Multi-Modal Mapping of Immune Dysregulation Across the Spectrum of CFTR Dysfunction

Résumé fourni par la source

While elexacaftor-tezacaftor-ivacaftor (ETI) improves clinical outcomes in people with CF (pwCF) with at least one F508del mutation, its effects on systemic immunity remain unclear. Moreover, healthy F508del carriers (~4% of individuals in Europe/N. America) are at risk for CF-related comorbidities. This study aimed to map immune alterations and intercellular communication across the spectrum of CFTR dysfunction. We previously assessed CFTR dysfunction at the single-cell level using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to profile >200,000 circulating PBMCs from pwCF homozygous for F508del (at baseline and on ETI), healthy F508del carriers, and non-carriers (Jonckheere L, ERJ(2024)64;suppl_68). Building on our single-cell atlas, we integrated ligand-receptor analysis of CITE-seq data with FlowSOM clustering of flow cytometry data. In pwCF on ETI, pro-inflammatory signaling is attenuated while TGF-β-mediated regulatory interactions are enhanced (Fig. 1A). Strikingly, healthy F508del carriers exhibit CF-like immune alterations, including reduced circulating mucosal-associated T cells (Fig. 1B). erj;66/suppl_69/OA4468/F1 F1 F1 This study maps immune shifts across the spectrum of CFTR dysfunction, showing that ETI modulates intercellular cross-talk. Importantly, CF-like immune dysregulation in healthy carriers suggests subclinical CFTR dysfunction may impact a broader population, with implications for other CFTR-related diseases.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.