Immune Responses in Cystic Fibrosis: Are They Intrinsically Defective?

Cystic fibrosis (CF), the most common lethal single-gene disorder affecting Northern Europeans and North Americans, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Cftr is a chloride channel and a regulator of other ion channels, and many aspects of the CF phenotype are directly related to ion channel abnormalities attributable to CFTR mutation. Lung disease is the most common limitation to the quantity and quality of life for patients with CF. One aspect that continues to be enigmatic is the observed alterations in innate and adaptive immune responses to certain pathogens. Altered responses to Pseudomonas aeruginosa and Aspergillus fumigatus, with an increase in neutrophil chemoattractants in the former case and a hyper-IgE-like state in the latter, are common in CF. Several lines of evidence suggest that the proinflammatory cytokine response to bacterial infection is exaggerated in CF. A literature search reveals that, although the abnormalities in CF immune cells have been recognized since the 1970s, few studies until recently have appreciated the role that CFTR plays in these cell types. A growing body of evidence has emerged that points to neutrophils, macrophages, and T cells as being central to the infectious and pulmonary pathology, accounting for the majority of CF mortality. Primary CFTR defects in T cells are providing new insights into the misorchestration of the CF immune system due to aberrant signaling pathways. Defective CFTR function disrupts the balance of intracellular ion concentrations, including [Ca(2+)], which is known to drive gene expression pathways. New evidence links this hypothesis to anomalies in immune activation observed across CF cell types, which could shed light on the inability of individuals with CF to effectively clear pathogens. This review focuses on the emerging role of Cftr in gene expression and other functions in cells of the innate and adaptive immune system.