Auto-Immunity May Be Involved in the Development of Pulmonary Fibrosis

Auto-immunity may have a role in the development of fibrotic idiopathic interstitial pneumonias (fIIP), a disease once thought to result solely from environmental factors. New research suggests a possible genetic link, associating two variants of the human leukocyte antigen (HLA) allele to an increased risk of fIIP.

The study, “Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia,” was published in the journal BMC Genetics.

fIIPs are a group of serious lung diseases characterized by progressive fibrosis. A few drugs, such as pirfenidone (Esbriet) and nintedanib (Ofev), have been shown to slow the progression of idiopathic pulmonary fibrosis (IPF), but only lung transplants prolong survival.

Although this disease was thought to develop spontaneously due to exposure to such factors as cigarette smoke, genetic variations are beginning to be seen as also having a role.

Previously, the researchers had performed a genome analysis to identify single nucleotide polymorphisms (SNP, mutations where one nucleotide is exchanged by another) in patients with fIIP. The team reported 10 genes, including genes involved in host defense from inhaled pathogens, in lung barrier function, and also in telomere maintenance, whose mutations increased the risk of developing the disease.

Nonetheless, the researchers believed that the greatest risk for fIIP remained unexplained, and attempted to identify additional genetic risk variants. They analyzed data from 1,616 patients with fIIP and 4,683 controls. After conducting a meta-analysis, researchers identified two new genetic risk variants in the region of the HLA gene.

To explore the biological significance of these HLA variants, the team at the National Jewish Health, in Colorado, compared the expression of 66 selected genes in the HLA region in 87 cases of IPF and 70 controls. They identified 21 differentially expressed genes, eight of which are known to have a role in immune and inflammatory function. Two other genes were also found to be involved in protein folding, a mechanism thought to be involved in the pathogenesis of IPF.

The authors believe their findings highlight how auto-immunity may drive the development of fIIP, and may provide useful information on diseases such as scleroderma, rheumatoid arthritis, and systemic lupus erythematosus, of which fibrotic interstitial lung disease is a common manifestation.