Mendelian randomization and mediation analysis reveal the role of immune cell subsets in the causal pathways between blood cell perturbation responses and rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by complex immune interactions. Elucidating the causal relationships between blood cell perturbations, immune cell subsets, and RA can provide valuable insights into its pathogenesis.

Methods: This study employed bidirectional two-sample Mendelian Randomization (MR) to explore the causal effects of blood cell perturbations on RA risk, with a focus on immune cell mediation. Genetic data from large-scale Genome-Wide Association Studies (GWAS) were utilized to select instrumental variables (IVs) for exposure, mediator, and outcome. Inverse Variance Weighted (IVW) analysis was applied, supplemented by sensitivity tests. Mediation analysis was conducted to assess the indirect effects mediated by immune cells.

Results: Significant causal associations were identified between perturbations in reticulocytes, monocytes, and lymphocytes and specific immune cell subsets, including CD3 + CD39 + regulatory T cells (Tregs) and CD45RA + terminally differentiated CD8 + T cells (CD45RA + TD CD8 + cells). Erythropoiesis perturbation was associated with a reduced RA risk, while perturbations in monocytes and lymphocytes were found to facilitate RA progression through immune-mediated mechanisms.

Conclusion: This study underscores the pivotal role of immune cell subsets in mediating the effects of blood cell perturbations on RA development. These findings suggest that targeting immune cell-mediated pathways, particularly those involving Tregs and CD8 + T cells, can provide new therapeutic strategies for RA management. Key Points • Causal Relationships: Mendelian randomization (MR) analysis identified significant causal relationships between specific blood cell disturbances (e.g., reticulocytes, monocytes, and lymphocytes) and rheumatoid arthritis (RA). • Role of Immune Cells: CD3 + CD39 + regulatory T cells (Tregs) and CD45RA + Terminally Differentiated CD8 + T cells (CD45RA + TD CD8 + cells) mediate the association between blood cell disturbances and RA. • Protective Role of Reticulocytes: Reticulocyte disturbances under potassium chloride (KCl) conditions are negatively associated with RA, potentially protecting joints from inflammatory damage by reducing oxidative stress. • Protective Role of Non-Classical Monocytes: Baseline disturbances in monocyte median side scatter are negatively associated with RA, suggesting non-classical monocytes may reduce RA-related inflammation. • Positive Association of Lymphocyte Disturbances with RA: Lymphocyte side scatter standard deviation under colchicine disturbances shows a significant positive association with RA, indicating abnormal T cell activation may exacerbate RA progression.AQ.