目的:抗黑色素瘤分化相关基因5抗体阳性(MDA5+)皮肌炎患者的临床特征因地域和种族/遗传分布而异。因此,我们研究了B细胞表位谱和相应的临床特征是否区分了MDA5皮肌炎的两个独立队列。
方法:我们使用基于ELISA的方法来确定来自日本的17例MDA5+皮肌炎患者的重叠155个氨基酸MDA5亚片段的抗体识别与临床特征之间的关系。通过BrunnerMunzel测试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/血清学概况进行比较。ROC分析和Kaplan-Meier曲线用于进一步评估抗MDA5片段抗体水平与特定临床特征/结果之间的关系。
结果:日本17名MDA5+皮肌炎患者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。血清学分析证明了MDA5片段A(aa1-155)的主要抗体识别,B(aa130-284),和E(aa517-671)的模式不同于北美MDA5患者(n=24),其血清优先识别片段H(aa905-1026)。统计学分析显示,在日本患者中,抗片段A抗体水平与快速进行性ILD(RP-ILD)之间存在显著关联(p<0.01)。ROC和KaplanMeier曲线也证明了抗片段A抗体水平之间的强关系,RP-ILD,合并队列分析中的肺部死亡。
结论:日本和北美MDA5+皮肌炎患者表现出明显不同的B细胞表位谱,这与日本患者中RP-ILD的患病率较高和临床预后较差有关。
OBJECTIVE: Anti-melanoma differentiation-associated gene 5 antibody-positive (MDA5+) dermatomyositis patients exhibit clinical features that vary by geographical and ethnic/genetic distribution. We therefore investigated whether B cell epitope profiles and corresponding clinical features distinguished two independent cohorts of MDA5+ dermatomyositis.
METHODS: We used ELISA-based methods to determine the relationship between antibody recognition of overlapping 155 amino acid MDA5 subfragments and clinical features of 17 MDA5+ dermatomyositis patients from Japan. Associations between clinical features and standardized anti-MDA5 subfragment antibody titers were assessed via Brunner Munzel testing and compared with clinical/serological profiles of an independent North American cohort. 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+ dermatomyositis 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+ dermatomyositis patients manifest markedly different B cell epitope profiles that are associated with higher prevalence of RP-ILD and worse clinical outcome among Japanese patients.