Comparative B cell epitope profiling in Japanese and North American cohorts of MDA5+ dermatomyositis patients reveals a direct association between immune repertoire and pulmonary mortality

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OBJECTIVES: Anti-melanoma differentiation-associated gene 5 antibody-positive (MDA5+) DM patients exhibit clinical features that vary by geographical and ethnic/genetic distribution. The objective of this study was to investigate whether B cell epitope profiles and corresponding clinical features distinguished two independent cohorts of MDA5+ DM. METHODS: ELISA-based methods were used to determine the relationship between antibody recognition of 155 overlapping amino acid MDA5 subfragments and clinical features of 17 MDA5+ DM patients from Japan. Associations between clinical features and standardized anti-MDA5 subfragment antibody titres were assessed via Brunner Munzel testing and compared with the clinical/serological profiles of an independent North American cohort. Receiver operater characteristic (ROC) analyses and Kaplan-Meier curves were used to further assess the relationship between anti-MDA5 fragment antibody levels and specific clinical features/outcomes. RESULTS: Clinical characterization of a Japanese cohort of 17 MDA5+ DM patients revealed a high prevalence of arthritis (47%) and interstitial lung disease (ILD) (100%). Serological profiling demonstrated predominant antibody recognition of MDA5 fragments A (aa 1-155), B (aa 130-284) and E (aa 517-671) in a pattern that was distinct from North American MDA5+ patients (n = 24), whose sera preferentially recognized fragment H (aa 905-1026). Statistical analysis revealed a striking association between anti-fragment A antibody levels and rapidly progressive ILD (RP-ILD) among Japanese patients (P < 0.01). ROC and Kaplan-Meier curves also demonstrated a strong relationship between anti-fragment A antibody levels, RP-ILD, and pulmonary death in combined cohort analyses. CONCLUSIONS: Japanese and North American MDA5+ DM patients manifest markedly different B cell epitope profiles that are associated with higher prevalence of RP-ILD and worse clinical outcome among Japanese patients.

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