Immune Cell Characteristics and Infections Associated with Chronic Obstructive Pulmonary Disease (COPD), Asthma, and Interstitial Lung Disease (ILD): A Mendelian Randomization Studies

<b>Aims/Background</b> Epidemiological studies indicate that the involvement of the immune system in the pathogenesis of infections associated with chronic obstructive pulmonary disease (COPD), asthma, and interstitial lung disease (ILD) remains unclear. This study aims to assess the potential causal link between infections associated with COPD, asthma, or ILD and immune system function. <b>Methods</b> We conducted a two-sample Mendelian randomization analysis using publicly available genome-wide association study (GWAS) datasets. The causal relationship between immune cell signaling and susceptibility to infections related to COPD, asthma, and ILD was evaluated using inverse variance weighting (IVW), Mendelian randomization (MR)-Egger regression, weighted median, weighted mode, and simple mode approaches. To concurrently assess the causal impact of immune cell signaling on infection susceptibility associated with COPD, asthma, and ILD, a reverse Mendelian randomization analysis was also conducted. <b>Results</b> Genetic predisposition to elevated counts of circulating blood cells and their subpopulations demonstrated significant causal associations with a higher risk of COPD/asthma/ILD-related infections, as determined by IVW analysis. Specifically, genetically predicted increases in white blood cell count (odds ratio (OR) 1.08 [95% confidence interval (CI): 1.04-1.11], <i>p</i> < 0.00001), neutrophil count (OR: 1.06 [95% CI: 1.02-1.10], <i>p</i> = 0.00190), lymphocyte count (OR: 1.04 [95% CI: 1.01-1.07], <i>p</i> = 0.01515), monocyte count (OR: 1.03 [95% CI: 1.01-1.06], <i>p</i> = 0.00440), and eosinophil count (OR: 1.07 [95% CI: 1.04-1.10], <i>p</i> = 0.00001) were causally correlated with an increased risk of these respiratory infections. Notably, four immunophenotypes were significantly associated with the risk of COPD/asthma/ILD-related infections: Human Leukocyte Antigen (HLA) DR⁺ NK% NK (OR: 0.98 [95% CI: 0.97-0.99], <i>p</i> = 0.0004), CD66b on CD66b⁺⁺ myeloid cell (OR: 0.98 [95% CI: 0.97-0.99], <i>p</i> = 0.0007), HLA DR on CD14⁺ monocyte (OR: 1.03 [95% CI: 1.01-1.04], <i>p</i> = 0.0002), and HLA DR on CD33^- HLA DR⁺ (OR: 1.03 [95% CI: 1.02-1.05], <i>p</i> < 0.00001). The causal effect of COPD/asthma/ILD-related infections on Immunoglobulin D (IgD) expression in IgD⁺ CD38^br and transitional B cells was estimated to be 0.64 (95% CI: 0.49-0.83, <i>p</i> = 0.00091) and 0.70 (95% CI: 0.54-0.91, <i>p</i> = 0.00727), respectively. Additionally, COPD/asthma/ILD-related infections demonstrated a significant causal effect on several B cell and T cell subpopulations: IgD⁺ CD38^- % B cells, IgD⁺ CD38^- AC, CD4⁺ CD8^dim AC, IgD⁺ CD38^- % lymphocyte, and TD CD4⁺ AC, with the OR 1.54 (95% CI: 1.19-2.00, <i>p</i> = 0.00113), 1.56 (95% CI: 1.16-2.10, <i>p</i> = 0.00340), 1.60 (95% CI: 1.15-2.22, <i>p</i> = 0.00478), 1.47 (95% CI: 1.12-1.92, <i>p</i> = 0.00483) and 1.63 (95% CI: 1.14-2.34, <i>p</i> = 0.00725), respectively. <b>Conclusion</b> Our study reveals a causal association between altered circulating blood cell counts and specific immunophenotypes with the susceptibility to respiratory infections related to COPD, asthma, and ILD.