Zhang X, Lindwall E, Gauthier C, Lyman J, Spencer N, Alarakhia A, Fraser A, Ing S, Chen M, Webb-Detiege T, Zakem J, Davis W, Choi Y Sung, Quinet R
Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
Department of Rheumatology, Ochsner Medical Center, New Orleans, Louisiana, USA.
Lupus. 2015 Aug;24(9):909-17. doi: 10.1177/0961203314567750. Epub 2015 Feb 5.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies. Recently, a specific highly activated T helper cell subset, follicular helper T (Tfh) cell, has emerged as a key immunoregulator of germinal center (GC) formation and high-affinity antibody production. To identify the pathophysiological role of Tfh cells in SLE patients, we compared the phenotypic and functional properties of circulating Tfh-like cells in lupus patients to GC-Tfh cells, and correlated the percentage of Tfh-like cells with autoantibody production and SLE disease activity.
Peripheral blood was collected from 29 lupus patients and 25 healthy controls. Tonsils were obtained surgically from non-SLE controls and used as a source of GC-Tfh cells. Tfh cells were defined by their signature surface markers (CXCR5, ICOS, CD57, PD-1 and BTLA) via flow cytometry. IL-21 expression levels from Tfh cells were measured by real-time PCR and intracellular staining. The function of Tfh cells was carried out by co-culture of Tfh cells and autologous B cells in vitro. IgG in the culture supernatant was detected by ELISA.
The frequency of circulating Tfh-like cells was significantly increased in SLE patients compared to healthy controls (p < 0.05). The Tfh-like cells not only display similar phenotypes and signature cytokines with GC-Tfh cells, but also are capable of driving B cells to differentiate into IgG-secreting plasma cells in vitro. In addition, the frequency of Tfh-like cells correlated positively with the percentage of circulating plasmablasts, levels of serum anti-dsDNA antibodies and ANA.
The accumulated circulating Tfh-like cells in lupus patients share phenotypic and functional properties with GC-Tfh cells. Tfh-like cells may serve as perpetuators in the pathogenesis of SLE by enhancing the self-reactive B cell clones to further differentiate into auto antibody-producing plasmablasts, and ultimately cause autoimmunity.
系统性红斑狼疮（SLE）是一种以自身抗体产生为特征的自身免疫性疾病。最近，一种特定的高度活化的T辅助细胞亚群，即滤泡辅助性T（Tfh）细胞，已成为生发中心（GC）形成和高亲和力抗体产生的关键免疫调节因子。为了确定Tfh细胞在SLE患者中的病理生理作用，我们比较了狼疮患者循环中Tfh样细胞与GC-Tfh细胞的表型和功能特性，并将Tfh样细胞的百分比与自身抗体产生及SLE疾病活动度相关联。
采集29例狼疮患者和25例健康对照者的外周血。通过手术从非SLE对照者获取扁桃体，用作GC-Tfh细胞的来源。通过流式细胞术根据其标志性表面标志物（CXCR5、ICOS、CD57、PD-1和BTLA）定义Tfh细胞。通过实时PCR和细胞内染色测量Tfh细胞的IL-21表达水平。Tfh细胞的功能通过体外将Tfh细胞与自体B细胞共培养来进行。通过ELISA检测培养上清液中的IgG。
与健康对照相比，SLE患者循环中Tfh样细胞的频率显著增加（p < 0.05）。Tfh样细胞不仅与GC-Tfh细胞表现出相似的表型和标志性细胞因子，而且在体外能够驱动B细胞分化为分泌IgG的浆细胞。此外，Tfh样细胞的频率与循环中浆母细胞的百分比、血清抗双链DNA抗体水平和ANA呈正相关。
狼疮患者中积累的循环Tfh样细胞与GC-Tfh细胞具有相同的表型和功能特性。Tfh样细胞可能通过增强自身反应性B细胞克隆进一步分化为产生自身抗体的浆母细胞，从而在SLE发病机制中起延续作用，并最终导致自身免疫。
