IL-36在结缔组织病相关间质性肺疾病患者血清中的表达水平及临床意义

Serum Interleukin-36 Expression Level and Clinical Significance in Patients with Connective Tissue Disease Associated Interstitial Lung Disease

摘要: 目的：通过检测原发性干燥综合征、系统性硬化症以及类风湿关节炎(rheumatoid arthritis, RA)等结缔组织病相关间质性肺疾病(connective tissue disease associated interstitial lung disease, CTD-ILD)患者血清中白细胞介素-36 (interleukin-36, IL-36) (包括IL-36α，IL-36β，IL-36γ，IL-36Ra和IL-38)的表达水平，评估IL-36作为CTD-ILD潜在生物标志物的价值，为CTD-ILD的早期筛查、分层管理及靶向治疗提供新型生物标志物筛选策略和探索发病机制提供理论支撑。方法：本研究纳入2024年5~12月湖北民族大学附属民大医院风湿免疫科确诊的111例CTD患者，依据是否合并间质性肺疾病(interstitial lung disease, ILD)，将患者分为CTD-ILD组(56例)和结缔组织病未合并间质性肺疾病(connective tissue disease-non interstitial lung disease, CTD-NILD)组(55例)；同时纳入55名同期健康体检者作为健康对照组。采用酶联免疫吸附试验检测各组的血清IL-36表达水平，并收集所有研究对象的一般临床资料，以及CTD患者的实验室检验结果和肺高分辨率计算机断层扫描结果。采用IBM SPSS Statistics 27.0统计软件对所有数据进行统计分析。结果：(1) IL-36α、IL-36β、IL-36γ、IL-38在CTD患者血清中的表达水平均高于健康人群，差异均具有统计学意义(P < 0.05)；IL-36Ra在CTD患者血清中的表达水平低于健康人群，差异具有统计学意义(P < 0.05)。(2) IL-36β、IL-36γ、IL-38在CTD-ILD患者血清中的表达水平均高于CTD-NILD患者，差异均有统计学意义(P < 0.05)；IL-36Ra在CTD-ILD患者血清中的表达水平低于CTD-NILD患者，差异有统计学意义(P < 0.05)。通过受试者工作特征曲线分析得知，血清IL-36β、IL-38、IL-36β + IL-38从CTD中识别出ILD的曲线下面积分别为0.780、0.734、0.855，特异度分别为96.4%、92.7%、76.4%，敏感度分别为48.2%、44.6%、85.7%。(3) CTD-ILD患者的血清IL-36Ra表达水平与血沉呈负相关(r = −0.352, P = 0.008)；结论：(1) 血清IL-36β、IL-38可能是诊断CTD-ILD的潜在生物标志物，且二者联合诊断可明显提高敏感度。(2) IL-36激动剂和受体拮抗剂的失衡可能在CTD及其相关ILD的病理生理过程中发挥调控作用。

Abstract: Objective: By measuring serum levels of interleukin-36 (IL-36) isoforms (including IL-36α, IL-36β, IL-36γ, IL-36Ra, and IL-38) in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD)—specifically primary Sjögren’s syndrome, systemic sclerosis, and rheumatoid arthritis (RA)—this study aims to evaluate the value of IL-36 as a potential biomarker, thereby providing novel screening strategies for early detection, stratified management, and targeted therapy of CTD-ILD, while also advancing mechanistic insights into its pathogenesis. Methods: This study enrolled 111 patients with CTD diagnosed in the Department of Rheumatology and Immunology at Minda Hospital of Hubei Minzu University between May and December 2024. Participants were stratified into two groups based on interstitial lung disease (ILD) comorbidity status: the CTD-ILD group (56 cases) and the connective tissue disease-non interstitial lung disease (CTD-NILD) group (55 cases). A cohort of 55 healthy individuals undergoing routine physical examinations during the same recruitment period was concurrently enrolled as the healthy control (HC) group. Serum IL-36 expression levels in each group were measured using enzyme-linked immunosorbent assay, and general clinical data of all subjects were collected, along with laboratory test results of CTD patients and pulmonary high-resolution computed tomography findings. Statistical analysis of all data was performed using IBM SPSS Statistics 27.0 statistical software. Results: (1) The serum expression levels of IL-36α, IL-36β, IL-36γ, and IL-38 in CTD patients were significantly higher than those in HC group, and the differences were statistically significant (P < 0.05); whereas IL-36Ra levels were lower in CTD patients compared to HC group, and the difference was statistically significant (P < 0.05). (2) the serum levels of IL-36β, IL-36γ, and IL-38 in the CTD-ILD group were elevated compared to the CTD-NILD group, and the differences were statistically significant (P < 0.05); while IL-36Ra levels were reduced in CTD-ILD patients, and the difference was statistically significant (P < 0.05). Receiver operating characteristic curve analysis revealed that serum IL-36β, IL-38, and IL-36β + IL-38 exhibited areas under curve (AUC) of 0.780, 0.734, and 0.855, respectively, for distinguishing ILD from CTD, with specificities of 96.4%, 92.7%, and 76.4%, and sensitivities of 48.2%, 44.6%, and 85.7%. (3) In CTD-ILD patients, serum IL-36Ra concentrations were inversely associated with erythrocyte sedimentation rate (r = −0.352, P = 0.008). Conclusion: (1) Serum IL-36β and IL-38 may serve as potential biomarkers for diagnosing CTD-ILD, and their combined detection significantly improves sensitivity. (2) The imbalance between IL-36 agonists and receptor antagonists may play a regulatory role in the pathophysiological processes of CTD and associated ILD.