Inflammatory biomarkers predicting long-term remission and active disease in juvenile idiopathic arthritis: a population-based study of the Nordic JIA cohort.

OBJECTIVES: To assess the ability of baseline serum biomarkers to predict disease activity and remission status in juvenile idiopathic arthritis (JIA) at 18-year follow-up (FU) in a population-based setting. METHODS: Clinical data and serum levels of inflammatory biomarkers were assessed in the longitudinal population-based Nordic JIA cohort study at baseline and at 18-year FU. A panel of 16 inflammatory biomarkers was determined by multiplexed bead array assay. We estimated both univariate and multivariate logistic regression models on binary outcomes of disease activity and remission with baseline variables as explanatory variables. RESULTS: Out of 349 patients eligible for the Nordic JIA cohort study, 236 (68%) had available serum samples at baseline. We measured significantly higher serum levels of interleukin 1ß (IL-1ß), IL-6, IL-12p70, IL-13, MMP-3, S100A9 and S100A12 at baseline in patients with active disease at 18-year FU than in patients with inactive disease. Computing receiver operating characteristics illustrating the area under the curve (AUC), we compared a conventional prediction model (gender, age, joint counts, erythrocyte sedimentation rate, C reactive protein) with an extended model that also incorporated the 16 baseline biomarkers. Biomarker addition significantly improved the ability of the model to predict activity/inactivity at the 18-year FU, as evidenced by an increase in the AUC from 0.59 to 0.80 (p=0.02). Multiple regression analysis revealed that S100A9 was the strongest predictor of inactive disease 18 years after disease onset. CONCLUSION: Biomarkers indicating inflammation at baseline have the potential to improve evaluation of disease activity and prediction of long-term outcomes.

Aberrant Naive CD4-Positive T Cell Differentiation in Systemic Juvenile Idiopathic Arthritis Committed to B Cell Help.

OBJECTIVE: Systemic juvenile idiopathic arthritis (JIA) features characteristics of autoinflammation and autoimmunity, culminating in chronic arthritis. In this study, we hypothesized that aberrant or incomplete polarization of T helper cells contributes to disease pathology. METHODS: Cells or serum samples were obtained from healthy controls (n = 72) and systemic JIA patients (n = 171). Isolated naive T helper cells were cultured under Th1, Th17, and T follicular helper (Tfh) or T peripheral helper (Tph)-polarizing conditions and were partly cocultured with allogenic memory B cells. Cell samples were then analyzed for surface marker, transcription factor, and cytokine expression, as well as plasmablast generation. Serum samples were subjected to multiplexed bead and self-antigen arrays and enzyme-linked immunosorbent assays, and all data were compared to retrospective RNA profiling analyses. RESULTS: Differentiation of systemic JIA-naive T helper cells toward Th1 cells resulted in low expression levels of interferon-γ (IFNγ) and eomesodermin, which was associated in part with disease duration. In contrast, developing Th1 cells in patients with systemic JIA were found to produce elevated levels of interleukin-21 (IL-21), which negatively correlated with cellular expression of IFNγ and eomesodermin. In both in vitro and ex vivo analyses, IL-21 together with programmed cell death 1 (PD-1), inducible T cell costimulator (ICOS), and CXCR5 expression induced naive T helper cells from systemic JIA patients to polarize toward a Tfh/Tph cell phenotype. Retrospective analysis of whole-blood RNA-sequencing data demonstrated that Bcl-6, a master transcription factor in Tfh/Tph cell differentiation, was overexpressed specifically in patients with systemic JIA. Naive T helper cells from systemic JIA patients which were stimulated in vitro promoted B cellular plasmablast generation, and self-antigen array data indicated that IgG reactivity profiles of patients with systemic JIA differed from those of healthy controls. CONCLUSION: In the pathogenesis of systemic JIA, skewing of naive T helper cell differentiation toward a Tfh/Tph cell phenotype may represent an echo of autoimmunity, which may indicate the mechanisms driving progression toward chronic destructive arthritis.

Expression of toll-like receptors in neonatal sepsis.

Despite recent identification of specific pattern recognition receptors (PRR) for distinct microbial structures, data indicating their relevance in human infectious diseases are limited. We determined the expression levels of the Toll-like receptor (TLR)2 and TLR4 by flow cytometry on granulocytes and monocytes of healthy neonates compared with healthy adults. The basal expression of TLR2 was only slightly lower in neonatal phagocytes, whereas no differences could be detected for TLR4. Analyzing neonates with sepsis, we found an impressive up-regulation of TLR2 on blood phagocytes already at initial presentation of symptoms. Comparison with C-reactive protein, IL-8, and IL-6 suggested that TLR2 expression on monocytes is comparably valuable as an early sepsis marker. TLR2 was differentially regulated during neonatal sepsis, showing a constant up-regulation on monocytes but only a transient increase on granulocytes. Surprisingly, TLR4 showed no remarkable changes. Our results revealed a mild deficiency of TLR2 expression in newborns and demonstrated a differential expression of TLR2 but not TLR4 in the course of neonatal sepsis, which could reflect specific inflammatory responses to distinct pathogens. The definition of TLR expression patterns might open a new field of therapeutic targets for neonatal sepsis.