Muth I E, Barthel K, Bähr M, Dalakas M C, Schmidt J
Department of Neurology and Department of Experimental and Clinical Neuroimmunology, University Medicine Göttingen, Waldweg 33, 37073 Göttingen, Germany.
J Neurol Neurosurg Psychiatry. 2009 Dec;80(12):1344-9. doi: 10.1136/jnnp.2009.174276. Epub 2009 May 25.
In the pathology of sporadic inclusion body myositis (sIBM), the relevance of cell stress molecules such as the heat shock protein alphaB-crystallin, particularly in healthy appearing muscle fibres, has remained elusive.
10 muscle biopsies from sIBM patients were serially stained for haematoxylin-eosin, trichrome and multi-immunohistochemistry for neural cell adhesion molecule (NCAM), alphaB-crystallin, amyloid precursor protein (APP), desmin, major histocompatibility complex I, beta-amyloid and ubiquitin. Corresponding areas of all biopsies were quantitatively analysed for all markers. Primary myotube cultures were exposed to the proinflammatory cytokines interleukin (IL)-1beta and interferon (IFN)-gamma.
In human myotubes exposed to IL-1beta+IFN-gamma, overexpression of APP was accompanied by upregulation of alphaB-crystallin. In sIBM muscle biopsies, over 20% of all fibres displayed accumulation of beta-amyloid or vacuoles/inclusions. A clearly larger fraction of the fibres were positive for alphaB-crystallin or APP. In contrast with the accumulation of beta-amyloid in atrophic fibres, a major part of fibres positive for APP or alphaB-crystallin showed no morphological abnormalities. Expression of APP and alphaB-crystallin significantly correlated with each other and most double positive fibres displayed accumulation of beta-amyloid, vacuoles or an atrophic morphology. In almost all of these fibres, other markers of degeneration/regeneration such as NCAM and desmin were evident as additional indicators of a cell stress response. Some fibres double positive for APP and alphaB-crystallin displayed infiltration by inflammatory cells.
Our results suggest that alphaB-crystallin is associated with overexpression of APP in sIBM muscle and that upregulation of alphaB-crystallin precedes accumulation of beta-amyloid. The data help to better understand early pathological changes and underscore the fact that a network of cell stress, inflammation and degeneration is relevant to sIBM.
在散发性包涵体肌炎（sIBM）的病理学中，细胞应激分子如热休克蛋白αB-晶状体蛋白的相关性，尤其是在看似健康的肌纤维中的相关性，一直难以捉摸。
对10例sIBM患者的肌肉活检标本进行苏木精-伊红、三色染色以及针对神经细胞黏附分子（NCAM）、αB-晶状体蛋白、淀粉样前体蛋白（APP）、结蛋白、主要组织相容性复合体I、β-淀粉样蛋白和泛素的多重免疫组化染色。对所有活检标本的相应区域进行所有标志物的定量分析。将原代肌管培养物暴露于促炎细胞因子白细胞介素（IL）-1β和干扰素（IFN）-γ。
在暴露于IL-1β+IFN-γ的人肌管中，APP的过表达伴随着αB-晶状体蛋白的上调。在sIBM肌肉活检标本中，超过20%的所有纤维显示出β-淀粉样蛋白的积累或空泡/包涵体。明显更大比例的纤维对αB-晶状体蛋白或APP呈阳性。与萎缩纤维中β-淀粉样蛋白的积累相反，APP或αB-晶状体蛋白阳性的大部分纤维没有形态学异常。APP和αB-晶状体蛋白的表达彼此显著相关，大多数双阳性纤维显示出β-淀粉样蛋白的积累、空泡或萎缩形态。在几乎所有这些纤维中，其他变性/再生标志物如NCAM和结蛋白作为细胞应激反应的额外指标也很明显。一些APP和αB-晶状体蛋白双阳性的纤维显示有炎性细胞浸润。
我们的结果表明，αB-晶状体蛋白与sIBM肌肉中APP的过表达相关，并且αB-晶状体蛋白的上调先于β-淀粉样蛋白的积累。这些数据有助于更好地理解早期病理变化，并强调细胞应激、炎症和变性网络与sIBM相关这一事实。
