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.

中文翻译：

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日本和北美 MDA5+ 皮肌炎患者队列的 B 细胞表位比较分析揭示了免疫库与肺死亡率之间的直接关联


目的 抗黑色素瘤分化相关基因 5 抗体阳性 （MDA5+） DM 患者表现出因地理和种族/遗传分布而异的临床特征。本研究的目的是探讨 B 细胞表位谱和相应的临床特征是否区分两个独立的 MDA5 + DM 队列。方法 采用基于 ELISA 的方法确定 155 个重叠氨基酸 MDA5 亚片段的抗体识别与 17 例日本 MDA5 + DM 患者临床特征之间的关系。通过 Brunner Munzel 检验评估临床特征与标准化抗 MDA5 亚片段抗体滴度之间的关联，并与独立北美队列的临床/血清学特征进行比较。采用受试者操作者特征 （ROC） 分析和 Kaplan-Meier 曲线进一步评估抗 MDA5 片段抗体水平与特定临床特征/结局之间的关系。结果 17 例 MDA5+ DM 患者的日本队列的临床特征显示关节炎 （47%） 和间质性肺病 （ILD） （100%） 的患病率很高。血清学分析显示，MDA5 片段 A （aa 1-155）、B （aa 130-284） 和 E （aa 517-671） 的抗体识别模式与北美 MDA5+ 患者 （n = 24） 不同，后者的血清优先识别片段 H （aa 905-1026）。统计分析显示，日本患者的抗片段 A 抗体水平与急进性 ILD （RP-ILD） 之间存在显着关联 （P < 0.01）。在联合队列分析中，ROC 和 Kaplan-Meier 曲线也表明抗片段 A 抗体水平、RP-ILD 和肺死亡之间存在很强的关系。 结论 日本和北美 MDA5+ DM 患者表现出明显不同的 B 细胞表位谱，这与日本患者 RP-ILD 患病率较高和临床结局较差相关。