Background The etiopathogenesis of vernal keratoconjunctivitis (VKC) is incompletely understood. Bioactive lipids play a key role in allergic disorders. This study focused on the sphingolipid metabolism on the ocular surface of VKC and to explore if it has a contributory role in the refractoriness of the disease. Methods Active VKC cases, (n=87) (classified as mild/moderate and severe/very severe based on the disease symptoms) and age-matched healthy controls (n=60) were recruited as part of a 2-year prospective study at a tertiary eye care centre in South India. Conjunctival imprint cytology was used to assess gene expression of enzymes of sphingolipids metabolism. Sphingolipids were estimated in the tears by LC-MS/MS analysis. In vitro study was done to assess IgE-induced alterations in sphingosine-1-phosphate (S1P) receptor expression and histone modification in cultured mast cells. Results Significantly altered gene expression of the sphingolipids enzymes and S1P receptor (SIP3R) were observed in conjunctival imprint cells of VKC cases. Pooled tears analysis revealed significantly lowered levels of S1P(d17:0), S1P(d20:1) (p<0.001) and S1P(d17:1) (p<0.01) specifically in severe/very severe VKC compared with both mild/moderate VKC and control. Cer(d18:/17:0) (p<0.001), ceramide-1-phosphate (C1P)(d18:1/8:0) (p<0.01) and C1P(d18:1/2.0 (p<0.05) were lowered in severe/very severe VKC compared with mild/moderate VKC. Cultured mast cells treated with IgE revealed significantly increased gene expression of S1P1 and 3 receptors and the protein expression of histone deacetylases (1, 6). Conclusion Altered sphingolipid metabolism in the ocular surface results in low tear ceramide and sphingosine levels in severe/very severe VKC compared with the mild/moderate cases. The novel finding opens up fresh targets for intervention in these refractory cases. All data relevant to the study are included in the article or uploaded as online supplemental information.

中文翻译：

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眼表鞘脂与春季角结膜炎的难治性相关：VKC 发病机制的新见解

背景 春季角膜结膜炎 (VKC) 的发病机制尚不完全清楚。生物活性脂质在过敏性疾病中起着关键作用。本研究重点关注 VKC 眼表的鞘脂代谢，并探讨它是否对疾病的难治性有促进作用。方法 招募活动性 VKC 病例 (n=87)（根据疾病症状分为轻度/中度和重度/极重度）和年龄匹配的健康对照 (n=60) 作为 2 年前瞻性研究的一部分南印度的一家三级眼科保健中心。结膜印迹细胞学用于评估鞘脂代谢酶的基因表达。通过 LC-MS/MS 分析估计眼泪中的鞘脂。进行了体外研究以评估 IgE 诱导的鞘氨醇 1-磷酸 (S1P) 受体表达和培养的肥大细胞中组蛋白修饰的改变。结果 在 VKC 病例的结膜印记细胞中观察到鞘脂酶和 S1P 受体 (SIP3R) 的基因表达显着改变。汇集的眼泪分析显示，与轻度/非常严重的 VKC 相比，S1P(d17:0)、S1P(d20:1) (p<0.001) 和 S1P(d17:1) (p<0.01) 的水平显着降低，特别是在严重/非常严重的 VKC 中适度的 VKC 和控制。Cer(d18:/17:0) (p<0.001)、神经酰胺-1-磷酸 (C1P)(d18:1/8:0) (p<0.01) 和 C1P(d18:1/2.0 (p<0.05)与轻度/中度 VKC 相比，在严重/非常严重的 VKC 中降低。用 IgE 处理的培养肥大细胞显示 S1P1 和 3 受体的基因表达以及组蛋白脱乙酰酶的蛋白质表达显着增加 (1, 6)。结论 与轻度/中度 VKC 相比，眼表鞘脂代谢改变导致重度/极重度 VKC 患者的泪液神经酰胺和鞘氨醇水平较低。这一新发现为干预这些难治性病例开辟了新的目标。与研究相关的所有数据都包含在文章中或作为在线补充信息上传。