Hirt Nell, Manchon Enzo, Chen Qian, Delaroque Clara, Corneau Aurelien, Hemon Patrice, Saker-Delye Safaa, Bataille Pauline, Bouaziz Jean-David, Bourrat Emmanuelle, Hovnanian Alain, Le Buanec Helene, Aoudjit Fawzi, El Costa Hicham, Jabrane-Ferrat Nabila, Al-Daccak Reem
National Institute of Health and Medical Research (INSERM) UMRS-976 HIPI, Paris Cité University, Saint-Louis Hospital, 75010, Paris, France.
Boston Childrens Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Nat Commun. 2025 Jan 14;16(1):664. doi: 10.1038/s41467-025-55934-7.
Endotypes are characterized by the immunological, inflammatory, metabolic, and remodelling pathways that explain the mechanisms underlying the clinical presentation (phenotype) of a disease. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering disease caused by COL7A1 pathogenic variants. Although underscored by animal studies, the endotypes of human RDEB are poorly understood. To fill this gap, we apply systems immunology approaches using single-cell high-dimensional techniques to capture the signature of peripheral immune cells and the diversity of metabolic profiles in RDEB adults, sampled outside of any opportunistic infection and active cancer. Our study, demonstrates the particular inflammation and immunity characteristics of RDEB adults, with activated / effector T and dysfunctional natural killer cell signatures, concomitant with an overall pro-inflammatory lipid signature. Artificial intelligence prediction models and principal component analysis stress that RDEB is not solely confined to cutaneous issues but has complex systemic endotypes marked by immune dysregulation and hyperinflammation. By characterising the phenotype-endotype association in RDEB adults, our study lays the groundwork for translational interventions that could by lessening inflammation, alleviate the everlasting suffering of RDEB patients, while awaiting curative genetic therapies.
内型由免疫、炎症、代谢和重塑途径所表征，这些途径解释了疾病临床表现（表型）背后的机制。隐性营养不良型大疱性表皮松解症（RDEB）是一种由COL7A1致病变异引起的严重水疱性疾病。尽管动物研究强调了这一点，但人类RDEB的内型仍知之甚少。为了填补这一空白，我们应用系统免疫学方法，使用单细胞高维技术来捕捉RDEB成年患者外周免疫细胞的特征以及代谢谱的多样性，这些样本来自于任何机会性感染和活动性癌症之外。我们的研究表明了RDEB成年患者特定的炎症和免疫特征，具有活化/效应T细胞和功能失调的自然杀伤细胞特征，同时伴有整体促炎脂质特征。人工智能预测模型和主成分分析强调，RDEB不仅局限于皮肤问题，还具有以免疫失调和炎症过度为特征的复杂全身内型。通过表征RDEB成年患者的表型-内型关联，我们的研究为转化干预奠定了基础，这种干预可以通过减轻炎症，缓解RDEB患者的长期痛苦，同时等待治愈性基因治疗。
