Abstract:

Objective: This study aims to evaluate the causal relationship between immune cells and pulmonary tuberculosis (TB) using Mendelian Randomization (MR) analysis. This approach provides novel insights into vaccine development, TB prevention strategies, and prognosis evaluation. Methods: Summary data from genome-wide association studies (GWAS) were utilized, with genetic loci related to pulmonary TB selected as instrumental variables. Five methods were applied for two-sample MR analysis: MR-Egger regression, weighted median, inverse variance weighted, simple mode, and weighted mode. The causal relationship between immune cells and pulmonary TB was assessed using odds ratios (OR, 95%CI). Heterogeneity was evaluated using Cochran’s Q, and pleiotropy was examined through the MR-pleiotropy residual sum and outlier (MR-PRESSO) test and MR-Egger regression. The leave-one-out method was employed to verify the stability of the results. Results: The inverse variance weighted analysis revealed a strong association between pulmonary TB risk and Unsw mem %B cell (β=-0.257, OR=0.773, 95%CI: 0.607 to 0.985, P=0.037), CD19 on IgD⁺CD38^- (β=-0.493, OR=0.610, 95%CI: 0.379 to 0.982, P=0.042), CD39⁺ secreting Treg %CD4 Treg (β=0.425, OR=1.532, 95%CI: 1.099 to 2.135, P=0.012), CD25 on CD45RA^-CD4 not Treg (β=-0.719, OR=0.487, 95%CI: 0.262 to 0.904, P=0.023), CD45 on CD33br HLA-DR⁺ (β=-0.364, OR=0.695, 95%CI: 0.508 to 0.949, P=0.022), HLA-DR on CD33^-HLA-DR⁺ (β=0.153, OR=1.166, 95%CI: 1.024 to 1.323, P=0.020), HLA-DR on CD14^-CD16^- (β=0.134, OR=1.144, 95%CI: 1.006 to 1.300, P=0.040), and PDL-1 on monocyte (β=0.379, OR=1.462, 95%CI: 1.056 to 2.026, P=0.022). No significant heterogeneity or pleiotropy was found. Conclusion: Elevated levels of four immune cell phenotypes—unswitched memory B cells, CD19 on IgD⁺CD38^- cells, CD25 on CD45RA^-CD4 non-Treg cells, and CD45 on CD33bright HLA-DR⁺ cells—may be associated with a reduced risk of developing tuberculosis. In contrast, increased levels of four other immune cell phenotypes—CD39⁺ secreting regulatory T cells (%CD4 Treg), HLA-DR on CD33^-HLA-DR⁺ cells, PDL-1 on monocytes, and HLA-DR on CD14^-CD16^- cells—may be linked to an elevated risk of tuberculosis.

Key words: Mycobacterium tuberculosis, Infection, Immune system, Mendelian randomization, Causality