Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritis.
OBJECTIVE
To identify differences in peripheral blood gene expression between patients with different subclasses of juvenile idiopathic arthritis (JIA) and healthy controls in a multicenter study of patients with recent-onset JIA prior to treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents.


METHODS
Peripheral blood mononuclear cells (PBMCs) from 59 healthy children and 136 patients with JIA (28 with enthesitis-related arthritis [ERA], 42 with persistent oligoarthritis, 45 with rheumatoid factor [RF]-negative polyarthritis, and 21 with systemic disease) were isolated from whole blood. Poly(A) RNA was labeled using a commercial RNA amplification and labeling system (NuGEN Ovation), and gene expression profiles were obtained using commercial expression microarrays (Affymetrix HG-U133 Plus 2.0).


RESULTS
A total of 9,501 differentially expressed probe sets were identified among the JIA subtypes and controls (by analysis of variance; false discovery rate 5%). Specifically, 193, 1,036, 873, and 7,595 probe sets were different in PBMCs from the controls compared with those from the ERA, persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA patients, respectively. In patients with persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA subtypes, up-regulation of genes associated with interleukin-10 (IL-10) signaling was prominent. A hemoglobin cluster was identified that was underexpressed in ERA patients but overexpressed in systemic JIA patients. The influence of JAK/STAT, ERK/MAPK, IL-2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic JIA, up-regulation of innate immune pathways, including IL-6, Toll-like receptor/IL-1 receptor, and peroxisome proliferator-activated receptor signaling, were noted, along with down-regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were up-regulated in systemic JIA, with a subset of these genes being differentially expressed in other subtypes as well.


CONCLUSIONS
Expression analysis identified differentially expressed genes in PBMCs obtained early in the disease from patients with different subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences between these forms of childhood arthritis.
Barnes
Michael G
MG
Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. michael.barnes@cchmc.org
Grom
Alexei A
AA
Thompson
Susan D
SD
Griffin
Thomas A
TA
Pavlidis
Paul
P
Itert
Lukasz
L
Fall
Ndate
N
Sowders
Dawn Paxson
DP
Hinze
Claas H
CH
Aronow
Bruce J
BJ
Luyrink
Lorie K
LK
Srivastava
Shweta
S
Ilowite
Norman T
NT
Gottlieb
Beth S
BS
Olson
Judyann C
JC
Sherry
David D
DD
Glass
David N
DN
Colbert
Robert A
RA
D000293:Adolescent; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001168:Arthritis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D001171:Arthritis, Juvenile / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007223:Infant; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
D018501:Antirheumatic Agents; D015850:Interleukin-6; D047492:Peroxisome Proliferator-Activated Receptors; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors