AI Article Synopsis

  • * In a study of 13 individuals from 10 families, 9 different germline mutations in STAT3 were found to be associated with lymphoproliferation and early-onset solid-organ autoimmunity, showing symptoms like lymphadenopathy and autoimmune cytopenias.
  • * Functional analyses indicated that these mutations cause a gain-of-function in STAT3, affecting immune regulation, and treatment targeting this pathway showed clinical improvement in at least one patient, highlighting potential therapeutic strategies.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304103PMC
http://dx.doi.org/10.1182/blood-2014-09-602763DOI Listing

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