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Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.
- Source :
-
Blood [Blood] 2015 Jan 22; Vol. 125 (4), pp. 591-9. Date of Electronic Publication: 2014 Oct 30. - Publication Year :
- 2015
-
Abstract
- Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350.
- Subjects :
- Adolescent
Adult
Autoimmune Diseases immunology
Autoimmune Diseases pathology
Child
Child, Preschool
Female
Genetic Diseases, Inborn immunology
Genetic Diseases, Inborn pathology
Humans
Infant
Lymphoproliferative Disorders immunology
Lymphoproliferative Disorders pathology
Male
Mutation
Phosphorylation genetics
Phosphorylation immunology
STAT1 Transcription Factor genetics
STAT1 Transcription Factor immunology
STAT3 Transcription Factor immunology
STAT5 Transcription Factor genetics
STAT5 Transcription Factor immunology
T-Lymphocytes, Regulatory immunology
T-Lymphocytes, Regulatory pathology
Autoimmune Diseases genetics
Genetic Diseases, Inborn genetics
Lymphoproliferative Disorders genetics
STAT3 Transcription Factor genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 125
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 25359994
- Full Text :
- https://doi.org/10.1182/blood-2014-09-602763