Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type i and type ii interferon signatures

Laurent Chiche, Noémie Jourde-Chiche, Elizabeth Whalen, Scott Presnell, Vivian Gersuk, Kristen Dang, Esperanza Anguiano, Charlie Quinn, Stéphane Burtey, Yvon Berland, Gilles Kaplanski, Jean Robert Harle, Virginia Pascual, Damien J. Chaussabel

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

Objective The role of interferon-α (IFNα) in the pathogenesis of systemic lupus erythematosus (SLE) is strongly supported by gene expression studies. The aim of this study was to improve characterization of the blood IFN signature in adult SLE patients. Methods Consecutive patients were enrolled and followed up prospectively. Microarray data were generated using Illumina BeadChips. A modular transcriptional repertoire was used as a framework for the analysis. Results Our repertoire of 260 modules, which consisted of coclustered gene sets, included 3 IFN-annotated modules (M1.2, M3.4, and M5.12) that were strongly up-regulated in SLE patients. A modular IFN signature was observed in 54 of 62 patients (87%) or 131 of all 157 samples (83%). The IFN signature was more complex than expected, with each module displaying a distinct activation threshold (M1.2 < M3.4 < M5.12), thus providing a modular score by which to stratify SLE patients based on the presence of 0, 1, 2, or 3 active IFN modules. A similar gradient in modular IFN signature was observed within patients with clinically quiescent disease, for whom moderate/strong modular scores (2 or 3 active IFN modules) were associated with higher anti-double-stranded DNA titers and lower lymphocyte counts than those in patients with absent/mild modular scores (0 or 1 active IFN modules). Longitudinal analyses revealed both stable (M1.2) and variable (M3.4 and M5.12) components of modular IFN signature over time in single patients. Interestingly, mining of other data sets suggested that M3.4 and M5.12 could also be driven by IFNβ and IFNγ. Conclusion Modular repertoire analysis reveals complex IFN signatures in SLE, which are not restricted to the previous IFNα signature, but which also involve IFNβ and IFNγ.

Original languageEnglish
Pages (from-to)1583-1595
Number of pages13
JournalArthritis and Rheumatology
Volume66
Issue number6
DOIs
Publication statusPublished - 2014
Externally publishedYes

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Systemic Lupus Erythematosus
Interferons
Lymphocyte Count

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology

Cite this

Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type i and type ii interferon signatures. / Chiche, Laurent; Jourde-Chiche, Noémie; Whalen, Elizabeth; Presnell, Scott; Gersuk, Vivian; Dang, Kristen; Anguiano, Esperanza; Quinn, Charlie; Burtey, Stéphane; Berland, Yvon; Kaplanski, Gilles; Harle, Jean Robert; Pascual, Virginia; Chaussabel, Damien J.

In: Arthritis and Rheumatology, Vol. 66, No. 6, 2014, p. 1583-1595.

Research output: Contribution to journalArticle

Chiche, L, Jourde-Chiche, N, Whalen, E, Presnell, S, Gersuk, V, Dang, K, Anguiano, E, Quinn, C, Burtey, S, Berland, Y, Kaplanski, G, Harle, JR, Pascual, V & Chaussabel, DJ 2014, 'Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type i and type ii interferon signatures', Arthritis and Rheumatology, vol. 66, no. 6, pp. 1583-1595. https://doi.org/10.1002/art.38628
Chiche, Laurent ; Jourde-Chiche, Noémie ; Whalen, Elizabeth ; Presnell, Scott ; Gersuk, Vivian ; Dang, Kristen ; Anguiano, Esperanza ; Quinn, Charlie ; Burtey, Stéphane ; Berland, Yvon ; Kaplanski, Gilles ; Harle, Jean Robert ; Pascual, Virginia ; Chaussabel, Damien J. / Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type i and type ii interferon signatures. In: Arthritis and Rheumatology. 2014 ; Vol. 66, No. 6. pp. 1583-1595.
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abstract = "Objective The role of interferon-α (IFNα) in the pathogenesis of systemic lupus erythematosus (SLE) is strongly supported by gene expression studies. The aim of this study was to improve characterization of the blood IFN signature in adult SLE patients. Methods Consecutive patients were enrolled and followed up prospectively. Microarray data were generated using Illumina BeadChips. A modular transcriptional repertoire was used as a framework for the analysis. Results Our repertoire of 260 modules, which consisted of coclustered gene sets, included 3 IFN-annotated modules (M1.2, M3.4, and M5.12) that were strongly up-regulated in SLE patients. A modular IFN signature was observed in 54 of 62 patients (87{\%}) or 131 of all 157 samples (83{\%}). The IFN signature was more complex than expected, with each module displaying a distinct activation threshold (M1.2 < M3.4 < M5.12), thus providing a modular score by which to stratify SLE patients based on the presence of 0, 1, 2, or 3 active IFN modules. A similar gradient in modular IFN signature was observed within patients with clinically quiescent disease, for whom moderate/strong modular scores (2 or 3 active IFN modules) were associated with higher anti-double-stranded DNA titers and lower lymphocyte counts than those in patients with absent/mild modular scores (0 or 1 active IFN modules). Longitudinal analyses revealed both stable (M1.2) and variable (M3.4 and M5.12) components of modular IFN signature over time in single patients. Interestingly, mining of other data sets suggested that M3.4 and M5.12 could also be driven by IFNβ and IFNγ. Conclusion Modular repertoire analysis reveals complex IFN signatures in SLE, which are not restricted to the previous IFNα signature, but which also involve IFNβ and IFNγ.",
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T1 - Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type i and type ii interferon signatures

