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

Autor:	Haapaniemi EM; Folkhälsan Institute of Genetics and Research Programs Unit, Molecular Neurology, and., Kaustio M; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;, Rajala HL; Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland;, van Adrichem AJ; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;, Kainulainen L; Department of Pediatrics and Department of Medicine, Turku University Hospital, Turku, Finland;, Glumoff V; Department of Medical Microbiology and Immunology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland;, Doffinger R; Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital and National Institute for Health Research, Cambridge Biomedical Research Center, Cambridge, United Kingdom;, Kuusanmäki H; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;, Heiskanen-Kosma T; Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland;, Trotta L; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;, Chiang S; Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden;, Kulmala P; 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;, Eldfors S; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;, Katainen R; Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, University of Helsinki, Helsinki, Finland;, Siitonen S; Laboratory Services (Hospital District of Helsinki and Uusimaa Laboratory)., Karjalainen-Lindsberg ML; Laboratory Services (Hospital District of Helsinki and Uusimaa Laboratory)., Kovanen PE; Department of Pathology, and., Otonkoski T; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland;, Porkka K; Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland;, Heiskanen K; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland., Hänninen A; Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland;, Bryceson YT; Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden;, Uusitalo-Seppälä R; Department of Infectious Diseases, Satakunta Central Hospital, Pori, Finland;, Saarela J; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;, Seppänen M; Immunodeficiency Unit, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; and., Mustjoki S; Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland;, Kere J; 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.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2015 Jan 22; Vol. 125 (4), pp. 639-48. Date of Electronic Publication: 2014 Oct 27.
DOI:	10.1182/blood-2014-04-570101
Abstrakt:	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. (© 2015 by The American Society of Hematology.)
Databáze:	MEDLINE
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