Department of Paediatric Otolaryngology, Royal Manchester Children's Hospital, Manchester, United Kingdom.
Stem Cell and Neurotherapies, Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
PLoS One. 2018 Sep 18;13(9):e0203216. doi: 10.1371/journal.pone.0203216. eCollection 2018.
Mucopolysaccharide diseases are a group of lysosomal storage disorders caused by deficiencies of hydrolase enzymes, leading to pathological glycosaminoglycan accumulation. A number of mucopolysaccharidosis (MPS) types are characterised by severe airway disease, the aetiology of which is poorly understood. There is ongoing evidence of significant clinical disease in the long-term despite disease modifying therapeutic strategies, including enzyme-replacement therapy (ERT). To provide a better understanding of this aspect of disease, we have characterised extracellular matrix (ECM) and inflammatory alterations in adenotonsillar tissue samples from 8 MPS patients.
Adenotonsillar samples from MPS I, IVA and VI ERT treated patients and from a single enzyme naïve MPS IIIA individual were compared to non-affected control samples using quantitative immunohistochemistry, qPCR and biochemical analysis.
Significantly increased lysosomal compartment size and total sulphated glycosaminoglycan (p = 0.0007, 0.02) were identified in patient samples despite ERT. Heparan sulphate glycosaminoglycan was significantly elevated in MPS I and IIIA (p = 0.002), confirming incomplete reversal of disease. Collagen IV and laminin α-5 (p = 0.002, 0.0004) staining demonstrated increased ECM deposition within the reticular and capillary network of MPS samples. No significant change in the expression of the pro-inflammatory cytokines IL-1α, IL-6 or TNF-α was seen compared to control.
This study suggests a role for ECM remodelling contributing to the obstructive phenotype of airway disease in MPS. Current therapeutic strategies with ERT fail to normalise these pathological alterations within adenotonsillar samples. Our findings lend novel insight into the pathological cascade of events, with primarily structural rather than inflammatory changes contributing to the continuing phenotype seen in patients despite current therapeutic regimes.
黏多糖贮积症是一组由水解酶缺乏引起的溶酶体贮积症，导致病理性糖胺聚糖积累。许多黏多糖贮积症（MPS）类型的特征是严重的气道疾病，其病因尚不清楚。尽管有疾病修饰治疗策略，包括酶替代疗法（ERT），但仍有持续的证据表明长期存在显著的临床疾病。为了更好地了解疾病的这一方面，我们对 8 名 MPS 患者的腺样体组织样本中的细胞外基质（ECM）和炎症改变进行了特征描述。
使用定量免疫组织化学、qPCR 和生化分析，比较 MPS I、IVA 和 VI ERT 治疗患者以及单个未经酶治疗的 MPS IIIA 个体的腺样体样本与非受累对照样本。
尽管进行了 ERT，但在患者样本中仍发现溶酶体腔大小和总硫酸化糖胺聚糖显著增加（p = 0.0007，0.02）。MPS I 和 IIIA 中的肝素硫酸糖胺聚糖显著升高（p = 0.002），证实疾病未完全逆转。IV 型胶原和层粘连蛋白α-5（p = 0.002，0.0004）染色显示 MPS 样本中的 ECM 沉积在网状和毛细血管网络内增加。与对照相比，促炎细胞因子 IL-1α、IL-6 或 TNF-α 的表达没有明显变化。
本研究表明 ECM 重塑在 MPS 气道疾病的阻塞表型中起作用。ERT 目前的治疗策略未能使腺样体样本中的这些病理改变正常化。我们的发现为病理级联事件提供了新的见解，主要是结构改变而不是炎症改变导致尽管目前的治疗方案，但患者仍持续出现表型。
