A novel approach to analyze gene expression data demonstrates that the DeltaF508 mutation in CFTR downregulates the antigen presentation pathway.
Gene array studies comparing cystic fibrosis (CF) and non-CF genotypes should reveal factors that explain variability in CF lung disease progression, yielding insights that lead to improved CF care. To date, studies have reached conflicting conclusions, perhaps due to experimental differences and divergent statistical approaches. This review aims: 1) to summarize the findings of four recent gene studies comparing CF and non-CF genotypes, and 2) to reanalyze original data using a recently developed statistical approach, with the aim of identifying genes and paths consistently regulated by the CF genotype. We identified four studies evaluating the effect of the DeltaF508-CFTR mutation on human airway epithelial cell gene expression, restricting our investigation to human airway epithelial cell studies whose data were accessible in NCBI's Gene Expression Omnibus or the European Bioinformatic Institute's ArrayExpress. Gene expression patterns showed consistent repression of MHC class I antigen presentation genes in CF human airway epithelia, suggesting a novel mechanistic explanation for poor clearance of viral and bacterial infections by CF patients. We also examined proinflammatory and NF-kappaB genes, whose induction is widely accepted as a hallmark of the CF genotype, but found little evidence of induction, consistent with a recent review (Machen TE, Am J Physiol Cell Physiol 291: C218-C230, 2006.). In conclusion, our analysis suggests that the CF genotype may impair immune function in airway epithelial cells but may not increase inflammation. Additional studies are required to determine whether MHC class I gene repression in CF reduces antigen presentation at the protein level and whether repression impairs immune function.
Hampton
Thomas H
TH
Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Stanton
Bruce A
BA
D017951:Antigen Presentation / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis
C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator