Causal effect of type 1 diabetes on juvenile idiopathic arthritis and the mediating role of CD8+ natural killer T cells.

Abstract

Emerging observational evidence has suggested a comorbidity between type 1 diabetes (T1D) and juvenile idiopathic arthritis (JIA). The study aimed to evaluate the causal effect of T1D on JIA, explore the mediating role of circulating immune cells and verify the causal relationship in mouse models. We first assessed the genetic correlation using linkage disequilibrium score regression. We then evaluated the causal relationship through Mendelian randomization and subsequently conducted in vivo investigations using non-obese diabetic (NOD) mice, streptozotocin (STZ)-induced diabetic mice and mannan-induced arthritic mice. Our analysis confirmed a strong, positive genetic correlation between these two diseases, and identified a robust positive causal effect of T1D on JIA. Next, the Mediation analysis indicated that CD8+ natural killer T (NKT) absolute count had a significant mediating effect and accounted for 32.5% of the increased risk of JIA attributable to T1D. Furthermore, in vivo experiments revealed that young NOD mice spontaneously developed mild osteoarthritis and progressive synovitis, along with systemic inflammation. In contrast, no signs of osteoarthritis or synovitis were detected in young STZ-induced diabetic mice. Additionally, the CD8+ NKT cell count was negatively associated with the development of mannan-induced arthritis in SKG mice. The study confirmed a significant causal effect of T1D on JIA from a genetic perspective, revealed CD8+ NKT cells as a pivotal mediating factor in this causal pathway, and verified a predisposition to inflammatory arthritis in young NOD mice.