AU - Chiche, Laurent

AU - Jourde-Chiche, Noémie

AU - Whalen, Elizabeth

AU - Presnell, Scott

AU - Gersuk, Vivian

AU - Dang, Kristen

AU - Anguiano, Esperanza

AU - Quinn, Charlie

AU - Burtey, Stéphane

AU - Berland, Yvon

AU - Kaplanski, Gilles

AU - Harle, Jean Robert

AU - Pascual, Virginia

AU - Chaussabel, Damien J.

PY - 2014

Y1 - 2014

N2 - Objective The role of interferon-α (IFNα) in the pathogenesis of systemic lupus erythematosus (SLE) is strongly supported by gene expression studies. The aim of this study was to improve characterization of the blood IFN signature in adult SLE patients. Methods Consecutive patients were enrolled and followed up prospectively. Microarray data were generated using Illumina BeadChips. A modular transcriptional repertoire was used as a framework for the analysis. Results Our repertoire of 260 modules, which consisted of coclustered gene sets, included 3 IFN-annotated modules (M1.2, M3.4, and M5.12) that were strongly up-regulated in SLE patients. A modular IFN signature was observed in 54 of 62 patients (87%) or 131 of all 157 samples (83%). The IFN signature was more complex than expected, with each module displaying a distinct activation threshold (M1.2 < M3.4 < M5.12), thus providing a modular score by which to stratify SLE patients based on the presence of 0, 1, 2, or 3 active IFN modules. A similar gradient in modular IFN signature was observed within patients with clinically quiescent disease, for whom moderate/strong modular scores (2 or 3 active IFN modules) were associated with higher anti-double-stranded DNA titers and lower lymphocyte counts than those in patients with absent/mild modular scores (0 or 1 active IFN modules). Longitudinal analyses revealed both stable (M1.2) and variable (M3.4 and M5.12) components of modular IFN signature over time in single patients. Interestingly, mining of other data sets suggested that M3.4 and M5.12 could also be driven by IFNβ and IFNγ. Conclusion Modular repertoire analysis reveals complex IFN signatures in SLE, which are not restricted to the previous IFNα signature, but which also involve IFNβ and IFNγ.

AB - Objective The role of interferon-α (IFNα) in the pathogenesis of systemic lupus erythematosus (SLE) is strongly supported by gene expression studies. The aim of this study was to improve characterization of the blood IFN signature in adult SLE patients. Methods Consecutive patients were enrolled and followed up prospectively. Microarray data were generated using Illumina BeadChips. A modular transcriptional repertoire was used as a framework for the analysis. Results Our repertoire of 260 modules, which consisted of coclustered gene sets, included 3 IFN-annotated modules (M1.2, M3.4, and M5.12) that were strongly up-regulated in SLE patients. A modular IFN signature was observed in 54 of 62 patients (87%) or 131 of all 157 samples (83%). The IFN signature was more complex than expected, with each module displaying a distinct activation threshold (M1.2 < M3.4 < M5.12), thus providing a modular score by which to stratify SLE patients based on the presence of 0, 1, 2, or 3 active IFN modules. A similar gradient in modular IFN signature was observed within patients with clinically quiescent disease, for whom moderate/strong modular scores (2 or 3 active IFN modules) were associated with higher anti-double-stranded DNA titers and lower lymphocyte counts than those in patients with absent/mild modular scores (0 or 1 active IFN modules). Longitudinal analyses revealed both stable (M1.2) and variable (M3.4 and M5.12) components of modular IFN signature over time in single patients. Interestingly, mining of other data sets suggested that M3.4 and M5.12 could also be driven by IFNβ and IFNγ. Conclusion Modular repertoire analysis reveals complex IFN signatures in SLE, which are not restricted to the previous IFNα signature, but which also involve IFNβ and IFNγ.

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