Abstract
BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients.Methods/Principal FindingsHLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3–2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DLCO) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036).Conclusions/SignificanceDRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic, morbid, fibroproliferative lung disease that manifests with progressive pulmonary restriction and gas exchange abnormalities [1]
The pulmonary fibrosis that characterizes this disease is often considered to be uniquely dissociated from inflammatory processes [3], studies of patient-derived specimens show that abnormal adaptive immune responses are common in IPF [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18]
The subsequent disease validation cohorts were composed of IPF subjects for whom molecular human leukocyte antigen (HLA) typing results and/or tissue specimens for HLA typing were available from the National Institute of Health (NIH) (n = 35), University of Chicago Medical Center (n = 32), Inova Fairfax Hospital (n = 20), and Stanford University Medical Center (n = 14)
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic, morbid, fibroproliferative lung disease that manifests with progressive pulmonary restriction and gas exchange abnormalities [1]. The pulmonary fibrosis that characterizes this disease is often considered to be uniquely dissociated from inflammatory processes [3], studies of patient-derived specimens show that abnormal adaptive immune responses are common in IPF [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18]. Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. The etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may be present in IPF patients
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