Dysregulation of proinflammatory versus anti-inflammatory human TH17 cell functionalities in the autoinflammatory Schnitzler syndrome

Contains fulltext : 172371.pdf (publisher's version ) (Open Access)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-1beta 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-1beta. Considering the crucial role of IL-1beta in the pathogenesis of autoinflammatory syndromes, we hypothesized that IL-1beta 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-1beta 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-1beta-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-1beta translates into a profound loss of anti-inflammatory TH17 cell functionalities, which can be reversed by anti-IL-1beta treatment. CONCLUSION: IL-1beta 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-1beta mediated diseases. This demonstrates for the first time alterations in the adaptive immune system in patients with autoinflammatory syndromes