Mapping immune dysregulation across the spectrum of CFTR dysfunction

Cystic fibrosis (CF) is classically regarded as a lung disease caused by the buildup of thick mucus leading to local airway inflammation. However, patients also experience systemic inflammation, which is less well understood and partly linked to intrinsic CFTR dysfunction in immune cells. Since CFTR is expressed throughout the immune system, the immune system of CF patients is inherently pro-inflammatory at baseline, but it shows impaired responses to viral and bacterial infections. While CFTR modulators such as ETI (elexacaftor/tezacaftor/ivacaftor) dramatically improved clinical outcomes, their effects on systemic immunity remain unclear.

To address this, Dr Leander Jonckheere, pulmonologist in training and PhD student at the Ghent University Hospital, conducted a longitudinal study to analyze the immune system of CF patients before and after initiation of ETI, and compare this to age- and sex-matched healthy controls who were either CFTR mutation carriers or confirmed non-carriers. For this study, immune profiling was performed on serum and peripheral blood mononuclear cells, including high-resolution single-cell RNA sequencing.

Results showed that ETI therapy reduces the baseline inflammatory signaling in CF patients, while restoring the interferon responses that are critical for anti-viral and anti-bacterial defense. Subsequent cell-cell communication analyses revealed a decreased inflammatory and an increased regulatory signaling, supporting an improved immune homeostasis following ETI therapy. Strikingly, CFTR mutation carriers, traditionally considered healthy, displayed a CF-like immune profile, including depletion of mucosal T cells, which suggests the presence of subclinical mucosal inflammation.

These findings demonstrate that intrinsic CFTR dysfunction contributes directly to immune dysregulation in CF and that a treatment with ETI can (partially) restore immune balance. Furthermore, the observation that CFTR carriers (4-5% of the general population) may be at risk for CF-related comorbidities suggests that CFTR plays a more extensive role in regulating human immunity than previously thought.