关键信息 并帮助发现新的治疗靶点。而生发中心(GC)B细胞和 浆母细胞/浆细胞(PB/PC)与系统性红斑狼疮(SLE)的关系由来已久，最近的研究表明 狼疮发病机制中新的B细胞亚群，称为年龄/自身免疫相关B细胞(ABCs)。此外 对于经典的B细胞标志物，ABCs还表达CD11c和转录因子T-bet。作业成本的形成 由包括TLR7或TLR9参与的信号和干扰素-g等细胞因子的组合促进 和IL-21。在小鼠狼疮和系统性红斑狼疮患者中都观察到ABCs的异常聚集 它们是自体抗体的主要产生者，与疾病活动性和临床表现相关。我们的实验室 长期以来一直对剖析IRF家庭成员的监管和职能感兴趣，这 已经成为B细胞反应的关键控制因素。在鉴定IRF相互作用的蛋白质时，我们分离了 一种名为Def6的蛋白质。Def6及其唯一的同系物，SWAP-70，发挥着重要的免疫调节作用 对人类和小鼠的作用。Def6是人类SLE的遗传危险因素和Def6结果中的双等位基因突变 早发性全身性自身免疫。此外，在C57BL/6小鼠中，伴随而来的Def6和Def6基因的缺失 SWAP-70(双基因敲除小鼠=DKO)导致SLE的自发发展，同样，SLE 对人类来说，优先影响雌性小鼠。DKO小鼠的狼疮发展伴随着一种 ABC的显著积累，由IRF5控制。我们最近发现，相比于 来自DKO男性的ABC和来自DKO女性的ABC在更大程度上扩展，表达ISG签名， 并在TLR7刺激下容易产生自身抗体。此外，与DKO男性相比，DKO 女性积累了更多数量的GC B细胞和含有CD11c+亚群的PB/PC。 男性DKO患者TLR7表达异常导致ABCs和其他B细胞显著扩张 包括CD11c表达的B细胞亚群在内的效应细胞系可促进自身抗体的产生和疾病 DKO男性的发育。综上所述，这些数据表明，性别二型性是几个 自身免疫环境中的ABC生物学方面。在这个提案中，我们将研究性行为-- 特定的机制控制ABC的功能和分化，以及表征ABC的特征 ABC和其他效应器B细胞系之间的发育关系。