Insufficient IL-10 Production as a Mechanism Underlying the Pathogenesis of Systemic Juvenile Idiopathic Arthritis

Abstract

Systemic juvenile idiopathic arthritis (sJIA) is a childhood-onset immune disorder of unknown cause. One of the concepts is that the disease results from an inappropriate control of immune responses to an initially harmless trigger. In the current study, we investigated whether sJIA may be caused by defects in IL-10, a key cytokine in controlling inflammation. We used a translational approach, with an sJIA-like mouse model and sJIA patient samples. The sJIA mouse model relies on injection of CFA in IFN-g-deficient BALB/c mice; corresponding wild type (WT) mice only develop a subtle and transient inflammatory reaction. Diseased IFN-g-deficient mice showed a defective IL-10 production in CD4 + regulatory T cells, CD19 + B cells, and CD3 2 CD122 + CD49b + NK cells, with B cells as the major source of IL-10. In addition, neutralization of IL-10 in WT mice resulted in a chronic immune inflammatory disorder clinically and hematologically reminiscent of sJIA. In sJIA patients, IL-10 plasma levels were strikingly low as compared with proinflammatory mediators. Furthermore, CD19 + B cells from sJIA patients showed a decreased IL-10 production, both ex vivo and after in vitro stimulation. In conclusion, IL-10 neutralization in CFA-challenged WT mice converts a transient inflammatory reaction into a chronic disease and represents an alternative model for sJIA in IFN-g-competent mice. Cell-specific IL-10 defects were observed in sJIA mice and patients, together with an insufficient IL-10 production to counterbalance their proinflammatory cytokines. Our data indicate that a defective IL-10 production contributes to the pathogenesis of sJIA.

Innately Adaptive or Truly Autoimmune: Is There Something Unique About Systemic Juvenile Idiopathic Arthritis?

“…In fact, 2 independent studies in systemic JIA cohorts showed increased prevalence of IL10 promoter haplotypes that encode for low IL-10 expression (83,84). Recently, cell-specific IL-10 defects were observed in patients with systemic JIA and in a murine disease model, resulting in insufficient IL-10 production to counterbalance proinflammatory cytokines (85).…”

Regulatory Role for NK Cells in a Mouse Model of Systemic Juvenile Idiopathic Arthritis

“…Arthritis was not observed in the experiments, most likely because the mice were sacrificed before onset of arthritis [joint inflammation is a late feature seen in CFA-challenged IFN-g KO mice (21)]. A parameter that may predict the potential development of arthritis is the formation of TRAP + -multinucleated osteoclasts ex vivo as described by Imbrechts et al (24). Splenocytes were stimulated with osteoclastdifferentiating factor RANKL and M-CSF, and after 7 d the osteoclasts were stained for TRAP.…”

“…For differentiation to osteoclasts, the cells were incubated with receptor activator of NF-kB ligand (RANKL; 100 ng/ml; R&D Systems) and M-CSF (20 ng/ml; R&D Systems). After 3 d, the cells were restimulated with fresh medium and stimuli for 3-4 d, followed by staining of the cells for tartrate-resistant acid phosphatase (TRAP) as described (23,24).…”

Molecular and Cellular Mechanisms of Arthritis in Children and Adults: New Perspectives on Applied Photobiomodulation

“…In a study published by Imbrechts et al, experimental evidence was provided on a mouse model that there would be a relationship between IL-10 insufficient production and its consequence in the innate cellular immune response from sJIA pathogenesis [58].…”