Dysregulation of proinflammatory versus anti-inflammatory human TH 17 cell functionalities in the autoinflammatory Schnitzler syndrome

• Published in: Journal of allergy and clinical immunology 2016
• Main Authors: Noster, Rebecca, de Koning, Heleen D., MD, PhD, Maier, Elisabeth, PhD, Prelog, Martina, MD, Lainka, Elke, MD, Zielinski, Christina E., MD
• Format: Article
• Language: English
• Subjects: Allergy and Immunology
• ISSN: 0091-6749
• DOI: 10.1016/j.jaci.2015.12.1338

Background TH 17 cells have so far been considered to be crucial mediators of autoimmune inflammation. Two distinct types of TH 17 cells have been described recently, which differed in their polarization requirement for IL-1β and in their cytokine repertoire. Whether these distinct TH 17 phenotypes translate into distinct TH 17 cell functions with implications for human health or disease has not been addressed yet. Objective We hypothesized the existence of proinflammatory and anti-inflammatory human TH 17 cell functions based on the differential expression of IL-10, which is regulated by IL-1β. Considering the crucial role of IL-1β in the pathogenesis of autoinflammatory syndromes, we hypothesized that IL-1β mediates the loss of anti-inflammatory TH 17 cell functionalities in patients with Schnitzler syndrome, an autoinflammatory disease. Methods To assess proinflammatory versus anti-inflammatory TH 17 cell functions, we performed suppression assays and tested the effects of IL-1β dependent and independent TH 17 subsets on modulating proinflammatory cytokine secretion by monocytes. Patients with Schnitzler syndrome were analyzed for changes in TH 17 cell functions before and during therapy with IL-1β–blocking drugs. Results Both TH 17 cell subsets differ in their ability to suppress T-cell proliferation and their ability to modulate proinflammatory cytokine production by antigen-presenting cells because of their differential IL-10 expression properties. In patients with Schnitzler syndrome, systemic overproduction of IL-1β translates into a profound loss of anti-inflammatory TH 17 cell functionalities, which can be reversed by anti–IL-1β treatment. Conclusion IL-1β signaling determines the differential expression pattern of IL-10, which is necessary and sufficient to induce proinflammatory versus anti-inflammatory TH 17 cell functions. Our data introduce TH 17 cell subsets as novel players in autoinflammation and thus novel therapeutic targets in autoinflammatory syndromes including other IL-1β mediated diseases. This demonstrates for the first time alterations in the adaptive immune system in patients with autoinflammatory syndromes.