IgG subclass-specific N-glycosylation differentiates HRCT subtypes in idiopathic inflammatory myopathies-associated ILD

Tong Wu¹Yanhong Li¹Yingying Ling¹Yubin Luo¹Yinlan Wu¹Jing Zhao¹Lu Cheng²Chunyu Tan¹Yong Zhang^1*Yi Liu^1,3*

• ¹Department of Rheumatology and Immunology, Laboratory of Rheumatology and Immunology, West China Hospital of Sichuan University, Chengdu, China
• ²Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital of Sichuan University, Chengdu, China
• ³West China Lecheng Hospital, Sichuan University, Boao, China

Idiopathic inflammatory myopathies (IIMs) frequently involve interstitial lung disease (ILD), a major contributor to morbidity and mortality. However, immunological heterogeneity across radiologic ILD subtypes remains poorly defined. This study aimed to explore whether subclass-specific IgG N-glycopeptides could distinguish high-resolution computed tomography (HRCT)-based ILD patterns in IIM. We analyzed plasma IgG subclass-specific N-glycopeptides in 145 IIM patients, including 98 with ILD (IIM-ILD), via intact glycopeptide mass spectrometry. Among ILD patients with available HRCT scans (n = 92), three predominant subtypes were identified: fibrotic nonspecific interstitial pneumonia (fNSIP), cellular NSIP (cNSIP), and organizing pneumonia (OP). Fifteen intact N-glycopeptides (IGPs) were identified across all IIM patients, and six IGPs within the IgG2 subclass showed a significant difference between IIM-ILD patients and IIM patients without ILD. Subtype-specific glycoform signatures were observed across HRCT subtypes and correlated with clinical features such as muscle involvement and autoantibody profiles. A multinomial logistic regression model integrating seven glycopeptides and seven clinical variables achieved robust classification of HRCT subtypes (macro-AUC = 0.89). These findings suggest that subclass-specific IgG N-glycosylation profiles reflect immunological heterogeneity in IIM-ILD and could aid in the stratification of HRCT-defined endotypes. Our results provide a foundation for future studies exploring the role of immunoglobulin glycosylation in the pathogenesis of autoimmune-associated ILD.