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

Background 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. Objective To 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. Methods We 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. Results Spontaneous TNF alpha, IL-6, IL-1 beta, IL-1 alpha, 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, TNF alpha, IL-10, IFN gamma, IL-17A, and IL-4 production decreased in SchS patients compared to healthy controls, but less in treated patients. Whereas IL-1 beta serum level was not detected in most sera, IL-6, IL-10, and TNF alpha serum levels were higher in patients with SchS and IFN gamma and IL-4 levels were lower. Of note, IL-6 decreased after treatment in SchS (p = 0.04). Conclusion Our data strengthen the hypothesis of myeloid inflammation in SchS, mediated in particular by IL-1 beta, TNF alpha, 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.