Autoimmune and infectious skin diseases that target desmogleins.
Autoimmune and infectious skin diseases that target desmogleins.
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DOI：
10.2183/pjab.86.524
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Amagai M
中科院分区：
文献类型：
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作者：
Amagai M
桥粒是上皮细胞的细胞间黏附连接，包含两种主要的跨膜成分，桥粒蛋白（Dsg）和桥粒蛋白（Dsc），它们是钙粘蛋白型细胞-细胞黏附分子，通过与血小板红蛋白和桥粒蛋白的相互作用固定在角蛋白的中间丝上。桥粒在维持表皮和粘膜上皮的正常结构和屏障功能方面起着重要作用。迄今为止已鉴定出四种Dsg亚型Dsg1-Dsg4，它们与几种皮肤和心脏疾病有关。Dsg1和Dsg3是皮肤和粘膜中两种主要的Dsg亚型，在天疱疮（一种皮肤和粘膜自身免疫性疾病）中被IgG自身抗体靶向。在感染性皮肤疾病大疱性脓疱病和葡萄球菌烫伤性皮肤综合征（SSSS）中，金黄色葡萄球菌释放的剥脱毒素（ET）也是Dsg1的靶点。ET是一种独特的丝氨酸蛋白酶，对Dsg1具有锁定和关键特异性。Dsg2在所有具有桥粒的组织中表达，包括简单上皮和心肌，该基因的突变是致心律失常性右室心肌病/发育不良的原因。Dsg4主要在毛囊中起着重要的粘附作用，Dsg4突变导致毛发发育异常。最近，通过一种独特的方法，使用自身抗原缺陷小鼠产生了天疱疮的活动性疾病模型，这些小鼠不能获得对缺陷自身抗原的耐受性。将Dsg3−/−淋巴细胞过继转移到表达Dsg3的小鼠体内，随着天疱疮表型的发展，可诱导产生稳定的抗Dsg3 IgG。该小鼠模型是研究天疱疮中有害IgG自身抗体产生的免疫学机制的有价值的工具。对桥蛋白分子的进一步研究将继续为尚未解决的疾病病理生理机制提供见解，并有助于开发副作用最小的新型治疗策略。
Desmosomes are intercellular adhesive junctions of epithelial cells that contain two major transmembrane components, the desmogleins (Dsg) and desmocollins (Dsc), which are cadherin-type cell–cell adhesion molecules and are anchored to intermediate filaments of keratin through interactions with plakoglobin and desmoplakin. Desmosomes play an important role in maintaining the proper structure and barrier function of the epidermis and mucous epithelia. Four Dsg isoforms have been identified to date, Dsg1–Dsg4, and are involved in several skin and heart diseases. Dsg1 and Dsg3 are the two major Dsg isoforms in the skin and mucous membranes, and are targeted by IgG autoantibodies in pemphigus, an autoimmune disease of the skin and mucous membranes. Dsg1 is also targeted by exfoliative toxin (ET) released by Staphylococcus aureus in the infectious skin diseases bullous impetigo and staphylococcal scalded skin syndrome (SSSS). ET is a unique serine protease that shows lock and key specificity to Dsg1. Dsg2 is expressed in all tissues possessing desmosomes, including simple epithelia and myocardia, and mutations in this gene are responsible for arrhythmogenic right ventricular cardiomyopathy/dysplasia. Dsg4 plays an important adhesive role mainly in hair follicles, and Dsg4 mutations cause abnormal hair development. Recently, an active disease model for pemphigus was generated by a unique approach using autoantigen-deficient mice that do not acquire tolerance against the defective autoantigen. Adoptive transfer of Dsg3−/− lymphocytes into mice expressing Dsg3 induces stable anti-Dsg3 IgG production with development of the pemphigus phenotype. This mouse model is a valuable tool with which to investigate immunological mechanisms of harmful IgG autoantibody production in pemphigus. Further investigation of desmoglein molecules will continue to provide insight into the unsolved pathophysiological mechanisms of diseases and aid in the development of novel therapeutic strategies with minimal side effects.