4. Gaps in Knowledge and Perspectives

Studies on patients’ lung tissues show limitations related to the end-stage status of CF patients and the smoking status of controls recruited for tissue samples (lung explants and cell cultures). The accessibility to early diseased tissue remains difficult due to ethical issues. Concerning studies on expectorations, less than 10% of CF children at 6 years of age and around 40% at 10 years [134] can expectorate spontaneously and bacterial infection appears at a very early stage but induced sputum is effective.

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Different in vitro models are currently used. First, organoids and cell cultures of airway epithelial cells derived from patients in air–liquid conditions show some features observed in vivo in CF (and in other respiratory diseases) but do not recapitulate the complexity of the airways. Notably, they differ in terms of cell populations (notably basal cell subtypes), compared to in vivo [55]. However, they are promising tools for patients with rare mutations to evaluate the response to CFTR modulators.

More recent studies highlight the implication of different cell types and the interplay between them. Therefore, animal models further helped to recapitulate the complexity of CF disease and to study the molecular mechanisms of the changes and IgA-related immunity acquired in the airways of CF patients, but currently, mouse models mostly fail to reproduce intrinsic, CFTR-related lung disease [135]. The function/efficacy of S-IgA in CF is thus difficult to address although Marshall et al. demonstrated that SC's ability to neutralize IL-8/CXCL8 is reduced, leading to neutrophilic inflflammation [112] and that this reduction is caused by defective glycosylation, essential for SC antimicrobial roles [102] and proper localization of S-IgA at the interface between the lumen and the epithelium [99].

Finally, highly effective CFTR modulators have the potential to modify the microbiome of patients with CF, at least for Pseudomonas infection [136]. In the pipeline for future research, studying the impact of CFTR modulators on the pIgR/IgA system would be interesting, both in vivo and in vitro. Furthermore, the positive or negative impact of increased IgA secretion in the CF bronchial lumen remains unclear. We still do not know whether it affects their microbiological status, the long-term clinical outcome, or how it is affected by the CF microenvironment (impaired mucociliary clearance, proteases, etc.). 

5. Conclusions

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