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Blood. 2015 Jan 22;125(4):639-48. doi: 10.1182/blood-2014-04-570101. Epub 2014 Oct 27.

Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3.

Author information

1
Folkhälsan Institute of Genetics and Research Programs Unit, Molecular Neurology, and.
2
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;
3
Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland;
4
Department of Pediatrics and Department of Medicine, Turku University Hospital, Turku, Finland;
5
Department of Medical Microbiology and Immunology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland;
6
Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital and National Institute for Health Research, Cambridge Biomedical Research Center, Cambridge, United Kingdom;
7
Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland;
8
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden;
9
Department of Medical Microbiology and Immunology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of Pediatrics, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland;
10
Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, University of Helsinki, Helsinki, Finland;
11
Laboratory Services (Hospital District of Helsinki and Uusimaa Laboratory).
12
Department of Pathology, and.
13
Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland;
14
Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
15
Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland;
16
Department of Infectious Diseases, Satakunta Central Hospital, Pori, Finland;
17
Immunodeficiency Unit, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; and.
18
Folkhälsan Institute of Genetics and Research Programs Unit, Molecular Neurology, and Department of Biosciences and Nutrition, and Center for Innovative Medicine, Karolinska Institutet, Stockholm, Sweden.

Abstract

The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of immunodysregulation polyendocrinopathy enteropathy X-linked-like syndrome. Here, we immunologically characterized 3 patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T, and p.K658N, respectively). The patients displayed multiorgan autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B-cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4(-)CD8(-)) T cells, and decreased natural killer, T helper 17, and regulatory T-cell numbers. Notably, the patient harboring the K392R mutation developed T-cell large granular lymphocytic leukemia at age 14 years. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.

PMID:
25349174
PMCID:
PMC4304109
DOI:
10.1182/blood-2014-04-570101
[Indexed for MEDLINE]
Free PMC Article

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