Rebecca Noster1, Heleen D de Koning2, Elisabeth Maier3, Martina Prelog4, Elke Lainka5, Christina E Zielinski6. 1. Department of Dermatology and Allergology, Charité-Universitätsmedizin Berlin, Berlin, Germany. 2. Department of Dermatology, Radboud University Medical Center, Nijmegen, The Netherlands; Nijmegen Center for Immunodeficiency and Autoinflammation, Nijmegen, The Netherlands. 3. Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany. 4. Department of Pediatrics, University of Wuerzburg, Wuerzberg, Germany. 5. Pediatric Rheumatology, University Children's Hospital, Essen, Germany. 6. Department of Dermatology and Allergology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany. Electronic address: christina.zielinski@tum.de.
Abstract
BACKGROUND: TH17 cells have so far been considered to be crucial mediators of autoimmune inflammation. Two distinct types of TH17 cells have been described recently, which differed in their polarization requirement for IL-1β and in their cytokine repertoire. Whether these distinct TH17 phenotypes translate into distinct TH17 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 TH17 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 TH17 cell functionalities in patients with Schnitzler syndrome, an autoinflammatory disease. METHODS: To assess proinflammatory versus anti-inflammatory TH17 cell functions, we performed suppression assays and tested the effects of IL-1β dependent and independent TH17 subsets on modulating proinflammatory cytokine secretion by monocytes. Patients with Schnitzler syndrome were analyzed for changes in TH17 cell functions before and during therapy with IL-1β-blocking drugs. RESULTS: Both TH17 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 TH17 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 TH17 cell functions. Our data introduce TH17 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.
BACKGROUND: TH17 cells have so far been considered to be crucial mediators of autoimmune inflammation. Two distinct types of TH17 cells have been described recently, which differed in their polarization requirement for IL-1β and in their cytokine repertoire. Whether these distinct TH17 phenotypes translate into distinct TH17 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 TH17 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 TH17 cell functionalities in patients with Schnitzler syndrome, an autoinflammatory disease. METHODS: To assess proinflammatory versus anti-inflammatory TH17 cell functions, we performed suppression assays and tested the effects of IL-1β dependent and independent TH17 subsets on modulating proinflammatory cytokine secretion by monocytes. Patients with Schnitzler syndrome were analyzed for changes in TH17 cell functions before and during therapy with IL-1β-blocking drugs. RESULTS: Both TH17 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 TH17 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 TH17 cell functions. Our data introduce TH17 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.
Authors: Julia Matthias; Sylvia Heink; Felix Picard; Julia Zeiträg; Anna Kolz; Ying-Yin Chao; Dominik Soll; Gustavo P de Almeida; Elke Glasmacher; Ilse D Jacobsen; Thomas Riedel; Anneli Peters; Stefan Floess; Jochen Huehn; Dirk Baumjohann; Magdalena Huber; Thomas Korn; Christina E Zielinski Journal: J Clin Invest Date: 2020-09-01 Impact factor: 14.808
Authors: Hélène Fank; Jo Caers; Michel Lambert; Liliane Marot; Laurence De Montjoye; Dominique Tennstedt; Marie Baeck; Valérie Dekeuleneer Journal: JAAD Case Rep Date: 2018-04-06