Journal
BLOOD
Volume 125, Issue 4, Pages 591-599Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-09-602763
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Funding
- National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)
- Children's Discovery Institute
- St. Louis Children's Hospital
- Scleroderma Foundation
- Rheumatic Diseases Core Center at Washington University [P30AR048335]
- NIH [2T32AR007279]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [P30AR048335]
- Sir Jules Thorn Charitable Trust
- NIH National Human Genome Research Institute [U54HG006542, U54HG003273]
- National Cancer Institute (NCI) Cancer Center [P30 CA91842]
- Institute of Clinical and Translational Sciences/Clinical & Translational Science Awards (ICTS/CTSA) from the National Center for Research Resources, a component of the NIH [UL1TR000448]
- NIH Roadmap for Medical Research
- WT Kemper Foundation
- Marion Merrell Dow Foundation
- Black Veatch
- Pat and Gil Clements Foundation
- Claire Giannini Foundation
- National Institute of Child Health and Human Development (NICHD) [U19HD077693]
- BBSRC [BBS/E/T/000PR5885, BBS/E/T/000PR6193] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/T/000PR6193, BBS/E/T/000PR5885] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [12JTA] Funding Source: researchfish
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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, germlinemutations 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, withmost 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.
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