Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy
Journal of Clinical Immunology 40 巻
1065-1081 頁
2020-08-27 発行
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| ファイル情報(添付) | |
| タイトル ( eng ) |
Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy
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| 作成者 |
Asano Takaki
Moriya Kunihiko
Boisson-Dupuis Stephanie
Casanova Jean-Laurent
Puel Anne
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| 収録物名 |
Journal of Clinical Immunology
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| 巻 | 40 |
| 開始ページ | 1065 |
| 終了ページ | 1081 |
| 抄録 |
Heterozygous gain-of-function (GOF) mutations in STAT1 in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection by Candida fungi, and hypothyroidism results from autoimmune thyroiditis. Patients with these diseases develop other infectious diseases, including viral, bacterial, and fungal diseases, and other autoimmune manifestations, including enterocolitis, immune cytopenia, endocrinopathies, and systemic lupus erythematosus. STAT1-GOF mutations are highly penetrant with a median age at onset of 1 year and often underlie an autosomal dominant trait. As many as 105 mutations at 72 residues, including 65 recurrent mutations, have already been reported in more than 400 patients worldwide. The GOF mechanism involves impaired dephosphorylation of STAT1 in the nucleus. Patient cells show enhanced STAT1-dependent responses to type I and II interferons (IFNs) and IL-27. This impairs Th17 cell development, which accounts for CMC. The pathogenesis of autoimmunity likely involves enhanced type I IFN responses, as in other type I interferonopathies. The pathogenesis of other infections, especially those caused by intramacrophagic bacteria and fungi, which are otherwise seen in patients with diminished type II IFN immunity, has remained mysterious. The cumulative survival rates of patients with and without severe disease (invasive infection, cancer, and/or symptomatic aneurysm) at 60 years of age are 31% and 87%, respectively. Severe autoimmunity also worsens the prognosis. The treatment of patients with STAT1-GOF mutations who suffer from severe infectious and autoimmune manifestations relies on hematopoietic stem cell transplantation and/or oral JAK inhibitors.
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| 著者キーワード |
STAT1
chronic mucocutaneous candidiasis
Mendelian susceptibility to mycobacterial diseases
gain-of-function
virus
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| 内容記述 |
SO acknowledges Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (16H05355 and 19H03620), the Promotion of Joint International Research from the Japan Society for the Promotion of Science (18KK0228), and the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, AMED. KM acknowledges a fellowship grant from the Japan Foundation for Pediatric Research and the EURO CMC grant (ANR-14-RARE-0005-02). JLC acknowledges the National Institutes of Health grants (grant no. R01AI127564). AP acknowledges grants from the French National Research Agency (ANR) under the “Lymphocyte T helper (Th) cell differentiation in patients with inborn errors of immunity to Mycobacterium and/or Candida species” program (ANR-FNS LTh-MSMD-CMCD, ANR-18-CE93-0008-01).
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| 言語 |
英語
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| 資源タイプ | 学術雑誌論文 |
| 出版者 |
Springer
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| 発行日 | 2020-08-27 |
| 権利情報 |
This is not the published version. Please cite only the published version. この論文は出版社版ではありません。引用の際には出版社版をご確認、ご利用ください。
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| 出版タイプ | Author’s Original（十分な品質であるとして、著者から正式な査読に提出される版） |
| アクセス権 | オープンアクセス |
| 収録物識別子 |
[ISSN] 0271-9142
[ISSN] 1573-2592
[DOI] 10.1007/s10875-020-00847-x
[DOI] https://doi.org/10.1007/s10875-020-00847-x
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