Lind Sara M, Kuylenstierna Carlotta, Moll Markus, D Jordö Emilie, Winqvist Ola, Lundeberg Lena, Karlsson Maria A, T Linder Maria, Johansson Catharina, Scheynius Annika, Sandberg Johan K, Karlsson Mikael C I
Clinical Allergy Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
Eur J Immunol. 2009 Aug;39(8):2293-301. doi: 10.1002/eji.200839195.
Atopic eczema (AE) is a chronic relapsing inflammatory skin disease where the commensal yeast Malassezia can act as a microbial trigger factor. Malassezia activates human DC to produce IL-18, an innate cytokine that is elevated in serum of AE patients; however, the precise role of IL-18 in human AE etiology is unknown. Herein, we investigated the effect of IL-18 on the human invariant NKT (iNKT) cell compartment in AE. We found that IL-18 was a potent activator of human iNKT-cells and promoted a pro-inflammatory CD1d-dependent response, even in the absence of exogenous ligands. Chronic activation via IL-18 on the other hand was inhibitory and skewed the iNKT-cell pool by selectively suppressing CD4(+) iNKT-cells. This was mimicked in AE patients where the proportion of CD4(+) iNKT-cells was reduced in peripheral blood and coincided with elevated plasma levels of IL-18. Furthermore, a reduced CD4(+) iNKT-cell pool was associated with elevated IgE levels in plasma, and the plasma levels of IL-18 correlated with both total IgE and disease severity in the AE patients. Based on these findings, we propose that IL-18-mediated activation and subsequent dysregulation of the CD1d-restricted iNKT-cells plays a role in the pathogenesis of human AE.
特应性皮炎（AE）是一种慢性复发性炎症性皮肤病，共生酵母马拉色菌可作为微生物触发因素。马拉色菌激活人类树突状细胞（DC）产生白细胞介素-18（IL-18），这是一种先天性细胞因子，在AE患者血清中升高；然而，IL-18在人类AE病因学中的具体作用尚不清楚。在此，我们研究了IL-18对AE患者中人类不变自然杀伤T细胞（iNKT）亚群的影响。我们发现，IL-18是人类iNKT细胞的有效激活剂，即使在没有外源性配体的情况下，也能促进促炎性CD1d依赖性反应。另一方面，通过IL-18的慢性激活具有抑制作用，并通过选择性抑制CD4(+) iNKT细胞使iNKT细胞库发生偏移。这在AE患者中也有体现，其外周血中CD4(+) iNKT细胞比例降低，同时血浆IL-18水平升高。此外，CD4(+) iNKT细胞库减少与血浆中IgE水平升高相关，并且AE患者血浆中IL-18水平与总IgE及疾病严重程度均相关。基于这些发现，我们提出IL-18介导的激活以及随后CD1d限制性iNKT细胞的失调在人类AE发病机制中起作用。
