Abstract 1166: Is Polyarticular JRA a Disease of Neutrophils? Evidence for an Intrinsic Defect in Neutrophil Activation in Polyarticular JRA

Among the immune effector cells involved in the maintenance of the immune response in polyarticular juvenile rheumatoid arthritis (JRA), the role of neutrophils has been little studied and incompletely characterized. Previous work from these authors has shown that a clustering of proteins important for neutrophil function (i.e. S100 proteins and calgranulins) are differentially expressed in polyarticular JRA patients and that the differential expression of these proteins appears to be independent of response to therapy. Here, Jarvis et al continue their efforts to explore the role of neutrophils in the pathogenesis of polyarticular JRA.

Methods: First, the plasma levels of the S100 protein A8/A9 were compared in 24 children with polyarticular JRA vs. 10 healthy control children. Second, computer modeling was used to graphically order functional relationships among genes identified as being differentially expressed in polyarticular JRA. Third, fundamental metabolite oscillations in neutrophils of 6 children with polyarticular JRA were examined using real-time, high-speed, single-cell photoimaging to explore characteristic IL-8 and IFN-gregulated oscillatory patterns of neutrophils induced by NADPH and superoxide ion.

Results: Plasma S100 A8/A9 levels were significantly higher in children with JRA compared to healthy controls, and remained significantly elevated compared to controls when only children with inactive disease were considered:

Computer modeling demonstrated clusters of genes regulated by IFN-gand IL-8 with disruptions of gene regulatory networks. When IL-8 and IFN-gregulated fundamental metabolite oscillatory patterns were examined in MPO+ neutrophils of polyarticular JRA patients, all six JRA patients demonstrated a characteristic defect in NADPH and superoxide oscillations. This effect was independent of active or inactive disease.

Conclusions: Neutrophil activation is elevated in children with polyarticular JRA, an effect that is independent of disease activity. This effect is associated with a unique defect in the cytokine regulation of NADPH and superoxide oscillations of neutrophils in polyarticular JRA.

Editorial Comment: These are novel findings incorporating a creative use of technology to study the role of neutrophils in polyarticular JRA. These findings are important for both elucidating the underlying mechanisms of this disorder and potentially in identifying therapeutic targets for intervention. It is interesting to note that a subset of children with polyarticular JRA will go on to have persistent disease that is largely indistinguishable from rheumatoid arthritis, a disorder that is felt to be less driven by neutrophil activation. How these related disorders may differ in underlying mechanism may be an interesting subject for further investigation.

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