Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation.
Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation.
复制标题
DOI：
10.1016/j.jaci.2013.08.045
复制
发表时间：
2013-12
影响因子：
14.2
通讯作者：
Milner, Joshua D.
中科院分区：
文献类型：
--
作者：
Siegel, Andrea M.;Stone, Kelly D.;Cruse, Glenn;Lawrence, Monica G.;Olivera, Ana;Jung, Mi-yeon;Barber, John S.;Freeman, Alexandra F.;Holland, Steven M.;O'Brien, Michelle;Jones, Nina;Wisch, Laura B.;Kong, Heidi H.;Desai, Avanti;Farber, Orly;Gilfillan, Alasdair M.;Rivera, Juan;Milner, Joshua D.
关键词：
与血清IgE升高相关的严重特应性疾病是异质性的，几乎没有已知的原因。几乎每一个常染色体显性高IgE综合征（AD-HIES）由于信号转导和转录激活因子3（STAT 3）突变的患者有湿疹性皮炎和IgE升高的历史，然而，临床特应性从未进行过系统研究。了解过敏性疾病的遗传决定因素可能会导致控制过敏性疾病的新疗法。我们对AD-HIES患者的食物过敏和速发型过敏反应的发生率进行了临床评价，这是一组无STAT 3突变但有类似IgE升高和特应性皮炎病史的患者，以及无特应性病史的健康志愿者。吗啡皮肤点刺试验，过敏原特异性IgE的免疫CAP测定，嗜碱性粒细胞活化进行了测量。在携带AD-HIES突变的转基因小鼠中研究了全身过敏反应模型。STAT 3在LAD 2和原代人肥大细胞中沉默以研究STAT 3在IgE交联后的信号传导和脱粒中的作用。与一组无STAT 3突变但有相似的IgE升高和特应性皮炎病史的患者相比，AD-HIES患者的食物过敏和过敏反应明显减少。吗啡皮肤点刺试验和嗜碱性粒细胞活化减少与AD-HIES患者，而携带AD-HIES突变的小鼠对全身过敏反应模型反应迟钝。IgE交联后，肥大细胞STAT 3丝氨酸727快速磷酸化，肥大细胞中STAT 3信号传导的抑制导致Fcε RI介导的近端和远端信号传导受损，以及脱粒减少。这项研究作为一个例子，在特定的特应性途径的突变如何导致离散的过敏表型，包括一些表型的风险增加，但对其他相对保护。
Severe atopic conditions associated with elevated serum IgE are heterogeneous with few known causes. Nearly every patient with autosomal-dominant hyper-IgE syndrome (AD-HIES) due to signal transducer and activator of transcription 3 (STAT3) mutations has a history of eczematous dermatitis and elevated IgE; however, clinical atopy has never been systematically studied. Understanding of genetic determinants of allergic disease may lead to novel therapies in controlling allergic disease. We conducted clinical evaluation of the rates of food allergies and anaphylaxis in patients with AD-HIES, a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis, and healthy volunteers with no history of atopy. Morphine skin prick testing, ImmunoCAP assays for allergen-specific IgE, and basophil activation were measured. A model of systemic anaphylaxis was studied in transgenic mice carrying an AD-HIES mutation. STAT3 was silenced in LAD2 and primary human mast cells to study the role of STAT3 in signaling and degranulation after IgE cross-linking. Food allergies and anaphylaxis were markedly diminished in patients with AD-HIES compared with a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis. Morphine skin prick testing and basophil activation were diminished in patients with AD-HIES, whereas mice carrying an AD-HIES mutation were hyporesponsive to systemic anaphylaxis models. Rapid mast cell STAT3 serine727 phosphorylation was noted after IgE cross-linking, and inhibition of STAT3 signaling in mast cells lead to impaired FcεRI-mediated proximal and distal signaling, as well as reduced degranulation. This study serves as an example for how mutations in specific atopic pathways can lead to discrete allergic phenotypes, encompassing increased risk of some phenotypes but a relative protection from others.
登录
查看更多内容
DOI：
10.1084/jem.20111941
发表时间：
2012-02-13
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Xiong H;Dolpady J;Wabl M;Curotto de Lafaille MA;Lafaille JJ
通讯作者：
Lafaille JJ
DOI：
10.1016/j.jaci.2010.10.007
发表时间：
2010-12
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
NIAID-Sponsored Expert Panel;Boyce JA;Assa'ad A;Burks AW;Jones SM;Sampson HA;Wood RA;Plaut M;Cooper SF;Fenton MJ;Arshad SH;Bahna SL;Beck LA;Byrd-Bredbenner C;Camargo CA Jr;Eichenfield L;Furuta GT;Hanifin JM;Jones C;Kraft M;Levy BD;Lieberman P;Luccioli S;McCall KM;Schneider LC;Simon RA;Simons FE;Teach SJ;Yawn BP;Schwaninger JM
通讯作者：
Schwaninger JM
DOI：
10.1126/science.1176676
发表时间：
2009-08-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Nurieva RI;Chung Y;Martinez GJ;Yang XO;Tanaka S;Matskevitch TD;Wang YH;Dong C
通讯作者：
Dong C
影响因子：
32.4
作者：
Nurieva, Roza I.;Chung, Yeonseok;Hwang, Daehee;Yang, Xuexian O.;Kang, Hong Soon;Ma, Li;Wang, Yi-Hong;Watowich, Stephanie S.;Jetten, Anton M.;Tian, Qiang;Dong, Chen
通讯作者：
Dong, Chen
影响因子：
5.2
作者：
Sowerwine KJ;Holland SM;Freeman AF
通讯作者：
Freeman AF