Aberrant Expression and Secretion of Heat Shock Protein 90 in Patients with Bullous Pemphigoid
Aberrant Expression and Secretion of Heat Shock Protein 90 in Patients with Bullous Pemphigoid
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DOI：
10.1371/journal.pone.0070496
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发表时间：
2013-07-30
期刊：
影响因子：
3.7
通讯作者：
Kasperkiewicz, Michael
中科院分区：
文献类型：
--
作者：
Tukaj, Stefan;Kleszczynski, Konrad;Kasperkiewicz, Michael
细胞应激伴侣热休克蛋白90(Hsp90)与炎症反应有关，其抑制作用已在不同的自身免疫性疾病的小鼠模型中被证明是成功的，包括获得性大疱性表皮松解症。在这里，我们研究了大疱性类天疱疮(BP)患者Hsp90的表达水平和分泌反应，BP是最常见的表皮下自身免疫性水泡性皮肤病。与健康对照组相比，Hsp90在BP患者皮肤中高表达，而其血清水平降低，并与抗BP180自身抗原NC16A免疫优势区的抗体水平呈负相关；(Ii)在自身免疫性大疱病合并寻常型天疱疮的对照队列中，未发现循环Hsp90的异常水平，也未发现该蛋白与血清自身抗体的相关性；(Iii)BP患者的外周血单核细胞中Hsp90高表达并限制性释放。BP血清和分离的抗BP180 NC16A自身抗体分别能有效地诱导人角质形成细胞(HaCaT)分泌Hsp90，并能抑制HaCaT细胞分泌Hsp90。我们的结果显示，在BP患者中，炎症部位Hsp90的表达上调，并且自身抗体介导的这种伴侣蛋白在细胞内和细胞外分布的失调。这些发现表明，Hsp90可能起到病理生理作用，是治疗BP的一个新的潜在靶点。
The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses and its inhibition has proven successful in different mouse models of autoimmune diseases, including epidermolysis bullosa acquisita. Here, we investigated expression levels and secretory responses of Hsp90 in patients with bullous pemphigoid (BP), the most common subepidermal autoimmune blistering skin disease. In comparison to healthy controls, the following observations were made: (i) Hsp90 was highly expressed in the skin of BP patients, whereas its serum levels were decreased and inversely associated with IgG autoantibody levels against the NC16A immunodominant region of the BP180 autoantigen, (ii) in contrast, neither aberrant levels of circulating Hsp90 nor any correlation of this protein with serum autoantibodies was found in a control cohort of autoimmune bullous disease patients with pemphigus vulgaris, (iii) Hsp90 was highly expressed in and restrictedly released from peripheral blood mononuclear cells of BP patients, and (iv) Hsp90 was potently induced in and restrictedly secreted from human keratinocyte (HaCaT) cells by BP serum and isolated anti-BP180 NC16A IgG autoantibodies, respectively. Our results reveal an upregulated Hsp90 expression at the site of inflammation and an autoantibody-mediated dysregulation of the intracellular and extracellular distribution of this chaperone in BP patients. These findings suggest that Hsp90 may play a pathophysiological role and represent a novel potential treatment target in BP.