Chandesris Marie-Olivia, Azarine Arshid, Ong Kim-Thanh, Taleb Soraya, Boutouyrie Pierre, Mousseaux Elie, Romain Mélissa, Bozec Erwan, Laurent Stéphane, Boddaert Nathalie, Thumerelle Caroline, Tillie-Leblond Isabelle, Hoarau Cyrille, Lebranchu Yvon, Aladjidi Nathalie, Tron François, Barlogis Vincent, Body Gérard, Munzer Marine, Jaussaud Roland, Suarez Felipe, Clément Olivier, Hermine Olivier, Tedgui Alain, Lortholary Olivier, Picard Capucine, Mallat Ziad, Fischer Alain
Hematology Department, Necker Children's Hospital, Assistance Publique Hôpitaux de Paris, 149 rue de Sèvres, Paris, France.
Circ Cardiovasc Genet. 2012 Feb 1;5(1):25-34. doi: 10.1161/CIRCGENETICS.111.961235. Epub 2011 Nov 14.
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.
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.
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.
信号转导子和转录激活子3（STAT3）缺陷导致常染色体显性高免疫球蛋白E综合征，其特征为反复发生细菌和真菌感染、结缔组织异常、高免疫球蛋白E以及Th17淋巴细胞减少。尽管在一些患者中已报道存在血管异常，但这些特征的患病率、特点及病因尚未得到描述。
我们对21例成年STAT3缺陷患者（中位年龄26岁；范围17 - 44岁）进行前瞻性血管异常筛查。我们通过全身磁共振血管造影、冠状动脉多层计算机断层扫描以及专门针对颈动脉的基于回声跟踪的成像技术来探查整个动脉血管系统。我们还检测了炎症和内皮功能障碍的血清生物标志物。最后，我们研究了在有和没有STAT3依赖性信号抑制剂存在的情况下主动脉瘤的小鼠模型。95%的患者显示脑部异常（白质高信号、提示缺血性梗死的腔隙性病变和萎缩）。我们报告84%的患者存在外周及脑动脉异常，50%的患者检测到冠状动脉异常。最常见的血管异常是扩张和动脉瘤。颈动脉内膜中层厚度明显降低，周向壁应力大幅增加，表明在这个STAT3缺陷人群中发生了低营养性动脉重塑。全身炎症生物标志物水平与血管表型的相关性较差。在小鼠模型中，STAT3信号的体内抑制或IL - 17A的阻断导致动脉瘤严重程度显著增加及致命破裂。
血管异常在STAT3缺陷患者中高度普遍。这一特征与在小鼠模型中抑制STAT3依赖性信号后观察到的对血管动脉瘤的更高易感性一致。
