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Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade.

Allantaz F, Chaussabel D, Stichweh D, Bennett L, Allman W, Mejias A, Ardura M, Chung W, Smith E, Wise C, Palucka K, Ramilo O, Punaro M, Banchereau J, Pascual V - J. Exp. Med. (2007)

Bottom Line: Statistical group comparison and class prediction identified genes differentially expressed in SoJIA patients compared with healthy children.Transcripts that changed significantly in patients undergoing IL-1 blockade were also identified.Availability of early diagnostic markers may allow prompt initiation of therapy and prevention of disabilities.

View Article: PubMed Central - PubMed

Affiliation: Baylor National Institute of Allergy and Infectious Diseases Cooperative Center for Translational Research on Human Immunology and Biodefense, Dallas, TX 75204, USA.

ABSTRACT
Systemic onset juvenile idiopathic arthritis (SoJIA) represents up to 20% of juvenile idiopathic arthritis. We recently reported that interleukin (IL) 1 is an important mediator of this disease and that IL-1 blockade induces clinical remission. However, lack of specificity of the initial systemic manifestations leads to delays in diagnosis and initiation of therapy. To develop a specific diagnostic test, we analyzed leukocyte gene expression profiles of 44 pediatric SoJIA patients, 94 pediatric patients with acute viral and bacterial infections, 38 pediatric patients with systemic lupus erythematosus (SLE), 6 patients with PAPA syndrome, and 39 healthy children. Statistical group comparison and class prediction identified genes differentially expressed in SoJIA patients compared with healthy children. These genes, however, were also changed in patients with acute infections and SLE. An analysis of significance across all diagnostic groups identified 88 SoJIA-specific genes, 12 of which accurately classified an independent set of SoJIA patients with systemic disease. Transcripts that changed significantly in patients undergoing IL-1 blockade were also identified. Thus, leukocyte transcriptional signatures can be used to distinguish SoJIA from other febrile illnesses and to assess response to therapy. Availability of early diagnostic markers may allow prompt initiation of therapy and prevention of disabilities.

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Related in: MedlinePlus

Anakinra effect on the specific SoJIA signature. Transcription levels (raw values) corresponding to the genes that best differentiate SoJIA patients from healthy controls (from Fig. 1 and Table S2) were analyzed before and after the initiation of Anakinra in eight patients. The 10 genes with most significant p-values are displayed (p-values were calculated using a paired, two-tailed t test).
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fig5: Anakinra effect on the specific SoJIA signature. Transcription levels (raw values) corresponding to the genes that best differentiate SoJIA patients from healthy controls (from Fig. 1 and Table S2) were analyzed before and after the initiation of Anakinra in eight patients. The 10 genes with most significant p-values are displayed (p-values were calculated using a paired, two-tailed t test).

Mentions: The effect of IL-1 blockade on the SoJIA-specific signature was analyzed by comparing the expression of the 873 transcripts that differentiate SoJIA patients from healthy controls (Fig. 1 and Table S2) in eight active SoJIA patients before and after initiation of IL-1 blockade. Anakinra was found to induce a significant change (P < 0.05) in the expression levels of 389 transcripts. The 10 most significant are displayed in Fig. 5. They include genes encoding proteins with antiapoptotic function (Pim-1) (31), lysosomal ATP-ase activity (ATP6V0A1), Cdc42-binding proteins linked to F-actin accumulation at the immunological synapse (Cdc42SE2) (32), glutamate receptor (GRINA), MAP2 kinase 3 (MAP2K3), prohibitin (PHB), and the solute carrier protein family (SLC25A37). Of them, only MAP2K3 has a known potential link to IL-1, as this molecule has been shown to down-modulate IL-1 responses on fibroblast-like synoviocytes and to regulate p38 activation in experimental inflammatory arthritis (33, 34).


Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade.

Allantaz F, Chaussabel D, Stichweh D, Bennett L, Allman W, Mejias A, Ardura M, Chung W, Smith E, Wise C, Palucka K, Ramilo O, Punaro M, Banchereau J, Pascual V - J. Exp. Med. (2007)

Anakinra effect on the specific SoJIA signature. Transcription levels (raw values) corresponding to the genes that best differentiate SoJIA patients from healthy controls (from Fig. 1 and Table S2) were analyzed before and after the initiation of Anakinra in eight patients. The 10 genes with most significant p-values are displayed (p-values were calculated using a paired, two-tailed t test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2118700&req=5

fig5: Anakinra effect on the specific SoJIA signature. Transcription levels (raw values) corresponding to the genes that best differentiate SoJIA patients from healthy controls (from Fig. 1 and Table S2) were analyzed before and after the initiation of Anakinra in eight patients. The 10 genes with most significant p-values are displayed (p-values were calculated using a paired, two-tailed t test).
Mentions: The effect of IL-1 blockade on the SoJIA-specific signature was analyzed by comparing the expression of the 873 transcripts that differentiate SoJIA patients from healthy controls (Fig. 1 and Table S2) in eight active SoJIA patients before and after initiation of IL-1 blockade. Anakinra was found to induce a significant change (P < 0.05) in the expression levels of 389 transcripts. The 10 most significant are displayed in Fig. 5. They include genes encoding proteins with antiapoptotic function (Pim-1) (31), lysosomal ATP-ase activity (ATP6V0A1), Cdc42-binding proteins linked to F-actin accumulation at the immunological synapse (Cdc42SE2) (32), glutamate receptor (GRINA), MAP2 kinase 3 (MAP2K3), prohibitin (PHB), and the solute carrier protein family (SLC25A37). Of them, only MAP2K3 has a known potential link to IL-1, as this molecule has been shown to down-modulate IL-1 responses on fibroblast-like synoviocytes and to regulate p38 activation in experimental inflammatory arthritis (33, 34).

Bottom Line: Statistical group comparison and class prediction identified genes differentially expressed in SoJIA patients compared with healthy children.Transcripts that changed significantly in patients undergoing IL-1 blockade were also identified.Availability of early diagnostic markers may allow prompt initiation of therapy and prevention of disabilities.

View Article: PubMed Central - PubMed

Affiliation: Baylor National Institute of Allergy and Infectious Diseases Cooperative Center for Translational Research on Human Immunology and Biodefense, Dallas, TX 75204, USA.

ABSTRACT
Systemic onset juvenile idiopathic arthritis (SoJIA) represents up to 20% of juvenile idiopathic arthritis. We recently reported that interleukin (IL) 1 is an important mediator of this disease and that IL-1 blockade induces clinical remission. However, lack of specificity of the initial systemic manifestations leads to delays in diagnosis and initiation of therapy. To develop a specific diagnostic test, we analyzed leukocyte gene expression profiles of 44 pediatric SoJIA patients, 94 pediatric patients with acute viral and bacterial infections, 38 pediatric patients with systemic lupus erythematosus (SLE), 6 patients with PAPA syndrome, and 39 healthy children. Statistical group comparison and class prediction identified genes differentially expressed in SoJIA patients compared with healthy children. These genes, however, were also changed in patients with acute infections and SLE. An analysis of significance across all diagnostic groups identified 88 SoJIA-specific genes, 12 of which accurately classified an independent set of SoJIA patients with systemic disease. Transcripts that changed significantly in patients undergoing IL-1 blockade were also identified. Thus, leukocyte transcriptional signatures can be used to distinguish SoJIA from other febrile illnesses and to assess response to therapy. Availability of early diagnostic markers may allow prompt initiation of therapy and prevention of disabilities.

Show MeSH
Related in: MedlinePlus