title: Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome.
abstract: OBJECTIVE
  Systemic juvenile idiopathic arthritis (JIA) is frequently associated with the development of macrophage activation syndrome. This study was undertaken to better understand the relationship between systemic JIA and macrophage activation syndrome.
  
  
  METHODS
  Gene expression profiles were examined in 17 patients with untreated new-onset systemic JIA, 5 of whom showed evidence of subclinical macrophage activation syndrome (of whom 2 eventually developed overt macrophage activation syndrome). Peripheral blood mononuclear cells (PBMCs) were separated on Ficoll gradients, and purified RNA was analyzed using Affymetrix GeneChip expression arrays. A fraction of the PBMCs were used for flow cytometry to define the cellular composition of the samples.
  
  
  RESULTS
  Two hundred twenty-five differentially expressed genes (P < 0.05) that distinguished patients with systemic JIA from healthy controls (n = 30) were identified. Clustering analysis indicated that expression patterns correlated with serum ferritin levels. Three main clusters distinguished systemic JIA patients with highly elevated ferritin levels (including those with subclinical macrophage activation syndrome) from those with normal or only moderately elevated ferritin levels. The first cluster comprised genes involved in the synthesis of hemoglobins and structural proteins of erythrocytes. This transcriptional profile was consistent with immature nucleated red blood cells, likely reflective of high red blood cell turnover. Also included were transcripts indicating immature granulocytes. The second cluster was enriched for genes involved in cell cycle regulation. The third cluster was enriched for genes involved in innate immune responses, including those involved in the negative regulation of Toll-like receptor/interleukin-1 receptor-triggered inflammatory cascades and markers of the alternative pathway of macrophage differentiation. Additional differentially expressed genes of interest were those involved in the cytolytic pathway, including SH2D1A and Rab27a.
  
  
  CONCLUSIONS
  These data indicate that gene expression profiling can be a useful tool for identifying early macrophage activation syndrome in patients with systemic JIA.
authors.affiliation: Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Ndate
authors.initials: N
authors.lastname: Fall
authors.forename: Michael
authors.initials: M
authors.lastname: Barnes
authors.forename: Sherry
authors.initials: S
authors.lastname: Thornton
authors.forename: Lorie
authors.initials: L
authors.lastname: Luyrink
authors.forename: Judyann
authors.initials: J
authors.lastname: Olson
authors.forename: Norman T
authors.initials: NT
authors.lastname: Ilowite
authors.forename: Beth S
authors.initials: BS
authors.lastname: Gottlieb
authors.forename: Thomas
authors.initials: T
authors.lastname: Griffin
authors.forename: David D
authors.initials: DD
authors.lastname: Sherry
authors.forename: Susan
authors.initials: S
authors.lastname: Thompson
authors.forename: David N
authors.initials: DN
authors.lastname: Glass
authors.forename: Robert A
authors.initials: RA
authors.lastname: Colbert
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Grom
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000235:genetics* / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D004920:Erythropoiesis / Q000235:genetics; D005260:Female; D005293:Ferritins / Q000097:blood; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D006242:Haptoglobins / Q000235:genetics; D006801:Humans; D016130:Immunophenotyping; D008264:Macrophages / Q000502:physiology*; D008297:Male; D010641:Phenotype; D011237:Predictive Value of Tests
chemical_list: D006242:Haptoglobins; D005293:Ferritins