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.

摘要 B细胞亚群中的抗体在SLE中起关键作用，SLE是一种除了自身抗体产生和 多器官参与，通常包括干扰素刺激基因（ISG）的上调。之一 SLE的特点是它优先影响女性。性激素和X染色体（其中 TLR 7位于）与女性对SLE和其他疾病的易感性增加有关。 自身免疫性疾病了解性别偏见的分子机制， 因此，伴随SLE发病机制的蛋白质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。当生殖中心（GC）B细胞和 浆母细胞/浆细胞（PB/PC）长期以来与SLE相关，最近的研究表明， 新的B细胞亚群，称为年龄/自身免疫相关B细胞（ABC），在狼疮发病机制。此外 与经典的B细胞标志物不同，ABC也表达CD 11 c和转录因子T-bet。ABC的形成 由包括TLR 7或TLR 9接合和细胞因子如IFN-g的信号组合促进 IL-21。在小鼠狼疮和SLE患者中均观察到ABC的异常积累， 它们是自身抗体的主要生产者，并与疾病活动和临床表现相关。我们实验室 长期以来，他一直对剖析IRF家族成员的调节和功能感兴趣， 已经成为B细胞反应的关键控制者。在鉴定IRF相互作用蛋白质的同时，我们分离了 一种叫做Def 6的蛋白质Def 6和它唯一的其他同源物SWAP-70在免疫调节中起着重要的作用。 在人类和小鼠中的作用。Def 6是人类SLE的遗传危险因素，Def 6中的双等位基因突变导致 早期全身性自身免疫此外，在C57 BL/6小鼠中，伴随的Def 6和 SWAP-70（双敲除小鼠= DKO）导致SLE的自发发展，类似地， 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免疫抑制剂。 ABC的显著积累，这是由IRF 5控制的。我们最近发现，与 来自DKO雄性的ABC，来自DKO雌性的ABC扩增到更大程度，表达ISG标记， 并且在TLR 7刺激时容易产生自身抗体。此外，与DKO男性相比， 女性积累更多数量的GC B细胞和含有CD 11 c+亚群的PB/PC。 DKO雄性中TLR 7表达失调导致ABC和其他B细胞显著扩增 包括表达CD 11 c的B细胞亚群的效应子谱系，并促进自身抗体产生和疾病 DKO男性的发育。综合这些数据表明，两性异形是几个 自身免疫环境中ABC生物学的各个方面。在这个建议中，我们将调查性的假设- 特定的机制控制ABC的功能和分化，并表征 ABC和其他效应B细胞谱系之间的发育关系。