Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université, INSERM U938, Paris, France.
Service de Médecine Interne et de l'Inflammation (DHU i2B), AP-HP, Hôpital Saint-Antoine, Paris, France.
Ann Rheum Dis. 2019 Apr;78(4):539-550. doi: 10.1136/annrheumdis-2018-214382. Epub 2019 Feb 13.
Systemic sclerosis (SSc) is an autoimmune disease characterised by widespread fibrosis, microangiopathy and autoantibodies. Follicular helper T (Tfh) cells CD4CXCR5PD-1 cooperate with B lymphocytes to induce the differentiation of plasmocytes secreting immunoglobulins (Ig). Circulating Tfh (cTfh) cells are increased in several autoimmune diseases. However, there are no data about cTfh cells and their interaction with B cells in SSc. The aim of this study was to perform a quantitative and functional analysis of cTfh cells in SSc.
Using flow cytometry, we analysed cTfh cells from 50 patients with SSc and 32 healthy controls (HC). In vitro coculture experiments of sorted cTfh and B cells were performed for functional analysis. IgG and IgM production were measured by ELISA.
We observed that cTfh cell numbers are increased in patients with SSc compared with HC. Furthermore, the increase in cTfh cells was more potent in patients with severe forms of SSc such as diffuse SSc and in the presence of arterial pulmonary hypertension. cTfh cells from patients with SSc present an activated Tfh phenotype, with high expression of BCL-6, increased capacity to produce IL-21 in comparison with healthy controls. In vitro, cTfh cells from patients with SSc had higher capacity to stimulate the differentiation of CD19CD27CD38 B cells and their secretion of IgG and IgM through the IL-21 pathway than Tfh cells from healthy controls. Blocking IL-21R or using the JAK1/2 inhibitor ruxolitinib reduced the Tfh cells' capacity to stimulate the plasmablasts and decreased the Ig production.
Circulating Tfh cells are increased in SSc and correlate with SSc severity. The IL-21 pathway or JAK1/2 blockade by ruxolitinib could be a promising strategy in the treatment of SSc.
系统性硬化症（SSc）是一种以广泛纤维化、微血管病变和自身抗体为特征的自身免疫性疾病。滤泡辅助 T（Tfh）细胞 CD4CXCR5PD-1 与 B 淋巴细胞协同作用，诱导分泌免疫球蛋白（Ig）的浆母细胞分化。在几种自身免疫性疾病中，循环滤泡辅助 T（cTfh）细胞增加。然而，在 SSc 中，没有关于 cTfh 细胞及其与 B 细胞相互作用的资料。本研究旨在对 SSc 中的 cTfh 细胞进行定量和功能分析。
我们使用流式细胞术分析了 50 例 SSc 患者和 32 例健康对照者（HC）的 cTfh 细胞。对分选的 cTfh 和 B 细胞进行体外共培养实验，进行功能分析。通过 ELISA 测量 IgG 和 IgM 的产生。
我们观察到，与 HC 相比，SSc 患者的 cTfh 细胞数量增加。此外，在弥漫性 SSc 和存在动脉性肺动脉高压的情况下，cTfh 细胞的增加更为强烈。与健康对照者相比，来自 SSc 患者的 cTfh 细胞表现出活化的 Tfh 表型，BCL-6 表达增加，产生 IL-21 的能力增强。在体外，与健康对照者的 Tfh 细胞相比，来自 SSc 患者的 cTfh 细胞具有更高的能力通过 IL-21 途径刺激 CD19CD27CD38 B 细胞的分化及其 IgG 和 IgM 的分泌。阻断 IL-21R 或使用 JAK1/2 抑制剂鲁索利替尼可降低 Tfh 细胞刺激浆母细胞的能力，并减少 Ig 产生。
在 SSc 中，循环 Tfh 细胞增加，并与 SSc 的严重程度相关。IL-21 途径或 JAK1/2 阻断可能是治疗 SSc 的一种有前途的策略。
