Elucidating the Causal Relationships Between B Cells, Dendritic Cells, and Multiple Sclerosis Pathogenesis

Abstract

Background: Multiple sclerosis (MS) is a chronic autoimmune disease that leads to significant disability, with its precise etiology still not fully understood. Recent studies indicate the crucial role of immune cells in MS pathogenesis. However, traditional research often focuses on major immune cell populations, potentially neglecting the roles of newly identified immune cell subsets with distinct receptors and functions. Moreover, conventional observational studies are prone to biases, hindering the establishment of definitive causal relationships. This study aims to investigate the causal relationships between 731 immune cell traits and MS susceptibility using Mendelian randomization (MR) analysis to provide more robust insights into the underlying mechanisms of MS.

Methods: We performed MR analyses to assess associations between various immune cell traits and MS risk. Following this, we explored the molecular mechanisms of the significant associations, focusing particularly on B-cell antigen presentation and the involvement of human leukocyte antigen (HLA) pathways.

Results: Our analysis revealed specific causal links between B cells and dendritic cells with MS susceptibility. We identified 61 pleiotropic genes associated with MS. Notably, B-cell antigen presentation and HLA-related pathways play pivotal roles in MS pathogenesis. Additionally, alterations in immune cell populations post-MS onset were observed, suggesting potential biomarkers for early diagnosis.

Conclusion: This study offers a comprehensive examination of immune cell contributions to MS pathogenesis, identifying potential therapeutic targets and diagnostic markers. Given the side effects of anti-B cell monoclonal antibodies in MS treatment, our findings propose avenues for more precise therapeutic strategies aimed at minimizing adverse effects.

Keywords: Mendelian randomization; causal link; genome‐wide association study; human leukocyte antigen; immune cells; multiple sclerosis.