Aire通过ICOSL抑制滤泡辅助性T细胞来减轻胶原诱导的关节炎。

Aire attenuate collagen-induced arthritis by suppressing T follicular helper cells through ICOSL.

作者信息

Huo Fei-Fei, Zou Xue-Yang, Zhang Yi, Lu Yao-Ping, Zhao Meng-Wei, Yu Xin-Yue, Cao Fu-Guo, Yang Wei

机构信息

Department of Intensive Care Medicine, The First Hospital of Jilin University, Department of Immunology, College of Basic Medical Sciences. Clinical Laboratory, The First Hospital of Jilin University, Changchun, China.

出版信息

Int Immunopharmacol. 2025 Jan 10;144:113732. doi: 10.1016/j.intimp.2024.113732. Epub 2024 Dec 2.

DOI:10.1016/j.intimp.2024.113732

PMID:39626537

Abstract

OBJECTIVE

To assess the expression levels of autoimmune regulator (Aire) and inducible costimulator molecule ligand (ICOSL), as well as T follicular helper (Tfh) cell numbers in rheumatoid arthritis (RA) patients, and to explore their relationship with RA severity. We also aimed to investigate the effect of Aire on arthritis and its underlying mechanisms.

METHODS

The expression levels of Aire, ICOSL, and Tfh cell numbers were measured in RA patients. The relationship between these factors and the levels of anticyclic citrullinated peptide antibodies (Anti-CCP) as well as the Disease Activity Score in 28 joints (DAS28) was analyzed. To investigate the effect of Aire on arthritis, Aire-overexpressing bone marrow-derived dendritic cells (Aire-BMDCs) and recombinant ICOSL were transferred into collagen-induced arthritis (CIA) mice, the symptoms, clinical scores, anti-collagen type II antibodies (anti-CII Abs), rheumatoid factor (RF), proportions of Tfh cells, and percentages of germinal center (GC) B cells in CIA mice were examined.

RESULTS

The results showed that Aire levels were significantly decreased in CD14 PBMCs from patients with RA, and there were negative correlations between ICOSL expression levels, Tfh cell numbers, and Aire expression. Additionally, these factors were correlated with Anti-CCP levels and DAS28. Aire-BMDCs could influence Tfh differentiation, GC B cell development, as well as the levels of anti-CII Abs and RF, which further alleviate the symptoms and reduce clinical scores partly through ICOSL in CIA mice.

CONCLUSIONS

The findings suggest that Aire may alleviate rheumatoid arthritis by inhibiting ICOSL, which further inhibits Tfh cell differentiation and autoantibody production.

摘要

目的

评估类风湿关节炎（RA）患者中自身免疫调节因子（Aire）和诱导性共刺激分子配体（ICOSL）的表达水平以及滤泡辅助性T（Tfh）细胞数量，并探讨它们与RA严重程度的关系。我们还旨在研究Aire对关节炎的影响及其潜在机制。

方法

检测RA患者中Aire、ICOSL的表达水平以及Tfh细胞数量。分析这些因素与抗环瓜氨酸肽抗体（Anti-CCP）水平以及28个关节疾病活动评分（DAS28）之间的关系。为了研究Aire对关节炎的影响，将过表达Aire的骨髓来源树突状细胞（Aire-BMDCs）和重组ICOSL转入胶原诱导性关节炎（CIA）小鼠体内，检测CIA小鼠的症状、临床评分、抗II型胶原抗体（抗CII Abs）、类风湿因子（RF）、Tfh细胞比例以及生发中心（GC）B细胞百分比。

结果

结果显示，RA患者CD14⁺外周血单核细胞（PBMCs）中Aire水平显著降低，ICOSL表达水平、Tfh细胞数量与Aire表达之间呈负相关。此外，这些因素与Anti-CCP水平和DAS28相关。Aire-BMDCs可影响Tfh分化、GC B细胞发育以及抗CII Abs和RF水平，在CIA小鼠中部分通过ICOSL进一步减轻症状并降低临床评分。