Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China.
Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, China.
Eur J Immunol. 2021 Jul;51(7):1809-1823. doi: 10.1002/eji.202049093. Epub 2021 Apr 23.
Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is an autoimmune disease characterized by B cells-derived ANCAs, and ANCA was proved to be a key factor in its pathogenesis. Follicular regulatory T (Tfr) and follicular helper T (Tfh) cells were T-cell subsets that play important roles in B-cell maturation and antibody production. However, their significances in microscopic polyangiitis (MPA) patients, one type of AAV, has not been thoroughly studied. In this study, comprehensive pattern analyses of circulating Tfr and Tfh were performed in MPA patients and healthy controls (HCs), and we found Tfr levels and Tfr/Tfh ratios were significantly decreased in MPA patients. Compared with HCs, Helios+, CD45RA-FoxP3hi, and Ki-67+ Tfr were lower in MPA patients, while CD226+ Tfr cells were higher. These phenotypes suggest that function and proliferation ability of Tfr cells were relatively impaired. Tfh subsets, including ICOS+PD-1+ and Ki-67+ Tfh, were significantly increased, suggesting that the function of Tfh was enhanced in MPA although the total Tfh levels did not change significantly. Circulating memory B cells and plasmablasts were significantly elevated and negatively correlated with Tfr levels and Tfr/Tfh ratios in MPA patients. In addition, Tfr levels and Tfr/Tfh ratios were negatively while Tfh was positively correlated with serum myeloperoxidase (MPO)-ANCA levels. Furthermore, Tfr and Tfr/Tfh ratio were also reversely associated with SCr, BUN, IL-4, and IL-21 levels. Our results suggest that the imbalance of Tfr and Tfh functional subsets is related to increased level of autoantibodies in MPA patients, and we propose a new mechanism for the pathogenesis of MPA.
抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）是一种自身免疫性疾病，其特征为 B 细胞衍生的 ANCAs，且 ANCA 已被证实为其发病机制中的关键因素。滤泡调节性 T（Tfr）和滤泡辅助性 T（Tfh）细胞是 T 细胞亚群，它们在 B 细胞成熟和抗体产生中发挥重要作用。然而，它们在显微镜下多血管炎（MPA）患者中的意义尚未得到充分研究。在这项研究中，我们对 MPA 患者和健康对照者（HCs）进行了循环 Tfr 和 Tfh 的综合模式分析，结果发现 MPA 患者的 Tfr 水平和 Tfr/Tfh 比值明显降低。与 HCs 相比，MPA 患者的 Helios+、CD45RA-FoxP3hi 和 Ki-67+Tfr 较低，而 CD226+Tfr 细胞较高。这些表型提示 Tfr 细胞的功能和增殖能力相对受损。尽管 Tfh 总水平没有明显变化，但 ICOS+PD-1+和 Ki-67+Tfh 等 Tfh 亚群显著增加，提示 MPA 患者 Tfh 的功能增强。循环记忆 B 细胞和浆母细胞明显升高，并与 MPA 患者的 Tfr 水平和 Tfr/Tfh 比值呈负相关。此外，Tfr 水平和 Tfr/Tfh 比值与 Tfh 呈负相关，与血清髓过氧化物酶（MPO）-ANCA 水平呈正相关。此外，Tfr 和 Tfr/Tfh 比值与 SCr、BUN、IL-4 和 IL-21 水平也呈反向相关。我们的研究结果表明，Tfr 和 Tfh 功能亚群的失衡与 MPA 患者自身抗体水平升高有关，并且我们提出了 MPA 发病机制的新机制。
