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

Emma M Haapaniemi, Meri Kaustio, Hanna L M Rajala, Arjan J van Adrichem, Leena Kainulainen, Virpi Glumoff, Rainer Doffinger, Heikki Kuusanmäki, Tarja Heiskanen-Kosma, Luca Trotta, Samuel Chiang, Petri Kulmala, Samuli Eldfors, Riku Katainen, Sanna Siitonen, Marja-Liisa Karjalainen-Lindsberg, Panu E Kovanen, Timo Otonkoski, Kimmo Porkka, Kaarina Heiskanen, Arno Hänninen, Yenan T Bryceson, Raija Uusitalo-Seppälä, Janna Saarela, Mikko Seppänen, Satu Mustjoki, Juha Kere

文献索引：Blood 125(4) , 639-48, (2015)

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摘要

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.