Hritzo Ahye Molly K, Golding Amit
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Baltimore Veterans Affairs Hospital & Division of Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Lupus Sci Med. 2018 Oct 24;5(1):e000296. doi: 10.1136/lupus-2018-000296. eCollection 2018.
Systemic lupus erythematosus (SLE) is a manifestation of hyperactivated lymphocytes and results, in part, from the loss of normal tolerance checkpoints. FOXO1 is a transcription factor involved at critical early and late B cell development checkpoints; however, its role in regulating peripheral B cell tolerance is not fully understood. We have applied our published approach for using imaging flow cytometry to study native FOXO1 localisation in human lymphocytes to peripheral blood samples from healthy individuals versus patients with SLE. We report, here, on dramatic cytoplasmic localisation of FOXO1 in two peripheral B cell SLE subsets: IgD-CD27+ (class-switched memory) B cells and IgD-CD27- (atypical memory) B cells. The latter, so-called 'Double Negative' (DN) B cells have previously been shown to be increased in SLE and enriched in autoreactive clones. Cytoplasmic-predominant FOXO1 (CytoFOX) B cells are significantly increased in patients with SLE as compared to healthy controls, and the levels of CytoFoOX DN B cells correlate directly with SLE disease activity. The highest abundance of CytoFox DN B cells was observed in African American females with SLE Disease Activity Index (SLEDAI)≥6. The phenotype of CytoFOX DN B cells in SLE includes uniquely low CD20 expression and high granularity/side scatter. As FOXO1 phosphorylation downstream of B cell receptor-dependent signalling is required for nuclear exclusion, CytoFOX B cells likely represent a high state of B cell activation with excess signalling and/or loss of phosphatase activity. We hypothesise that CytoFOX B cells in lupus represent a novel biomarker for the expansion of pathological, autoreactive B cells which may provide new insights into the pathophysiology of SLE.
系统性红斑狼疮（SLE）是淋巴细胞过度活化的一种表现，部分原因是正常的免疫耐受检查点丧失。FOXO1是一种转录因子，参与关键的早期和晚期B细胞发育检查点；然而，其在调节外周B细胞耐受性中的作用尚未完全明确。我们应用已发表的方法，利用成像流式细胞术研究人淋巴细胞中天然FOXO1的定位，检测对象为健康个体和SLE患者的外周血样本。在此，我们报告FOXO1在SLE患者外周血两个B细胞亚群中显著定位于细胞质：IgD-CD27 +（类别转换记忆）B细胞和IgD-CD27 -（非典型记忆）B细胞。后者即所谓的“双阴性”（DN）B细胞，先前已证实在SLE患者中数量增加且富含自身反应性克隆。与健康对照相比，SLE患者中以细胞质为主的FOXO1（CytoFOX）B细胞显著增多，且CytoFoOX DN B细胞水平与SLE疾病活动度直接相关。在SLE疾病活动指数（SLEDAI）≥6的非裔美国女性中观察到CytoFox DN B细胞丰度最高。SLE中CytoFOX DN B细胞的表型包括独特的低CD20表达和高颗粒度/侧向散射。由于B细胞受体依赖性信号传导下游的FOXO1磷酸化是核排除所必需的，因此CytoFOX B细胞可能代表B细胞活化的高状态，伴有过度信号传导和/或磷酸酶活性丧失。我们推测，狼疮中的CytoFOX B细胞代表了病理性自身反应性B细胞扩增的一种新型生物标志物，这可能为SLE的病理生理学提供新的见解。
