A novel human STAT3 mutation presents with autoimmunity involving Th17 hyperactivation.
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.
Paediatric Immunology, Laboratory of Translational Immunology LTI, University Medical Center Utrecht, Utrecht, The Netherlands.
Judith
J
Wienke
Paediatric Immunology, Laboratory of Translational Immunology LTI, University Medical Center Utrecht, Utrecht, The Netherlands.
Willemijn
W
Janssen
Paediatric Immunology, Laboratory of Translational Immunology LTI, University Medical Center Utrecht, Utrecht, The Netherlands.|Multiplex core facility, Laboratory of Translational Immunology LTI, University Medical Center Utrecht, Utrecht, The Netherlands.
Rianne
R
Scholman
Paediatric Immunology, Laboratory of Translational Immunology LTI, University Medical Center Utrecht, Utrecht, The Netherlands.
Hilde
H
Spits
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Marielle
M
van Gijn
Paediatric Immunology, Laboratory of Translational Immunology LTI, University Medical Center Utrecht, Utrecht, The Netherlands.
Marianne
M
Boes
Paediatric Immunology, Laboratory of Translational Immunology LTI, University Medical Center Utrecht, Utrecht, The Netherlands.
Joris
J
van Montfrans
Department of Paediatric Gastroenterology, Hepatology and Nutrition, University Medical Center Groningen, Groningen, The Netherlands.
Nicolette
N
Moes
Paediatric Immunology, Laboratory of Translational Immunology LTI, University Medical Center Utrecht, Utrecht, The Netherlands.
Sytze
S
de Roock
D000293:Adolescent; D015551:Autoimmunity / Q000276:immunology; D005260:Female; D006801:Humans; D009154:Mutation; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000276:immunology*; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology*
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
IL-17; IL-21; Immune response; Immunity; Immunology and Microbiology Section; STAT3; Th17; autoimmunity