New mechanism of oral immunity to mucosal candidiasis in hyper-IgE syndrome.
New mechanism of oral immunity to mucosal candidiasis in hyper-IgE syndrome.
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口咽念珠菌病（OPC，鹅口疮）是一种机会性感染所造成的真菌念珠菌白色。对念珠菌免疫的理解最近开始随着真菌模式识别受体如C型凝集素受体的鉴定而展开，该受体在粘膜中触发保护性T辅助细胞（Th）17反应。高IgE综合征（HIES/Job's syndrome）是一种罕见的先天性免疫缺陷，其特征在于信号转导子和转录激活子3的显性负突变，其是Th 17诱导细胞因子白细胞介素（IL）-6和IL-23的下游，因此患有HIES的患者表现出显著的Th 17缺陷。HIES患者发生口腔和粘膜皮肤念珠菌病，支持Th 17细胞在对OPC的免疫中的保护作用。然而，OPC中抗真菌免疫的Th 17依赖性机制仍然不清楚。口腔免疫的一个通常不受重视的方面是唾液，它富含抗菌蛋白（AMP）并发挥直接的抗真菌活性。在这项研究中，我们发现HIES患者的唾液AMP，包括β-防御素2和组胺素显着受损。这与唾液的杀念珠菌活性降低和伴随的念珠菌定植增加密切相关。此外，IL-17在培养的唾液腺细胞中诱导组胺素。这是首次证明HIES与唾液活性缺陷有关，并为这些患者对OPC的严重易感性提供了机制。
Oropharyngeal candidiasis (OPC, thrush) is an opportunistic infection caused by the commensal fungus Candida albicans. An understanding of immunity to Candida has recently begun to unfold with the identification of fungal pattern-recognition receptors such as C-type lectin receptors, which trigger protective T-helper (Th)17 responses in the mucosa. Hyper-IgE syndrome (HIES/Job’s syndrome) is a rare congenital immunodeficiency characterized by dominant-negative mutations in signal transducer and activator of transcription 3, which is downstream of the Th17-inductive cytokines interleukin (IL)-6 and IL-23, and hence patients with HIES exhibit dramatic Th17 deficits. HIES patients develop oral and mucocutaneous candidiasis, supporting a protective role for Th17 cells in immunity to OPC. However, the Th17-dependent mechanisms of antifungal immunity in OPC are still poorly defined. An often unappreciated aspect of oral immunity is saliva, which is rich in antimicrobial proteins (AMPs) and exerts direct antifungal activity. In this study, we show that HIES patients show significant impairment in salivary AMPs, including β-defensin 2 and Histatins. This tightly correlates with reduced candidacidal activity of saliva and concomitantly elevated colonization with Candida. Moreover, IL-17 induces histatins in cultured salivary gland cells. This is the first demonstration that HIES is associated with defective salivary activity, and provides a mechanism for the severe susceptibility of these patients to OPC.
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