TY  - JOUR
A1  - Noster, Rebecca
A1  - de Koning, Heleen D.
A1  - Maier, Elisabeth
A1  - Prelog, Martina
A1  - Lainka, Elke
A1  - Zielinski, Christina E.
T1  - Dysregulation of proinflammatory versus anti-inflammatory human T\(_H\)17 cell functionalities in the autoinflammatory Schnitzler syndrome
JF  - Journal of Allergy and Clinical Immunology
N2  - 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.
KW  - Regulatory T-cells
KW  - IL-1 blockade
KW  - Big picture
KW  - Cytokine GM-CSF
KW  - Mechanisms
KW  - IL-1 beta
KW  - Diseases
KW  - Gamma
KW  - Autoinflammation
KW  - Schnitzler syndrome
KW  - T\(_H\)17 cells
KW  - IL-10
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187205
VL  - 138
IS  - 4
ER  -