Dysregulation of proinflammatory versus anti-inflammatory human TH_H17 cell functionalities in the autoinflammatory Schnitzler syndrome

Background: T$_H$17 cells have so far been considered to be crucial mediators of autoimmune inflammation. Two distinct types of T$_H$17 cells have been described recently, which differed in their polarization requirement for IL-1b and in their cytokine repertoire. Whether these distinct T$_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$17 cell functions, we performed suppression assays and tested the effects of IL-1 beta dependent and independent T$_H$17 subsets on modulating proinflammatory cytokine secretion by monocytes. Patients with Schnitzler syndrome were analyzed for changes in T$_H$17 cell functions before and during therapy with IL-1 beta-blocking drugs. Results: Both T$_H$17 cell subsets differ in their ability to suppress T-cell proliferation and their ability to modulate proinflammatory cytokine production by antigen-presenting cells because of their differential IL-10 expression properties. In patients with Schnitzler syndrome, systemic overproduction of IL-1 beta translates into a profound loss of anti-inflammatory T$_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