Follicular helper and follicular regulatory T cell subset imbalance is associated with higher activated B cells and abnormal autoantibody production in primary anti-phospholipid syndrome patients,Clinical & Experimental Immunology

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Follicular helper and follicular regulatory T cell subset imbalance is associated with higher activated B cells and abnormal autoantibody production in primary anti-phospholipid syndrome patients
Clinical & Experimental Immunology ( IF 3.4 ) Pub Date : 2021-07-26 , DOI: 10.1111/cei.13647
Yan Long ₁ , Wenyi Li ₁ , Jinghong Feng ₁ , Yinting Ma ₁ , Yuanyuan Sun ₁ , Lijuan Xu ₂ , Ying Song ₁ , Chen Liu ₁

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Primary anti-phospholipid antibody syndrome (pAPS) is a multi-organ autoimmune disease, and autoantibodies are involved in its pathogenesis. Follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr) are critical for B cell maturation and antibody production, but their roles in pAPS remain unknown. We enrolled 32 pAPS patients and 23 healthy controls (HCs) and comprehensively analyzed circulating Tfh and Tfr, as well as their subsets, using flow cytometry. Clinical data including autoantibody levels were collected and their correlations with Tfh and Tfr subsets were analyzed. In addition, correlation analyses between B cell functional subsets and Tfh and Tfr were performed. Changes and potential effects of serum cytokines on Tfr and Tfh were further explored. We found the circulating Tfr was significantly decreased while Tfh and Tfh/Tfr ratios were increased in pAPS patients. Tfh2, inducible T cell co-stimulator (ICOS)⁺ programmed cell death 1 (PD-1)⁺ Tfh and Ki-67⁺ Tfh percentages were elevated, while CD45RA⁻forkhead box protein 3 (FoxP3)^hi, Helios⁺, T cell immunoglobulin and ITIM (TIGIT)⁺ and Ki-67⁺ Tfr percentages were decreased in pAPS patients. New memory B cells and plasmablasts were increased and altered B cell subsets and serum autoantibodies were positively correlated with Tfh, Tfh2, ICOS⁺PD-1⁺ Tfh cells and negatively associated with Tfr, CD45RA⁻FoxP3^hi Tfr and Helios⁺ Tfr cells. In addition, pAPS with LA/aCL/β2GPI autoantibodies showed lower functional Tfr subsets and higher activated Tfh subsets. Serum interleukin (IL)-4, IL-21, IL-12 and transforming growth factor (TGF)-β1 were up-regulated and associated with Tfh and Tfr subset changes. Our study demonstrates that imbalance of circulating Tfr and Tfh, as well as their functional subsets, is associated with abnormal autoantibody levels in pAPS, which may contribute to the pathogenesis of pAPS.

中文翻译：

滤泡辅助细胞和滤泡调节性 T 细胞亚群失衡与原发性抗磷脂综合征患者中较高的活化 B 细胞和异常自身抗体产生相关

原发性抗磷脂抗体综合征（pAPS）是一种多器官自身免疫性疾病，自身抗体参与其发病机制。滤泡辅助 T 细胞 (Tfh) 和滤泡调节 T 细胞 (Tfr) 对于 B 细胞成熟和抗体产生至关重要，但它们在 pAPS 中的作用仍不清楚。我们招募了 32 名 pAPS 患者和 23 名健康对照 (HC)，并使用流式细胞术全面分析了循环 Tfh 和 Tfr 及其子集。收集包括自身抗体水平在内的临床数据，并分析其与 Tfh 和 Tfr 子集的相关性。此外，还进行了B细胞功能亚群与Tfh和Tfr之间的相关性分析。进一步探讨血清细胞因子对 Tfr 和 Tfh 的变化和潜在影响。我们发现 pAPS 患者的循环 Tfr 显着降低，而 Tfh 和 Tfh/Tfr 比值升高。Tfh2、诱导性 T 细胞共刺激剂 (ICOS) ⁺ 程序性细胞死亡 1 (PD-1) ⁺ Tfh 和 Ki-67 ⁺ Tfh 百分比升高，而 CD45RA ^-叉头盒蛋白 3 (FoxP3) ^hi、Helios ⁺、T 细胞pAPS 患者的免疫球蛋白和 ITIM (TIGIT) ⁺ 和 Ki-67 ⁺ Tfr 百分比降低。新记忆 B 细胞和浆母细胞增加，B 细胞亚群改变，血清自身抗体与 Tfh、Tfh2、ICOS ⁺ PD-1 ⁺ Tfh 细胞呈正相关，与 Tfr、CD45RA ⁻ FoxP3 ^hi Tfr 和 Helios ⁺ Tfr 细胞呈负相关。此外，具有 LA/aCL/β2GPI 自身抗体的 pAPS 显示出较低的功能性 Tfr 子集和较高的活化 Tfh 子集。血清白细胞介素 (IL)-4、IL-21、IL-12 和转化生长因子 (TGF)-β1 上调，并与 Tfh 和 Tfr 亚群变化相关。我们的研究表明，循环 Tfr 和 Tfh 及其功能子集的失衡与 pAPS 中自身抗体水平异常相关，这可能有助于 pAPS 的发病机制。

更新日期：2021-07-26

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