Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md., USA.
J Allergy Clin Immunol. 2013 Jun;131(6):1586-93. doi: 10.1016/j.jaci.2013.02.038. Epub 2013 Apr 25.
Autosomal dominant hyper-IgE syndrome (AD-HIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3). We describe 2 subjects in whom somatic mosaicism was associated with intermediate phenotypes.
Somatic mosaics might shed light on the pathogenesis of dominant STAT3 mutations and the mechanisms behind the immunologic and nonimmunologic features of the disease.
Clinical evaluations were conducted. Mutant STAT3 was amplified from different tissues and sequenced, and the percentage of mosaicism in various cell types was calculated. Flow cytometry was performed to determine percentages of IL-17(+) cells, IL-22(+) cells, or both. Suction blisters were induced in 1 subject, and exudate fluid was analyzed for whether emigrating neutrophils were STAT3 mutant or wild-type; neutrophils from peripheral blood were simultaneously examined.
The 2 subjects with STAT3 somatic mosaicism had intermediate phenotypes and were found to have preserved TH17 cell compartments and apparently normal CD8 cells. However, they still had infections, including mucocutaneous candidiasis. The percentage of STAT3 mutant neutrophils migrating into blisters at 16 hours was the same as in peripheral blood, suggesting normal chemotaxis.
STAT3 mosaicism accounts for a milder phenotype and allows for further investigation into the pathogenesis of AD-HIES. Despite having a preserved TH17 cell compartment, both subjects with mosaicism had chronic mucocutaneous candidiasis, suggesting that candidiasis in subjects with AD-HIES is not driven solely by low TH17 cell numbers. The percentage of STAT3 mutant neutrophils emigrating into a suction blister at 16 hours was the same as the percentage in peripheral blood, suggesting that early chemotaxis of STAT3 neutrophils is normal in vivo.
常染色体显性高免疫球蛋白 E 综合征（AD-HIES）是由信号转导子和转录激活子 3（STAT3）突变引起的。我们描述了 2 例与中间表型相关的体细胞嵌合体病例。
体细胞嵌合体可能为显性 STAT3 突变的发病机制以及疾病的免疫和非免疫特征背后的机制提供线索。
进行了临床评估。从不同组织扩增突变 STAT3 并测序，并计算各种细胞类型中的嵌合体百分比。通过流式细胞术确定 IL-17(+)细胞、IL-22(+)细胞或两者的百分比。在 1 例患者中诱导抽吸水疱，并分析渗出液中迁移的中性粒细胞是否为 STAT3 突变型或野生型；同时检查外周血中的中性粒细胞。
2 例具有 STAT3 体细胞嵌合体的患者具有中间表型，并且发现 TH17 细胞区室得到保留，CD8 细胞显然正常。然而，他们仍然存在感染，包括黏膜皮肤念珠菌病。16 小时时 STAT3 突变型中性粒细胞迁移到水疱中的百分比与外周血中的百分比相同，表明正常趋化性。
STAT3 嵌合体解释了更温和的表型，并允许进一步研究 AD-HIES 的发病机制。尽管具有保留的 TH17 细胞区室，但 2 例嵌合体患者均患有慢性黏膜皮肤念珠菌病，这表明 AD-HIES 患者的念珠菌病不仅仅是由低 TH17 细胞数量驱动的。16 小时时 STAT3 突变型中性粒细胞迁移到抽吸水疱中的百分比与外周血中的百分比相同，这表明 STAT3 中性粒细胞的早期趋化性在体内是正常的。
