Research Papers: Immunology:
A novel human STAT3 mutation presents with autoimmunity involving Th17 hyperactivation
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Judith Wienke1,*, Willemijn Janssen1,*, Rianne Scholman1,2, Hilde Spits1, Marielle van Gijn3, Marianne Boes1, Joris van Montfrans1, Nicolette Moes4 and Sytze de Roock1
1 Paediatric Immunology, Laboratory of Translational Immunology LTI, University Medical Center Utrecht, Utrecht, The Netherlands
2 Multiplex core facility, Laboratory of Translational Immunology LTI, University Medical Center Utrecht, Utrecht, The Netherlands
3 Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
4 Department of Paediatric Gastroenterology, Hepatology and Nutrition, University Medical Center Groningen, Groningen, The Netherlands
* These authors have contributed equally to this work
Sytze de Roock, email:
Keywords: autoimmunity, STAT3, Th17, IL-17, IL-21, Immunology and Microbiology Section, Immune response, Immunity
Received: May 20, 2015 Accepted: June 28, 2015 Published: July 30, 2015
Mutations in STAT3 have recently been shown to cause autoimmune diseases through increased lymphoproliferation. We describe a novel Pro471Arg STAT3 mutation in a patient with multiple autoimmune diseases, causing hyperactivation of the Th17 pathway. We show that IL-17 production by primary T cells was enhanced and could not be further increased by IL-6, while IL-10 reduced Th17 cell numbers. Moreover, specific inhibition of STAT3 activation resulted in diminished IL-17 production. We show that the Pro471Arg STAT3 mutation yields both increased levels of IgA and IgG, probably due to high IL-21 levels. When remission was reached through medical intervention, IL-17 levels normalized and the clinical symptoms improved, supporting the idea that STAT3 gain-of-function mutations can cause hyperactivation of the Th17 pathway and thereby contribute to autoimmunity.
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