Mucosal Immunity in Cystic Fibrosis

Abstract

The highly complex and variable genotype-phenotype relationships observed in cystic fibrosis (CF) have been an area of growing interest since the discovery of the CF transmembrane conductance regulator (CFTR) gene >30 y ago. The consistently observed excessive, yet ineffective, activation of both the innate and adaptive host immune systems and the establishment of chronic infections within the lung, leading to destruction and functional decline, remain the primary causes of morbidity and mortality in CF. The fact that both inflammation and pathogenic bacteria persist despite the introduction of modulator therapies targeting the defective protein, CFTR, highlights that we still have much to discover regarding mucosal immunity determinants in CF. Gene modifier studies have overwhelmingly implicated immune genes in the pulmonary phenotype of the disease. In this context, we aim to review recent advances in our understanding of the innate and adaptive immune systems in CF lung disease.

Figure 1:

Simplified overview of CFTR in the normal (left) and CF (right) airway and the key aberrancies in innate mucosal immunity namely deyhydrated and thickened airway surface liquid (in part due to increased activity of ENaC), tethered and thickened mucus, decreased pH, impaired mucociliary clearance, hyperinflammation, pathogenic biofilm formation and the establishment of bacterial colonization.

Figure 2:

Simplified overview of the aberrancies in CF adaptive immunity marked by robust responses that are infective in mediating inflammation and eradicating bacterial pathogens. Insert Panel 1. T helper cells: Th2 and Th17 immune responses predominate in CF. Elevated Th17 cells in CF are associated with worsened lung function with proinflammatory cytokine IL-17A (IL-17) recruiting and activating neutrophils to promote continued inflammation. IFN-γ, a key product of Th1 cells, is an important regulator of neutrophil accumulation and survival. Mucus accumulation and goblet cell hyperplasia are driven by Th2 cells, particularly IL-4 and Il-13. Insert Panel 2. Regulatory T cells: Vitamin D supplementation has been associated with a higher percentage of T reg cells in healthy subjects and in subjects with autoimmune disease. Low levels of T reg cells have been shown in the people with CF and ABPA and is associated with chronic P. aeruginosa infection and lower lung function. Insert Panel 3. B cells: Increased immunoglobulins and elevated circulating immune complexes (CICs) are seen in the CF lung and have been investigated as potential poor prognostic markers in CF given their association with decreased lung function and death particularly in individuals colonized with P. aeruginosa. It is unclear why the immunoglobulin response is ineffective in CF. Defects in somatic hypermutation, impaired antibody transport and entrapment in thickened biofilms and mucous, or increased degradation by proteases have been hypothesized.