The causal role of immune cells in primary Sjögren's syndrome: A two‐sample Mendelian randomization

BACKGROUND: Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by the destruction of exocrine glands primarily via T-cell-mediated B-cell over-activation and cytokine production. This leads to pronounced dryness of the mouth and eyes and can result in multi-systemic involvement affecting the kidneys, lungs, and blood. In recent years, there has been increasing attention on the role of immune cells in pSS. However, studies investigating the causal role of immune cells in pSS have been relatively limited. METHODS: In this study, we employed a two-way two-sample Mendelian randomization approach to assess the causal relationship between immune cells and pSS. Utilizing publicly available genome-wide association study (GWAS) data, we explored the causal links between 731 immunophenotypically labeled immune cells and the risk of pSS. RESULTS: Through the use of instrumental variables derived from GWAS data and corrected for false discovery rate (FDR), we identified three immune cells with increased levels that were causally associated with pSS risk (FDR < 0.05). These included IgD+ CD38br AC B cells, CD27 on IgD+ CD38- unswitched memory B cells, and Granulocyte % leukocyte. Additionally, three immune cells with reduced levels were found to be causally associated with pSS risk, namely CD4+ CD8dim %lymphocyte, CD4+ CD8dim %leukocyte, and CD28 on activated and secreting regulatory T cells (Tregs). Furthermore, the development of pSS was associated with elevated levels of CD33br HLA DR+ CD14- % CD33br HLA DR+ in myeloid cells. CONCLUSION: This study demonstrates that immune responses influence the progression of pSS in a complex pattern. Our findings may provide new insights into the immunology of pSS pathogenesis and more experimental studies should be conducted to further explore the potential mechanisms between identified immune features and pSS risk, which may provide a basis for exploring early intervention methods for pSS and developing targeted therapeutic strategies or even reshaping immune homeostasis.