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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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Transcription of CLIC-2 in blood cell subsets. (A) Total RNA was extracted from the PBMCs of 16 healthy donors and 16 SoJIA patients; B cells, T cells, and monocytes from 3 healthy donors and 4 SoJIA patients, and neutrophils from 6 healthy donors and 7 SoJIA patients. Amplified cRNA was hybridized on Affymetrix HG-U133 chips. Raw intensity values from each chip were first pre-scaled to the 500 target intensity value in Affymetrix Microarray suite before being imported and analyzed in GeneSpring 6.1. (B) Total RNA was extracted from the PBMCs of 16 healthy donors and 16 SoJIA patients, mDCs from 9 healthy donors, and pDCs from 6 healthy donors. Amplified cRNA was hybridized to Affymetrix HG-U133 chips. Raw intensity values from each chip were pre-scaled to the 500 target intensity value in Affymetrix Microarray suite before being imported and analyzed in GeneSpring 6.1.
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fig4: Transcription of CLIC-2 in blood cell subsets. (A) Total RNA was extracted from the PBMCs of 16 healthy donors and 16 SoJIA patients; B cells, T cells, and monocytes from 3 healthy donors and 4 SoJIA patients, and neutrophils from 6 healthy donors and 7 SoJIA patients. Amplified cRNA was hybridized on Affymetrix HG-U133 chips. Raw intensity values from each chip were first pre-scaled to the 500 target intensity value in Affymetrix Microarray suite before being imported and analyzed in GeneSpring 6.1. (B) Total RNA was extracted from the PBMCs of 16 healthy donors and 16 SoJIA patients, mDCs from 9 healthy donors, and pDCs from 6 healthy donors. Amplified cRNA was hybridized to Affymetrix HG-U133 chips. Raw intensity values from each chip were pre-scaled to the 500 target intensity value in Affymetrix Microarray suite before being imported and analyzed in GeneSpring 6.1.

Mentions: To determine if a specific cell type is preferentially contributing to the overrepresentation of these transcripts, their expression was analyzed in B cells, T cells, monocytes, and neutrophils from healthy donors and SoJIA patients, as well as myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) from healthy donors. Interestingly, 5/12 transcripts showed the highest expression levels in mDCs (not depicted). Within the cells that we analyzed, expression of CLIC-2 is restricted to this cell type (Fig. 4, A and B). However, whether the 12 transcript signature derives from a cell type not normally present in the blood (i.e., a bone marrow precursor) needs to be ruled out.


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)

Transcription of CLIC-2 in blood cell subsets. (A) Total RNA was extracted from the PBMCs of 16 healthy donors and 16 SoJIA patients; B cells, T cells, and monocytes from 3 healthy donors and 4 SoJIA patients, and neutrophils from 6 healthy donors and 7 SoJIA patients. Amplified cRNA was hybridized on Affymetrix HG-U133 chips. Raw intensity values from each chip were first pre-scaled to the 500 target intensity value in Affymetrix Microarray suite before being imported and analyzed in GeneSpring 6.1. (B) Total RNA was extracted from the PBMCs of 16 healthy donors and 16 SoJIA patients, mDCs from 9 healthy donors, and pDCs from 6 healthy donors. Amplified cRNA was hybridized to Affymetrix HG-U133 chips. Raw intensity values from each chip were pre-scaled to the 500 target intensity value in Affymetrix Microarray suite before being imported and analyzed in GeneSpring 6.1.
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Related In: Results  -  Collection

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fig4: Transcription of CLIC-2 in blood cell subsets. (A) Total RNA was extracted from the PBMCs of 16 healthy donors and 16 SoJIA patients; B cells, T cells, and monocytes from 3 healthy donors and 4 SoJIA patients, and neutrophils from 6 healthy donors and 7 SoJIA patients. Amplified cRNA was hybridized on Affymetrix HG-U133 chips. Raw intensity values from each chip were first pre-scaled to the 500 target intensity value in Affymetrix Microarray suite before being imported and analyzed in GeneSpring 6.1. (B) Total RNA was extracted from the PBMCs of 16 healthy donors and 16 SoJIA patients, mDCs from 9 healthy donors, and pDCs from 6 healthy donors. Amplified cRNA was hybridized to Affymetrix HG-U133 chips. Raw intensity values from each chip were pre-scaled to the 500 target intensity value in Affymetrix Microarray suite before being imported and analyzed in GeneSpring 6.1.
Mentions: To determine if a specific cell type is preferentially contributing to the overrepresentation of these transcripts, their expression was analyzed in B cells, T cells, monocytes, and neutrophils from healthy donors and SoJIA patients, as well as myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) from healthy donors. Interestingly, 5/12 transcripts showed the highest expression levels in mDCs (not depicted). Within the cells that we analyzed, expression of CLIC-2 is restricted to this cell type (Fig. 4, A and B). However, whether the 12 transcript signature derives from a cell type not normally present in the blood (i.e., a bone marrow precursor) needs to be ruled out.

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