title: Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation.
abstract: BACKGROUND
  Gain-of-function (GOF) mutations in the human signal transducer and activator of transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity with impaired TH17 cell differentiation and exaggerated responsiveness to type I and II interferons. Allogeneic bone marrow transplantation has been attempted in severely affected patients, but outcomes have been poor.
  
  
  OBJECTIVE
  We sought to define the effect of increased STAT1 activity on T helper cell polarization and to investigate the therapeutic potential of ruxolitinib in treating autoimmunity secondary to STAT1 GOF mutations.
  
  
  METHODS
  We used in vitro polarization assays, as well as phenotypic and functional analysis of STAT1-mutated patient cells.
  
  
  RESULTS
  We report a child with a novel mutation in the linker domain of STAT1 who had life-threatening autoimmune cytopenias and chronic mucocutaneous candidiasis. Naive lymphocytes from the affected patient displayed increased TH1 and follicular T helper cell and suppressed TH17 cell responses. The mutation augmented cytokine-induced STAT1 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reduced hyperresponsiveness to type I and II interferons, normalized TH1 and follicular T helper cell responses, improved TH17 differentiation, cured mucocutaneous candidiasis, and maintained remission of immune-mediated cytopenias.
  
  
  CONCLUSIONS
  Autoimmunity and infection caused by STAT1 GOF mutations are the result of dysregulated T helper cell responses. Janus kinase inhibitor therapy could represent an effective targeted treatment for long-term disease control in severely affected patients for whom hematopoietic stem cell transplantation is not available.
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Mass; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Mass. Electronic address: kgw1@stanford.edu.
authors.forename: Katja G
authors.initials: KG
authors.lastname: Weinacht
authors.affiliation: Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Louis-Marie
authors.initials: LM
authors.lastname: Charbonnier
authors.affiliation: Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Fayhan
authors.initials: F
authors.lastname: Alroqi
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Mass; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Mass.
authors.forename: Ashley
authors.initials: A
authors.lastname: Plant
authors.affiliation: Program in Molecular and Cellular Medicine, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Qi
authors.initials: Q
authors.lastname: Qiao
authors.affiliation: Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Mass; Program in Molecular and Cellular Medicine, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Mass; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Mass.
authors.forename: Clement
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Immunology, Seattle Children's Hospital, Seattle, Wash; Department of Pediatrics, Immunology Division, University of Washington, Seattle, Wash.
authors.forename: Troy R
authors.initials: TR
authors.lastname: Torgerson
authors.affiliation: Primary Immunodeficiency Clinic, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md; Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Md.
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Rosenzweig
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Md.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.affiliation: Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Mass; Harvard Stem Cell Institute, Cambridge, Mass.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Baylor College of Medicine and Texas Children's Hospital, Department of Pediatrics, Section of Immunology, Allergy and Rheumatology and Center for Human Immunobiology, Houston, Tex.
authors.forename: Imelda C
authors.initials: IC
authors.lastname: Hanson
authors.affiliation: Baylor College of Medicine and Texas Children's Hospital, Department of Pediatrics, Section of Immunology, Allergy and Rheumatology and Center for Human Immunobiology, Houston, Tex.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Forbes
authors.affiliation: Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Talal A
authors.initials: TA
authors.lastname: Chatila
mesh_terms: D000744:Anemia, Hemolytic, Autoimmune / Q000235:genetics* / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects; D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics / Q000276:immunology; D002648:Child; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D009154:Mutation; D009570:Nitriles; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000235:genetics* / Q000276:immunology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology
chemical_list: D016207:Cytokines; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C540383:ruxolitinib; D053612:Janus Kinases
keywords: IFN-γ; STAT1 gain of function; T helper cell polarization; T(H)1 cell; T(H)17 cell; autoimmunity; follicular T helper cell; ruxolitinib