Research article

Evidence for chronic, peripheral activation of neutrophils in polyarticular juvenile rheumatoid arthritis

James N Jarvis¹ , Howard R Petty² , Yuhong Tang³ , Mark Barton Frank³ , Philippe A Tessier⁴ , Igor Dozmorov³ , Kaiyu Jiang¹ , Andrei Kindzelski² , Yanmin Chen¹ , Craig Cadwell³ , Mary Turner³ , Peter Szodoray³ , Julie L McGhee⁵ and Michael Centola³

¹Department of Pediatrics, University of Oklahoma College of Medicine, 940 Stanton L. Young Blvd., Oklahoma City, OK 73104, USA

²Kellogg Eye Center, University of Michigan School of Medicine, 1000 Wall St., Ann Arbor, MI 48105, USA

³Arthritis & Immunology Program, Oklahoma Medical Research Foundation, 820 NE 13^th St., Oklahoma City, OK 73104, USA

⁴Centre de Recherche en Infectiologie, Centre de Recherche du CHUL, 2705 boul. Laurier, Ste-Foy, Québec, G1V 4G2, Canada

⁵University of Oklahoma College of Medicine, 940 Stanton L. Young Blvd., Oklahoma City, OK 73104, USA

author email corresponding author email

Arthritis Research & Therapy 2006, 8:R154doi:10.1186/ar2048

Published:	26 September 2006

Abstract

Although strong epidemiologic evidence suggests an important role for adaptive immunity in the pathogenesis of polyarticular juvenile rheumatoid arthritis (JRA), there remain many aspects of the disease that suggest equally important contributions of the innate immune system. We used gene expression arrays and computer modeling to examine the function in neutrophils of 25 children with polyarticular JRA. Computer analysis identified 712 genes that were differentially expressed between patients and healthy controls. Computer-assisted analysis of the differentially expressed genes demonstrated functional connections linked to both interleukin (IL)-8- and interferon-γ (IFN-γ)-regulated processes. Of special note is that the gene expression fingerprint of children with active JRA remained essentially unchanged even after they had responded to therapy. This result differed markedly from our previously reported work, in which gene expression profiles in buffy coats of children with polyarticular JRA reverted to normal after disease control was achieved pharmacologically. These findings suggest that JRA neutrophils remain in an activated state even during disease quiescence. Computer modeling of array data further demonstrated disruption of gene regulatory networks in clusters of genes modulated by IFN-γ and IL-8. These cytokines have previously been shown to independently regulate the frequency (IFN-γ) and amplitude (IL-8) of the oscillations of key metabolites in neutrophils, including nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and superoxide ion. Using real-time, high-speed, single-cell photoimaging, we observed that 6/6 JRA patients displayed a characteristic defect in 12% to 23% of the neutrophils tested. Reagents known to induce only frequency fluctuations of NAD(P)H and superoxide ion induced both frequency and amplitude fluctuations in JRA neutrophils. This is a novel finding that was observed in children with both active (n = 4) and inactive (n = 2) JRA. A subpopulation of polyarticular JRA neutrophils are in a chronic, activated state, a state that persists when the disease is well controlled pharmacologically. Furthermore, polyarticular JRA neutrophils exhibit an intrinsic defect in the regulation of metabolic oscillations and superoxide ion production. Our data are consistent with the hypothesis that neutrophils play an essential role in the pathogenesis of polyarticular JRA.