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OP0099 Modular Repertoire Analysis Identifies Complex Coordinated Type I- Type II Transcriptional Signatures in Adult SLE Patients
  1. L. Chiche1,2,
  2. N. Jourde-Chiche3,4,
  3. E. Whalen1,
  4. K. Dang1,
  5. S. Presnell1,
  6. V. Gersuk1,
  7. Q.-A. Nguyen1,
  8. E. Anguiano4,
  9. C. Quinn1,
  10. B. Dussol5,
  11. S. Burtey5,
  12. Y. Berland5,
  13. N. Bardin6,
  14. N. Schleinitz2,
  15. G. Kaplanski2,
  16. J.-M. Durand2,
  17. J.-R. Harle2,
  18. V. Pascual4,
  19. D. Chaussabel1
  1. 1Chaussabel Lab, Benaroya Research Institute, Seattle, United States
  2. 2Internal Medicine
  3. 3APHM, CHU la Conception, Marseille, France
  4. 4Baylor Institute for Immunologic Research, Dallas, United States
  5. 5Nephrology, APHM, CHU la Conception, Marseille, France
  6. 6Immunology, APHM, CHU la Conception, Marseille, France

Abstract

Background A pivotal role for Type I interferon (IFN) in SLE is supported by gene expression studies that identified the so-called type I IFN signature (IS).

Objectives The aim of this study was to improve characterization of the blood-IFN signature in adult SLE patients.

Methods Consecutive SLE patients fulfilling the ACR criteria were enrolled and followed-up prospectively. Microarray data were generated using Illumina beadchips. A modular transcriptional repertoire was employed as a framework for the analysis.

Results Our repertoire of 260 modules, which consist of co-clustered gene sets, included 3 IFN-annotated modules (M1.2, M3.4 and M5.12) that were strongly up-regulated in SLE patients. At the individual level, a modular IS (ie, over-expression of at least 1 of the 3 IFN modules) was observed in 54/62 (87%) of patients or 131/157 (83%) of samples. 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 to stratify SLE patients based on the presence of 0, 1, 2 or 3 active IFN modules. This “gradient” mIS was similarly observed in 2 independent SLE datasets. Samples were then classified in 4 groups according to their individual “modular IFN score” corresponding to the number of up-regulated IFN modules: Absent (0) in 26 (17%), Mild (1) in 17 (11%), Moderate (2) in 68 (43%) and Strong (3) in 46 (29%) samples. No differences in age, gender, ethnicity or disease duration was observed between the 4 groups. Compared to patients with absent/mild mIS, those with moderate/strong mIS had significantly higher anti-dsDNA titers (p=0.03) and lower lymphocyte count (p<0.0001). SLEDAI score was not significantly different between groups, but patients with moderate/strong mIS were less likely to be treated with antimalarials (p=0.002) or with a combination of immunosuppressant and antimalarials (p=0.0006). A similar gradient in mIS was observed within clinically quiescent patients, for whom moderate/strong modular scores (2 or 3 active IFN modules) were associated with higher anti-dsDNA titers and lower lymphocyte count than patients with absent/mild modular scores (0 or 1 active IFN modules). Longitudinal analyses (at least 3 consecutive visits, n=29) showed that whereas module M1.2 was very stable (mean coefficient of variation CV=0.05), M3.4 and M5.12 could vary over time in a single patient (mean CV=0.39 and 0.91 respectively). Interestingly, mining of other datasets suggested that M3.4 and M5.12 could be also driven by INF-b and g.

Conclusions Modular repertoire analysis reveals complex IFN signatures in SLE, not restricted to the previous IFN-a signature, but involving also b and g IFNs. These modular IFN signatures may help in the design of disease activity biomarkers.

Disclosure of Interest None declared

DOI 10.1136/annrheumdis-2014-eular.2405

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