Becker K L, Rösler B, Wang X, Lachmandas E, Kamsteeg M, Jacobs C W, Joosten L A, Netea M G, van de Veerdonk F L
Department of Internal Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), Nijmegen, The Netherlands.
Department of Dermatology, Peking University First Hospital, Beijing, China.
Clin Exp Allergy. 2016 Dec;46(12):1564-1574. doi: 10.1111/cea.12787. Epub 2016 Sep 18.
STAT1 mutations cause chronic mucocutaneous candidiasis (CMC), while STAT3 mutations cause hyper-IgE syndrome (HIES). CMC and HIES patients have T helper (Th) 17 defects suffering from mucosal Candida infections, but only patients with HIES show an allergic phenotype with eczema, eosinophilia and high IgE levels.
We investigated whether differential Th2 and Th9 responses may explain the clinical differences.
Peripheral blood mononuclear cells of patients with CMC (n = 4), patients with HIES (n = 4), patients with atopic dermatitis (n = 4) and healthy volunteers (n = 13) were stimulated with Candida and Staphylococcus aureus, with and without IL-4. The cytokines IL-5, IL-13, IL-9, IL-17 and TGFβ and regulatory T cells were measured in cell culture supernatants by ELISA or flow cytometry, respectively.
Peripheral blood mononuclear cells of patients with CMC showed a significantly impaired production of the Th2 cytokines IL-5 and IL-13, especially in the presence of IL-4. Moreover, IL-9 production was significantly lower in patients with CMC compared to healthy controls. In contrast, patients with HIES and patients with AD showed normal IL-5 and IL-13 production, while IL-9 production was significantly lower in patients with HIES compared to healthy controls. Although TGFβ was involved in the IL-4-induced IL-9 production, TGFβ levels and the frequency of regulatory T cells did not differ between patients with HIES and controls. Flow cytometry analysis demonstrated an IL-9 IL-17 CD4 subset in healthy controls after stimulation with Candida which was less present in patients with HIES.
Patients with CMC have a general Th defect including Th2 and Th9, while patients with HIES have normal Th2 cytokines. These differences are in line with their clinical presentation. Surprisingly, the allergic cytokine IL-9 was deficient in both HIES and CMC, suggesting a Th-17-derived origin.
信号转导和转录激活因子1（STAT1）突变可导致慢性黏膜皮肤念珠菌病（CMC），而信号转导和转录激活因子3（STAT3）突变可导致高免疫球蛋白E综合征（HIES）。CMC和HIES患者存在辅助性T（Th）17缺陷，易患黏膜念珠菌感染，但只有HIES患者表现出伴有湿疹、嗜酸性粒细胞增多和高免疫球蛋白E水平的过敏表型。
我们研究了Th2和Th9反应的差异是否可以解释临床差异。
用念珠菌和金黄色葡萄球菌刺激CMC患者（n = 4）、HIES患者（n = 4）、特应性皮炎患者（n = 4）和健康志愿者（n = 13）的外周血单个核细胞，刺激时添加或不添加白细胞介素-4（IL-4）。分别通过酶联免疫吸附测定（ELISA）或流式细胞术检测细胞培养上清液中的细胞因子IL-5、IL-13、IL-9、IL-17和转化生长因子β（TGFβ）以及调节性T细胞。
CMC患者的外周血单个核细胞显示Th2细胞因子IL-5和IL-13的产生明显受损，尤其是在有IL-4存在的情况下。此外，与健康对照相比，CMC患者的IL-9产生明显较低。相比之下，HIES患者和特应性皮炎患者的IL-5和IL-13产生正常，而与健康对照相比，HIES患者的IL-9产生明显较低。尽管TGFβ参与了IL-4诱导的IL-9产生，但HIES患者和对照之间的TGFβ水平和调节性T细胞频率没有差异。流式细胞术分析显示，念珠菌刺激后，健康对照中存在一个IL-9 IL-17 CD4亚群，而HIES患者中该亚群较少。
CMC患者存在包括Th2和Th9在内的一般性Th缺陷，而HIES患者的Th2细胞因子正常。这些差异与它们的临床表现一致。令人惊讶的是，过敏细胞因子IL-9在HIES和CMC中均缺乏，提示其来源于Th17。
