Snorradottir Asbjorg Osk, Isaksson Helgi J, Ingthorsson Saevar, Olafsson Elias, Palsdottir Astridur, Bragason Birkir Thor
Institute for Experimental Pathology at Keldur, University of Iceland, Reykjavik, Iceland.
Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
Lab Invest. 2017 Apr;97(4):383-394. doi: 10.1038/labinvest.2016.133. Epub 2017 Jan 9.
Hereditary cystatin C amyloid angiopathy (HCCAA) is a genetic disease caused by a mutation in the cystatin C gene. Cystatin C is abundant in cerebrospinal fluid and the most prominent pathology in HCCAA is cerebral amyloid angiopathy due to mutant cystatin C amyloid deposition with associated cerebral hemorrhages, typically in young adult carriers. Analyses of post-mortem brain samples shows that pathological changes are limited to arteries and regions adjacent to arteries. The severity of pathological changes at post-mortem has precluded the elucidation of the evolution of histological changes. Mutant cystatin C deposition in carriers is systemic and has, for example, been described in the skin, suggesting similar pathological mechanisms both in the brain and outside of the central nervous system. The aim of this study was to use skin biopsies from asymptomatic and symptomatic carriers to study intermediate events in HCCAA pathogenesis. We found that cystatin C deposition in minimally affected samples was limited to the basement membrane (BM) between the dermis and epidermis. When the deposits were more advanced, they extended to other BM regions in the skin. Our results showed that the immunoreactivity of the BM protein COLIV was increased to a similar extent in all carrier biopsies and cystatin C deposits were in close association with COLIV. The density of fibroblasts in the upper dermis of carrier skin was increased, whereas the distribution of other cell types examined did not differ compared with control biopsies. COLIV and cystatin C immunoreactivity in carrier biopsies was closely associated with the fibroblasts. The results of this study, in conjunction with our previous results regarding pathological BM changes in leptomeningeal arteries of patients, suggest that BM changes are early and important events in HCCAA pathogenesis that could facilitate cystatin C deposition and aggregation.
遗传性胱抑素C淀粉样血管病（HCCAA）是一种由胱抑素C基因突变引起的遗传性疾病。胱抑素C在脑脊液中含量丰富，HCCAA最显著的病理特征是由于突变的胱抑素C淀粉样蛋白沉积导致的脑淀粉样血管病，并伴有脑出血，典型发生于年轻的携带者。对死后脑样本的分析表明，病理变化仅限于动脉及其相邻区域。死后病理变化的严重程度阻碍了对组织学变化演变的阐明。携带者体内突变的胱抑素C沉积是全身性的，例如，已在皮肤中被描述，这表明在大脑和中枢神经系统之外存在类似的病理机制。本研究的目的是使用无症状和有症状携带者的皮肤活检样本，来研究HCCAA发病机制中的中间事件。我们发现，在受影响最小的样本中，胱抑素C沉积仅限于真皮和表皮之间的基底膜（BM）。当沉积物更严重时，它们会扩展到皮肤中的其他BM区域。我们的结果表明，在所有携带者的活检样本中，BM蛋白COLIV的免疫反应性均有类似程度的增加，且胱抑素C沉积物与COLIV密切相关。携带者皮肤真皮上层的成纤维细胞密度增加，而与对照活检样本相比，所检测的其他细胞类型的分布没有差异。携带者活检样本中的COLIV和胱抑素C免疫反应性与成纤维细胞密切相关。本研究结果与我们之前关于患者软脑膜动脉病理BM变化的结果相结合，表明BM变化是HCCAA发病机制中的早期重要事件，可能促进胱抑素C的沉积和聚集。
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