Cytokines in Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome: Tipping the Balance Between Interleukin-18 and Interferon-Gamma

Karen Put¹, Anneleen Avau¹, Ellen Brisse¹, Tania Mitera¹, Stéphanie Put¹, Paul Proost², Brigitte Bader-Meunier³, Rene Westhovens⁴, Benoît Van den Eynde⁵, Ciriana Orabona⁶, Francesca Fallarino⁶, Lien De Somer⁷, Thomas Tousseyn⁸, Pierre Quartier³, Carine Wouters⁷ and Patrick Matthys¹, ¹University of Leuven, Laboratory of Immunobiology, Rega Institute, Leuven, Belgium, ²University of Leuven, Laboratory of Molecular Immunology, Rega Institute, Leuven, Belgium, ³Pediatric Rheumatology, IMAGINE Institute, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Université Paris-Descartes, Paris, France, ⁴University of Leuven, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration; Rheumatology, University Hospital Leuven, Leuven, Belgium, ⁵Institut de Duve, Université catholique de Louvain, Brussels, Belgium, ⁶Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy, ⁷University of Leuven, Laboratory of Pediatric Immunology, University Hospital Leuven, Leuven, Belgium, ⁸University of Leuven, Department of Imaging and Pathology, Leuven, Belgium

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Cytokines and macrophage activation syndrome, Systemic JIA

Session Information

Title: Pediatric Rheumatology - Pathogenesis and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose

To study the role of interferon-gamma (IFN-γ) in the pathogenesis of systemic juvenile idiopathic arthritis (sJIA) and macrophage activation syndrome (MAS) by searching for an IFN-γ profile and assess its relation with other cytokines.

Methods

Patients with inactive (n=10) and active sJIA (n=10), MAS (n=5) and healthy controls (n=16) were enrolled in the study. Cytokines and IFN-γ-induced proteins were determined in plasma by ELISA and HPLC-MS, in patient peripheral blood mononuclear cells (PBMCs) (qPCR, flow cytometry, western blot and ELISA) and in lymph node biopsies of one patient during both sJIA and MAS episodes (immunohistochemistry). IFN‑γ responses were investigated in healthy donor PBMCs, primary fibroblasts and endothelial cells.

Results

Plasma IFN-γ, IL-6 and IL-18 were elevated in active sJIA and MAS. Levels of IFN‑γ and IFN‑γ-induced proteins (IP‑10/CXCL-10, IL-18BP and IDO) in MAS were highly surpassing levels in active sJIA. Free IL-18 and ratios of IL‑18/IFN-γ were higher in active sJIA versus MAS. MAS PBMCs showed a hyporesponsiveness to IFN-γ in vitro. Endothelial cells and fibroblasts expressed IFN-γ-induced proteins in situ in lymph node stainings of a MAS patient and in vitro upon stimulation with IFN-γ.

Conclusion

Patients with active sJIA and MAS show distinct cytokine profiles with highly elevated plasma levels of IFN-γ and induced proteins typically found in MAS. In addition to PBMCs, histiocytes, endothelial cells and fibroblasts may contribute to an IFN‑γ profile in plasma. Increasing levels of IFN-γ compared to IL-18 may raise suspicion for development of MAS in sJIA.

Disclosure:

K. Put,
None;

A. Avau,
None;

E. Brisse,
None;

T. Mitera,
None;

S. Put,
None;

P. Proost,
None;

B. Bader-Meunier,
None;

R. Westhovens,
None;

B. Van den Eynde,
None;

C. Orabona,
None;

F. Fallarino,
None;

L. De Somer,
None;

T. Tousseyn,
None;

P. Quartier,
None;

C. Wouters,
None;

P. Matthys,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cytokines-in-systemic-juvenile-idiopathic-arthritis-and-macrophage-activation-syndrome-tipping-the-balance-between-interleukin-18-and-interferon-gamma/