Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China.
Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China.
J Autoimmun. 2019 May;99:1-14. doi: 10.1016/j.jaut.2019.01.013. Epub 2019 Feb 14.
Interleukin-21 (IL-21), an autocrine cytokine predominantly produced by follicular helper T (Tfh) and T helper 17 (Th17) cells, has been proven to play an important role in the immune system, for example, by promoting proliferation and the development of Tfh and Th17 cells, balancing helper T cell subsets, inducing B cell generation and differentiation into plasma cells, and enhancing the production of immunoglobulin. These effects are mainly mediated by activation of the JAK/STAT, MAPK and PI3K pathways. Some IL-21 target genes, such as B lymphocyte induced maturation protein-1 (Blimp-1), suppressor of cytokine signaling (SOCS), CXCR5 and Bcl-6, play important roles in the immune response. Therefore, IL-21 has been linked to autoimmune diseases. Indeed, IL-21 levels are increased in the peripheral blood and tissues of patients with systematic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D), immune thrombocytopenia (ITP), primary Sjogren's syndrome (pSS), autoimmune thyroid disease (AITD) and psoriasis. This increased IL-21 even positively associates with Tfh cells, plasma cells, autoantibodies and disease activity in SLE and RA. Additionally, IL-21 has been utilized as a therapeutic target in SLE, RA, T1D and psoriatic mouse models. Profoundly, clinical trials have shown safety and improvement in RA patients. However, tolerance and long-term pharmacodynamics effects with low bioavailability have been found in SLE patients. Therefore, this review aims to summarize the latest progress on IL-21 function and its signaling pathway and discuss the role of IL-21 in the pathogenesis of and therapy for autoimmune diseases, with the hope of providing potential therapeutic and diagnostic strategies for clinical use.
白细胞介素 21（IL-21）是一种主要由滤泡辅助 T（Tfh）和辅助性 T 细胞 17（Th17）细胞产生的自分泌细胞因子，已被证明在免疫系统中发挥重要作用，例如促进 Tfh 和 Th17 细胞的增殖和发育、平衡辅助性 T 细胞亚群、诱导 B 细胞生成和分化为浆细胞，以及增强免疫球蛋白的产生。这些作用主要通过激活 JAK/STAT、MAPK 和 PI3K 途径来介导。一些 IL-21 靶基因，如 B 细胞诱导成熟蛋白 1（Blimp-1）、细胞因子信号转导抑制物（SOCS）、CXCR5 和 Bcl-6，在免疫反应中发挥重要作用。因此，IL-21 与自身免疫性疾病有关。事实上，系统性红斑狼疮（SLE）、类风湿关节炎（RA）、1 型糖尿病（T1D）、免疫性血小板减少症（ITP）、原发性干燥综合征（pSS）、自身免疫性甲状腺疾病（AITD）和银屑病患者的外周血和组织中 IL-21 水平升高。这种增加的 IL-21 甚至与 SLE 和 RA 中的 Tfh 细胞、浆细胞、自身抗体和疾病活动呈正相关。此外，IL-21 已被用作 SLE、RA、T1D 和银屑病小鼠模型的治疗靶点。值得注意的是，临床试验表明 RA 患者的安全性和改善。然而，在 SLE 患者中发现了耐受性和长期药效学效应以及低生物利用度。因此，本综述旨在总结 IL-21 功能及其信号通路的最新进展，并讨论 IL-21 在自身免疫性疾病发病机制和治疗中的作用，以期为临床应用提供潜在的治疗和诊断策略。
