title: Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency.
abstract: BACKGROUND
  Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described.
  
  
  RESULTS
  We prospectively screened 21 adult STAT3-deficient patients [corrected] (median age, 26 years; range, 17-44 years) [corrected] for vascular abnormalities. We explored the entire arterial vasculature with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography, and echo-tracking-based imaging specifically for the [corrected] carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, we studied murine models of aortic aneurysm in the presence and absence of inhibitors of STAT3-dependent signaling. Ninety-five percent of patients showed brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, and atrophy). We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress, indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models.
  
  
  CONCLUSIONS
  Vascular abnormalities are highly prevalent in patients with STAT3 deficiency. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.
authors.affiliation: Hematology Department, Necker Children's Hospital, Assistance Publique Hôpitaux de Paris, 149 rue de Sèvres, Paris, France.
authors.forename: Marie-Olivia
authors.initials: MO
authors.lastname: Chandesris
authors.forename: Arshid
authors.initials: A
authors.lastname: Azarine
authors.forename: Kim-Thanh
authors.initials: KT
authors.lastname: Ong
authors.forename: Soraya
authors.initials: S
authors.lastname: Taleb
authors.forename: Pierre
authors.initials: P
authors.lastname: Boutouyrie
authors.forename: Elie
authors.initials: E
authors.lastname: Mousseaux
authors.forename: Mélissa
authors.initials: M
authors.lastname: Romain
authors.forename: Erwan
authors.initials: E
authors.lastname: Bozec
authors.forename: Stéphane
authors.initials: S
authors.lastname: Laurent
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Caroline
authors.initials: C
authors.lastname: Thumerelle
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tillie-Leblond
authors.forename: Cyrille
authors.initials: C
authors.lastname: Hoarau
authors.forename: Yvon
authors.initials: Y
authors.lastname: Lebranchu
authors.forename: Nathalie
authors.initials: N
authors.lastname: Aladjidi
authors.forename: François
authors.initials: F
authors.lastname: Tron
authors.forename: Vincent
authors.initials: V
authors.lastname: Barlogis
authors.forename: Gérard
authors.initials: G
authors.lastname: Body
authors.forename: Marine
authors.initials: M
authors.lastname: Munzer
authors.forename: Roland
authors.initials: R
authors.lastname: Jaussaud
authors.forename: Felipe
authors.initials: F
authors.lastname: Suarez
authors.forename: Olivier
authors.initials: O
authors.lastname: Clément
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Alain
authors.initials: A
authors.lastname: Tedgui
authors.forename: Olivier
authors.initials: O
authors.lastname: Lortholary
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000818:Animals; D001014:Aortic Aneurysm / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D004195:Disease Models, Animal; D006579:Heterozygote; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D007589:Job Syndrome / Q000235:genetics* / Q000473:pathology; D018810:Magnetic Resonance Angiography; D008279:Magnetic Resonance Imaging; D051379:Mice; D009154:Mutation; D011446:Prospective Studies; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography; D051598:Whole Body Imaging; D055815:Young Adult
chemical_list: D015415:Biomarkers; D020381:Interleukin-17; D050796:STAT3 Transcription Factor