Immune factors have a complex causal regulation on pulmonary fibrosis: Insights from a two-sample Mendelian randomization analysis

Abstract

Pulmonary fibrosis is a chronic, progressive lung disease characterized by excessive scarring of lung tissue, and its pathophysiological mechanisms have not been fully elucidated. Immune cells play a key role in many diseases, and this study aims to explore the causal link between immune cell characteristics and pulmonary fibrosis using Mendelian randomization. Utilizing the public GWAS database Open GWAS, this study collected whole-genome association study datasets of peripheral blood immune phenotypes and summary data of GWAS related to pulmonary fibrosis. Through Mendelian randomization (MR) analysis, we identified single nucleotide polymorphisms (SNPs) significantly associated with immune traits as instrumental variables. After pleiotropy and heterogeneity tests, causal effects were assessed using methods such as inverse-variance weighted (IVW), weighted median, and MR-Egger. Comprehensive MR analysis indicated a significant causal relationship between various immune cell types, including regulatory T cells (Tregs), natural killer (NK) cells, and specific monocyte subgroups, with the risk of pulmonary fibrosis. Specifically, phenotypes such as Activated & resting Treg %CD4+, CCR2-positive monocytes, and CD16-CD56 positive NK cells were associated with a reduced risk of pulmonary fibrosis. In contrast, CD8 + T cell subgroups were associated with an increased risk. This study provides evidence of a causal relationship between immune cell characteristics and pulmonary fibrosis, highlighting the protective role of regulatory T cells and specific NK cell subgroups, as well as the potential harm of CD8 + T cell subgroups. These findings offer new insights into the immunoregulatory mechanisms of pulmonary fibrosis and the development of novel therapeutic strategies.