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Oncotarget. 2015 Aug 21;6(24):20037-42.

A novel human STAT3 mutation presents with autoimmunity involving Th17 hyperactivation.

Author information

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.

Abstract

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.

KEYWORDS:

IL-17; IL-21; Immune response; Immunity; Immunology and Microbiology Section; STAT3; Th17; autoimmunity

PMID:
26343524
PMCID:
PMC4652985
DOI:
10.18632/oncotarget.5042
[Indexed for MEDLINE]
Free PMC Article

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