Cytokine Signature in Schnitzler Syndrome: Proinflammatory Cytokine Production Associated to Th Suppression.

M Masson Regnault ,Bouchra Asli,Dan Lipsker,Xavier Puéchal,François Lifermann,Franck Morel,Rita Rizzi,Isabelle Jéru,Adriana Delwail,Didier Bessis,Claire Blanchard-Delaunay,Franco Rongioletti,Sandrine Charreau,A Masseau ,T Boyé ,A Néel ,S Barbarot ,L Gusdorf ,F Aubin ,X Kyndt ,S Gayet ,E Hainaut ,X Balguérie ,Éric Frouin ,Jean‐Claude Lecron

doi:10.3389/fimmu.2020.588322

Abstract

BackgroundSchnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal IgM gammopathy. Overactivation of the interleukin(IL)-1 system is reported, even though the exact pathophysiological pathways remain unknown.ObjectiveTo determine ex vivo cytokine profiles of Peripheral Blood Mononuclear Cells (PBMCs) from SchS patients prior to treatment and after initiation of anti-IL-1 therapy (anakinra). The sera cytokine profile was studied in parallel.MethodsWe collected blood samples from thirty-six untreated or treated SchS. PBMCs were cultured with and without LPS or anti-CD3/CD28. Cytokine levels were evaluated in serum and cell culture supernatants using Luminex technology.ResultsSpontaneous TNFα, IL-6, IL-1β, IL-1α, and IL-1RA release by PBMCs of SchS patients were higher than in controls. LPS-stimulation further induced the secretion of these cytokines. In contrast, after T-cell stimulation, TNFα, IL-10, IFNγ, IL-17A, and IL-4 production decreased in SchS patients compared to healthy controls, but less in treated patients. Whereas IL-1β serum level was not detected in most sera, IL-6, IL-10, and TNFα serum levels were higher in patients with SchS and IFNγ and IL-4 levels were lower. Of note, IL-6 decreased after treatment in SchS (p = 0.04).ConclusionOur data strengthen the hypothesis of myeloid inflammation in SchS, mediated in particular by IL-1β, TNFα, and IL-6, associated with overproduction of the inhibitors IL-1RA and IL-10. In contrast, we observed a loss of Th1, Th2, and Th17 cell functionalities that tends to be reversed by anakinra.

Highlights

Schnitzler syndrome (SchS), first described in 1972 by Liliane Schnitzler [1], entered into the classification of autoinflammatory syndromes several decades later, when knowledge of this group of disorders involving the innate immune system started to improve
For IL-1a, spontaneous release by peripheral blood mononuclear cells (PBMC) was slightly higher in untreated patients than in controls (Figure 1E)
LPS-stimulated PBMCs from untreated or treated SchS patients produced a significant higher levels of TNFa, IL-1a, IL-1b, and IL-1RA compared to LPS-stimulated PBMCs from healthy controls, whereas IL-6 levels were not significantly increased

Summary

Introduction

Schnitzler syndrome (SchS), first described in 1972 by Liliane Schnitzler [1], entered into the classification of autoinflammatory syndromes several decades later, when knowledge of this group of disorders involving the innate immune system started to improve. SchS is characterized by chronic urticarial exanthema with neutrophilic infiltrate, monoclonal gammopathy, and signs of systemic inflammation including recurrent fever attacks, as well as bone and joint manifestations. Patients suffer from major quality of life impairment with impact on social and professional life [6]. It is a late-onset disease compared to most other autoinflammatory disorders, with median age at clinical onset of 55 years. It affects both males and females with a ratio of 1.5:1 [7]. Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal IgM gammopathy. Overactivation of the interleukin(IL)-1 system is reported, even though the exact pathophysiological pathways remain unknown

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Conclusion