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

Ndate Fall, Michael Barnes, Sherry Thornton, Lorie Luyrink, Judyann Olson, Norman Todd Ilowite, Beth S. Gottlieb, Thomas Griffin, David D. Sherry, Susan Thompson, David N. Glass, Robert A. Colbert, Alexei A. Grom

Research output: Contribution to journalArticle

146 Citations (Scopus)

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. Conclusion. These data indicate that gene expression profiling can be a useful tool for identifying early macrophage activation syndrome in patients with systemic JIA.

Original languageEnglish (US)
Pages (from-to)3793-3804
Number of pages12
JournalArthritis and Rheumatism
Volume56
Issue number11
DOIs
StatePublished - Nov 2007

Fingerprint

Macrophage Activation Syndrome
Juvenile Arthritis
Gene Expression Profiling
Ferritins
Erythrocytes
Genes
Blood Cells
Toll-Like Receptor 1
Ficoll
Interleukin-1 Receptors
Multigene Family
Transcriptome
Granulocytes
Innate Immunity
Cluster Analysis
Cell Cycle
Flow Cytometry
Hemoglobins
Macrophages
RNA

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

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. / Fall, Ndate; Barnes, Michael; Thornton, Sherry; Luyrink, Lorie; Olson, Judyann; Ilowite, Norman Todd; Gottlieb, Beth S.; Griffin, Thomas; Sherry, David D.; Thompson, Susan; Glass, David N.; Colbert, Robert A.; Grom, Alexei A.

In: Arthritis and Rheumatism, Vol. 56, No. 11, 11.2007, p. 3793-3804.

Research output: Contribution to journalArticle

Fall, N, Barnes, M, Thornton, S, Luyrink, L, Olson, J, Ilowite, NT, Gottlieb, BS, Griffin, T, Sherry, DD, Thompson, S, Glass, DN, Colbert, RA & Grom, AA 2007, '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', Arthritis and Rheumatism, vol. 56, no. 11, pp. 3793-3804. https://doi.org/10.1002/art.22981
Fall, Ndate ; Barnes, Michael ; Thornton, Sherry ; Luyrink, Lorie ; Olson, Judyann ; Ilowite, Norman Todd ; Gottlieb, Beth S. ; Griffin, Thomas ; Sherry, David D. ; Thompson, Susan ; Glass, David N. ; Colbert, Robert A. ; Grom, Alexei A. / 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. In: Arthritis and Rheumatism. 2007 ; Vol. 56, No. 11. pp. 3793-3804.
@article{e372624a3cd543e58647635711323a83,
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. Conclusion. These data indicate that gene expression profiling can be a useful tool for identifying early macrophage activation syndrome in patients with systemic JIA.",
author = "Ndate Fall and Michael Barnes and Sherry Thornton and Lorie Luyrink and Judyann Olson and Ilowite, {Norman Todd} and Gottlieb, {Beth S.} and Thomas Griffin and Sherry, {David D.} and Susan Thompson and Glass, {David N.} and Colbert, {Robert A.} and Grom, {Alexei A.}",
year = "2007",
month = "11",
doi = "10.1002/art.22981",
language = "English (US)",
volume = "56",
pages = "3793--3804",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
publisher = "John Wiley and Sons Ltd",
number = "11",

}

TY - JOUR

T1 - 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

AU - Fall, Ndate

AU - Barnes, Michael

AU - Thornton, Sherry

AU - Luyrink, Lorie

AU - Olson, Judyann

AU - Ilowite, Norman Todd

AU - Gottlieb, Beth S.

AU - Griffin, Thomas

AU - Sherry, David D.

AU - Thompson, Susan

AU - Glass, David N.

AU - Colbert, Robert A.

AU - Grom, Alexei A.

PY - 2007/11

Y1 - 2007/11

N2 - 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. Conclusion. These data indicate that gene expression profiling can be a useful tool for identifying early macrophage activation syndrome in patients with systemic JIA.

AB - 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. Conclusion. These data indicate that gene expression profiling can be a useful tool for identifying early macrophage activation syndrome in patients with systemic JIA.

UR - http://www.scopus.com/inward/record.url?scp=36049020585&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36049020585&partnerID=8YFLogxK

U2 - 10.1002/art.22981

DO - 10.1002/art.22981

M3 - Article

VL - 56

SP - 3793

EP - 3804

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

IS - 11

ER -