Lymphocytes in cystic fibrosis lung disease: a tale of two immunities.

After over half a century of research a clear, comprehensive and correct understanding of the pathogenesis of the chronic bronchocentric pulmonary infection and inflammation that characterizes cystic fibrosis (CF) lung disease continues to elude us. The earliest hypothesis, postulating the critical role of impaired mucociliary clearance by dessicated, hyperviscous airway fluids, is alive and well, having been updated by intensive study of the ion transport regulatory properties of the cystic fibrosis transmembrane conductance regulator (CFTR). Mutations in the CFTR gene on both alleles result in defective chloride secretion and sodium hyperabsorption in the conducting airways with resulting volume depletion of the airway surface liquid [1,2]. However, in the case of CF the application of Occam’s razor, seeking a parsimonious cause-and-effect relationship between CFTR’s well-described chloride channel function and all the downstream pathogenetic effects, has been undermined completely by the discovery of the astounding multi-functionality of this protein, the pleotropic effects of its dysfunction on a large number of other genes and cell functions, and the contributory effects of modifying genes in this supposedly monogenic disease [3‐5]. To cite just one example among several that have potentially important clinical implications for immune responses, CFTR directly influences expression of the regulated upon activation, normal T cell expressed, and presumably secreted (RANTES) chemokine [6]. Thus over the last decade the net has again widened to examine how CFTR mutations may result in a variety of host defence defects leading to the disease we observe as clinicians. The task is complicated by the onset of lung disease in early infancy, making primary CFTRrelated defects difficult to distinguish from secondary effects [7]. Furthermore, in many cases (for example, in vitro studies of cytokine and chemokine secretion by CF respiratory epithelial cells at baseline and upon activation) understanding is also obscured by the substantial impact of methodological variables such as cell source, culture conditions, stimulus and kinetics [8,9]. All this counsels a healthy dose of scepticism and great caution in interpreting any particular set of results without much confirmatory work. For several decades the problem of chronic airways infection with a restricted spectrum of bacterial pathogens, especially Pseudomonas aeruginosa , led to a large effort to find underlying defects in the adaptive immune response in CF. The lack of systemic infection in CF suggests strongly that any such defects are local, and thus likely as secondary effects of established infection and/or inflammation. Indeed, a large literature exists that demonstrates myriad immunomodulatory effects arising from established CF lung disease, such as proteolytic degradation of opsonins, effects of chronic antigenic stimulation upon antibody responses and mutual bacterial‐host interactive effects [10‐12]. Direct effects of P. aeruginosa exoproducts upon lymphocyte function probably account for early reports of suppressed cellmediated immunity in CF patients [13,14], but overall responses probably represent a complex net effect of both suppressive and demonstrably stimulatory effects of P. aeruginosa or other microbes, as well as the accompanying proinflammatory milieu [15].