儿童哮喘中鼻腔鞘脂降低及17q21变异对特定细胞类型的影响

文献信息

中文摘要

背景： 17q21哮喘风险位点的遗传变异调控GSDMB和ORMDL3，影响炎症通路和鞘脂代谢。尽管rs7216389和rs12936231等17q21变异与免疫细胞和气道平滑肌细胞中ORMDL3表达相关，但其对气道上皮鞘脂的影响仍不清楚。
目的： 确定哮喘或17q21哮喘基因型是否改变儿童上呼吸道鞘脂组成，并明确上皮细胞与免疫细胞的贡献。
方法： 采用质谱法对哮喘和非哮喘儿童的鼻液和血浆中的鞘脂进行定量。对rs7216389 C/C或T/T（风险）纯合的健康成人鼻上皮细胞和PBMC进行分析，检测鞘脂水平及ORMDL3/GSDMB相关基因表达。
结果： 特应性哮喘儿童的鼻腔二氢神经酰胺、神经酰胺和鞘氨醇显著降低，且独立于吸入性糖皮质激素和过敏性鼻炎。哮喘与血浆鞘脂升高相关，但血细胞中鞘脂降低，与鼻腔发现一致。在PBMC中，rs7216389 T等位基因与ORMDL3表达增加和从头鞘脂合成受抑制相关。在鼻上皮细胞中，T等位基因主要增加GSDMB表达，并未改变鞘脂代谢。
结论： 特应性哮喘儿童的鼻黏膜鞘脂降低，从头鞘脂合成产生的鞘脂可能作为疾病的非侵入性生物标志物。17q21风险等位基因可发挥细胞类型特异性效应：ORMDL3介导的鞘脂合成抑制发生在免疫细胞中，而非气道上皮细胞中。全身免疫或炎症细胞驱动的改变可能促成哮喘中气道鞘脂降低。

英文摘要

BACKGROUND: Genetic variations at the 17q21 asthma-risk locus regulate GSDMB and ORMDL3, influencing inflammatory pathways and sphingolipid metabolism. Although 17q21 variants such as rs7216389 and rs12936231 are associated with ORMDL3 expression in immune and airway smooth muscle cells, their effects on airway epithelial sphingolipids remain unclear.
OBJECTIVES: To determine whether asthma or 17q21 asthma genotypes alter sphingolipid composition in the upper respiratory tract in children, and to define contributions of epithelial versus immune cells.
METHODS: Sphingolipids were quantified by mass spectrometry in nasal fluid and plasma from children with and without asthma. Nasal epithelial cells and PBMCs from healthy adults homozygous for rs7216389 C/C or T/T (risk) were analyzed for sphingolipid levels and ORMDL3/GSDMB associated gene expression.
RESULTS: Children with atopic asthma had significantly lower nasal dihydroceramides, ceramides, and sphingosine independent of inhaled corticosteroids and allergic rhinitis. Asthma was associated with increased plasma sphingolipids but decreased sphingolipids in blood cells, mirroring nasal findings. In PBMCs, the rs7216389 T allele was associated with increased ORMDL3 expression and suppressed de-novo sphingolipid synthesis. In nasal epithelial cells, the T allele predominantly increased GSDMB expression and did not alter sphingolipid metabolism.
CONCLUSIONS: Nasal mucosal sphingolipids are reduced in children with atopic asthma and sphingolipids generated by de-novo sphingolipid synthesis may serve as a noninvasive biomarker of disease. 17q21 risk alleles can exert cell-type-specific effects: ORMDL3-mediated suppression of sphingolipid synthesis occurs in immune cells but not in airway epithelial cells. Systemic immune or inflammatory cell-driven alterations may contribute to reduced airway sphingolipids in asthma.