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

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-1b and in their cytokine repertoire. Whether these distinct T(H)17 phenotypes translate into distinct T(H)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 T(H)17 cell functions based on the differential expression of IL-10, which is regulated by IL-1 beta. Considering the crucial role of IL-1 beta in the pathogenesis of autoinflammatory syndromes, we hypothesized that IL-1 beta mediates the loss of anti-inflammatory T(H)17 cell functionalities in patients with Schnitzler syndrome, an autoinflammatory disease. Methods: To assess proinflammatory versus anti-inflammatory T(H)17 cell functions, we performed suppression assays and tested the effects of IL-1 beta dependent and independent TH17 subsets on modulating proinflammatory cytokine secretion by monocytes. Patients with Schnitzler syndrome were analyzed for changes in T(H)17 cell functions before and during therapy with IL-1 beta-blocking drugs. Results: Both T(H)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-1 beta translates into a profound loss of anti-inflammatoryT(H)17 cell functionalities, which can be reversed by anti-IL-1b treatment. Conclusion: IL-1 beta signaling determines the differential expression pattern of IL-10, which is necessary and sufficient to induce proinflammatory versus anti-inflammatory T(H)17 cell functions. Our data introduce T(H)17 cell subsets as novel players in autoinflammation and thus novel therapeutic targets in autoinflammatory syndromes including other IL-1 beta mediated diseases. This demonstrates for the first time alterations in the adaptive immune system in patients with autoinflammatory syndromes.