Immunobiology Of Ifrd1 A Novel Genetic Modifier Of Cystic Fibrosis Lung Disease

Cystic fibrosis is the most common, lethal autosomal recessive disorder in the United States. Lung disease is the major cause of morbidity and mortality in CF. In the CF lung, chronic infection and dysregulated neutrophilic inflammation lead to progressive airway destruction. Despite the molecular insights afforded by identification of disease-causing gene, CFTR, a clear understanding of the pathogenesis of lung disease in CF remains elusive. There is a poor correlation of genotype with phenotype in lung disease in CF, which strongly suggests that the expression of lung disease in CF is influenced by environmental exposures and/or modifier genes. To search for genes modifying CF lung disease, the Karp lab performed a genome-wide association study in collaboration with GMSG cohort, validating top candidates in collaboration with the CFTSS cohort. Using this approach, genetic variation in IFRD1 was identified and verified as a modifier of lung disease severity in CF. IFRD1 is a HDAC-dependent transcriptional co-activator or co-repressor whose expression is particularly enriched in neutrophils. The goal of my dissertation studies was mechanistic insight into the modulation of CF lung disease by IFRD1. This dissertation research provides evidence in favor of the hypothesis that IFRD1 modulates the course of airway disease in CF through regulation of neutrophil effector function. This study also strongly suggests a mechanism by which IFRD1 modulates neutrophil function in a HDAC-dependent manner to co-suppress the expression of ATF3, a transcriptional repressor of NF-[kappa]B activity in neutrophils. Finally, this research emphasizes the translational implications for therapeutic targeting of neutrophils in CF. This study suggests that the IFRD1/HDAC axis may provide a tractable therapeutic target in CF, and the plethora of other diseases in which neutrophils play an important pathogenic role.