白细胞介素-35 在特发性炎性肌病中的作用。

Interleukin-35 in idiopathic inflammatory myopathies.

机构信息

Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.

出版信息

Cytokine. 2021 Jan;137:155350. doi: 10.1016/j.cyto.2020.155350. Epub 2020 Oct 28.

DOI:10.1016/j.cyto.2020.155350

PMID:33128920

Abstract

BACKGROUND

Interleukin-35 (IL-35) is a recently described heterodimeric cytokine that belongs to the IL-12 family and consists of p35 (IL-12a) and EBI3 (IL-27b) subunits. The expression of IL-35 in humans is inducible in response to inflammatory stimuli. Increased IL-35 levels were documented in several autoimmune inflammatory diseases, suggesting a possible immunomodulatory role in their pathogenesis.

OBJECTIVES

The aim of this study was to explore a potential role of IL-35 in the pathogenesis of idiopathic inflammatory myopathies (IIM) by studying the expression of IL-35 subunits in muscle biopsy samples and by evaluating serum levels of IL-35 and their association with disease activity in IIM patients.

METHODS

The expression of IL-35 subunits was studied in serial sections of 9 muscle biopsy samples [4 polymyositis (PM), 5 dermatomyositis (DM)] and in 7 non-inflammatory control muscle biopsies. Serum levels of IL-35 were measured in 23 PM, 28 DM and 15 cancer associated myositis (CAM) patients as well as in 40 healthy controls. Disease activity was evaluated using the Myositis Disease Activity Assessment Tool (MDAAT) and by serum muscle enzymes.

RESULTS

Expression of both IL-35 subunits was evident in the inflammatory infiltrates in IIM muscle biopsies, while no IL-35 expression was observed in control muscle samples. IL-35 serum levels were increased in all IIM patients compared to healthy controls [median 119.5 (range 32.1-1074.5) vs 36.2 (range 1.5-86.5) pg/ml, P < 0.001]. There were no differences in IL-35 serum levels between myositis subgroups (DM, PM or CAM). Serum IL-35 levels correlated significantly with physician's assessment of global (r = 0.29, p = 0.021), muscle (r = 0.30, p = 0.017) and extramuscular (r = 0.30, p = 0.016) disease activity as well as creatine kinase (r = 0.26, p = 0.044) and lactate dehydrogenase (r = 0.40, p = 0.003) levels. There was a significant correlation with pulmonary activity in patients with interstitial lung disease (r = 0.39, p = 0.037). Serum IL-35 correlated negatively with duration of treatment (r = -34, p = 0.009).

CONCLUSIONS

IL-35 is overexpressed in inflammatory infiltrates in muscle tissue and serum in IIM patients and there is correlation with several disease activity parameters. These data suggest potential role of locally produced IL-35 in the pathogenesis of inflammatory myopathies.

摘要

背景

白细胞介素-35 (IL-35) 是一种新描述的异二聚体细胞因子，属于 IL-12 家族，由 p35 (IL-12a) 和 EBI3 (IL-27b) 亚基组成。在人类中，IL-35 的表达可被炎症刺激诱导。在几种自身免疫性炎症性疾病中，IL-35 水平升高，提示其在发病机制中可能具有免疫调节作用。

目的

本研究通过研究肌肉活检样本中 IL-35 亚基的表达，以及评估 IL-35 血清水平及其与特发性炎性肌病 (IIM) 患者疾病活动的相关性，探讨 IL-35 在 IIM 发病机制中的潜在作用。

方法

对 9 例肌肉活检样本（4 例多发性肌炎 [PM]，5 例皮肌炎 [DM]）和 7 例非炎症性对照肌肉活检样本的连续切片进行 IL-35 亚基表达研究。测量 23 例 PM、28 例 DM 和 15 例癌相关肌炎 (CAM) 患者以及 40 名健康对照者的 IL-35 血清水平。使用肌炎疾病活动评估工具 (MDAAT) 和血清肌肉酶评估疾病活动。

结果

在 IIM 肌肉活检样本的炎症浸润中均可见到两种 IL-35 亚基的表达，而在对照肌肉样本中则未见 IL-35 表达。与健康对照组相比，所有 IIM 患者的 IL-35 血清水平均升高[中位数 119.5 (范围 32.1-1074.5) vs 36.2 (范围 1.5-86.5) pg/ml，P < 0.001]。肌炎亚组之间（DM、PM 或 CAM）的 IL-35 血清水平无差异。血清 IL-35 水平与医生评估的总体疾病活动（r = 0.29，p = 0.021）、肌肉疾病活动（r = 0.30，p = 0.017）和肌肉外疾病活动（r = 0.30，p = 0.016）以及肌酸激酶（r = 0.26，p = 0.044）和乳酸脱氢酶（r = 0.40，p = 0.003）水平显著相关。在有间质性肺病的患者中，与肺部活动有显著相关性（r = 0.39，p = 0.037）。血清 IL-35 与治疗时间呈负相关（r = -34，p = 0.009）。