The myeloid-related proteins 8 and 14 complex, a novel ligand of toll-like receptor 4, and interleukin-1beta form a positive feedback mechanism in systemic-onset juvenile idiopathic arthritis.
OBJECTIVE
Fever of unknown origin is a diagnostic challenge in children, especially for differentiation of systemic-onset juvenile idiopathic arthritis (systemic-onset JIA) and infectious diseases. We undertook this study to analyze the relevance of myeloid-related proteins (MRPs) 8 and 14, endogenous activators of Toll-like receptor 4, in diagnosis and pathogenesis of systemic-onset JIA.


METHODS
Serum concentrations of MRP-8/MRP-14 were analyzed in 60 patients with systemic-onset JIA, 85 patients with systemic infections, 40 patients with acute lymphoblastic leukemia, 5 patients with acute myeloblastic leukemia, 18 patients with neonatal-onset multisystem inflammatory disease (NOMID), and 50 healthy controls. In addition, we investigated the link between interleukin-1beta (IL-1beta) and MRP-8/MRP-14 in systemic-onset JIA.


RESULTS
Serum MRP-8/MRP-14 concentrations were significantly (P < 0.001) elevated in patients with active systemic-onset JIA (mean +/- 95% confidence interval 14,920 +/- 4,030 ng/ml) compared with those in healthy controls (340 +/- 70 ng/ml), patients with systemic infections (2,640 +/- 720 ng/ml), patients with acute lymphoblastic leukemia (650 +/- 280 ng/ml), patients with acute myeloblastic leukemia (840 +/- 940 ng/ml), and patients with NOMID (2,830 +/- 580 ng/ml). In contrast to C-reactive protein levels, MRP-8/MRP-14 concentrations distinguished systemic-onset JIA from infections, with a specificity of 95%. MRP-14 in serum of patients with systemic-onset JIA was a strong inducer of IL-1beta expression in phagocytes.


CONCLUSIONS
The analysis of MRP-8/MRP-14 in serum is an excellent tool for the diagnosis of systemic-onset JIA, allowing early differentiation between patients with systemic-onset JIA and those with other inflammatory diseases. MRP-8/MRP-14 and IL-1beta represent a novel positive feedback mechanism activating phagocytes via 2 major signaling pathways of innate immunity during the pathogenesis of systemic-onset JIA.
Frosch
Michael
M
University of Muenster, Muenster, Germany.
Ahlmann
Martina
M
Vogl
Thomas
T
Wittkowski
Helmut
H
Wulffraat
Nico
N
Foell
Dirk
D
Roth
Johannes
J
D000293:Adolescent; D000328:Adult; D001171:Arthritis, Juvenile / Q000097:blood* / Q000175:diagnosis*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D040501:Calgranulin A / Q000097:blood*; D040502:Calgranulin B / Q000097:blood*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003141:Communicable Diseases / Q000097:blood / Q000175:diagnosis; D003937:Diagnosis, Differential; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D006801:Humans; D007223:Infant; D053583:Interleukin-1beta / Q000378:metabolism*; D007938:Leukemia / Q000097:blood / Q000175:diagnosis; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D055815:Young Adult
D015415:Biomarkers; D040501:Calgranulin A; D040502:Calgranulin B; D053583:Interleukin-1beta; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D002097:C-Reactive Protein