Abstract
INTRODUCTION: Psoriatic arthritis (PsA) involves intricate immune-mediated pathways that extend beyond the well-characterized IL-23/IL-17 axis. Given that many patients show inadequate responses to current therapies, identifying novel immune drivers is essential. To clarify how specific immune cell populations influence PsA susceptibility, we performed a bidirectional two-sample Mendelian randomization (MR) study. METHODS: We used genetic instruments for immune traits from a GWAS of 3,757 European individuals and PsA summary data from the IEU database (5,065 cases and 21,286 controls). Applying inverse variance weighting as our principal method. RESULTS: At a nominal significance level (P < 0.05), we detected 14 immune phenotypes linked to heightened risk and 12 associated with reduced risk. Among the risk-associated phenotypes, activated B cells-particularly those expressing CD25 and BAFF-R on IgD(+)CD24(+) subsets-emerged as prominent markers, a finding that shifts focus toward humoral involvement alongside the conventional emphasis on T cells alone. We also identified pathogenic contributions from specific T cell subsets, notably CCR7(+)naïve CD4(+)T cells and CD127(+)CD45RA(+)CD4(+)T cells. Conversely, certain natural killer T cell phenotypes appeared protective, hinting at a regulatory role for these populations. Reverse MR indicated that PsA liability itself may drive changes in 23 immune phenotypes, including depletion of circulating plasmacytoid dendritic cells and alterations in myeloid compartments-patterns likely reflecting cellular migration into inflamed synovial tissue. Importantly, none of these associations survived false discovery rate correction, indicating that these findings are exploratory. CONCLUSION: Our findings map the genetic underpinnings of immune dysregulation in PsA and provide a hypothesis-generating resource for therapeutic strategies targeting B cell stimulation. The preliminary nature and uncertainty of these associations necessitates further investigation and validation in independent, larger cohorts alongside current cytokine-directed approaches.