Multi-omics profiling links B-cell activation, cytokine signalling, and IgG glycosylation to CFTR modulator response in cystic fibrosis

Résumé fourni par la source

Cystic fibrosis (CF) is characterised by chronic inflammation and systemic immune dysregulation, yet how CFTR modulation alters these processes remains unclear. We integrated single-cell transcriptomics, serum cytokine profiling, and glycomics to assess the immunological effects of elexacaftor/tezacaftor/ivacaftor (ETI) in people with CF (pwCF). Single-cell profiling of PBMCs from eight pwCF before and on ETI revealed reduced activation-associated transcriptional programs in B cells, including downregulation of NF-κB and cytokine signalling pathways. Longitudinal serum cytokine profiling in 90 pwCF showed corresponding reductions in IL-6, IL-1β, IL-8, and IL-17A with increased IFN-γ, reflecting rebalanced immune signalling. Given that glycosylation modulates protein structure and IgG effector function, we profiled the total serum N-glycome in paired samples from 66 pwCF before and on ETI, alongside healthy controls. IgG-associated glycans exhibited marked re-galactosylation in pwCF on ETI, with decreased pro-inflammatory agalactosylated and increased anti-inflammatory galactosylated forms, partially restoring profiles towards healthy levels. Importantly, greater reductions in IL-6 and IL-1β and higher degrees of IgG re-galactosylation were associated with larger ppFEV1 gains, higher BMI and fewer exacerbations on ETI. Our multi-omics approach reveals coordinated changes across cellular activation, systemic inflammation, and post-translational protein modification that converge on clinical benefit. These findings provide a framework for understanding how CFTR modulation remodels immunity in CF and may inform biomarker-driven therapeutic monitoring.

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