Epidermolysis bullosa acquisita develops in dominant dystrophic epidermolysis bullosa
Epidermolysis bullosa acquisita develops in dominant dystrophic epidermolysis bullosa
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获得性大疱性表皮松解症发生于显性营养不良性大疱性表皮松解症
DOI：
10.1038/jid.2015.370
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发表时间：
2016
影响因子：
6.5
通讯作者：
Shimomura Y
中科院分区：
文献类型：
--
作者：
Hayashi R;Natsuga K;Watanabe M;Iwata H;Shinkuma S;Ito A;Masui Y;Ito M;Shimomura Y
营养不良性大疱性表皮松解症(DEB)是一种先天性遗传性水疱性疾病，由编码VII型胶原(COL7)的基因COL7A1突变引起，COL7A1是半桥体锚定纤维的主要结构成分。COL7蛋白由一个中央三螺旋结构域和一个145 kDa的非胶原性氨基末端(Nc1)和一个30 kDa的羧基末端结构域组成(Burgeson，1993)。DEB表现为常染色体显性(DDEB；OMIM#131750)或隐性(RDEB；OMIM#226600)遗传(Fine等人，2014年)。相比之下，大疱性表皮松解症(EBA)是一种慢性、自身免疫性、表皮下水疱性皮肤病，具有循环中的抗COL7抗体(Kim和Kim，2013)。在EBA患者的皮肤中，直接免疫荧光显示Ig G和C3沿真皮-表皮交界处(DEJ)呈线性沉积；此外，与患者血清的间接免疫荧光显示，正常人1M氯化钠剥离皮肤上，Ig G沿DEJ真皮一侧呈线性沉积。在大多数EBA病例中，自身抗体的表位在COL7的NC1域内(Lapiere等人，1993)。有趣的是，抗COL7抗体可在RDEB患者中产生(Pendary等人，2010年；Tampoia等人，2013年；Woodley等人，2014年)，或DEB瘙痒病，这是DDEB的一种等位基因疾病(OMIM#604129)(Jedlickova等人，2012年)。除了这些发现，DEB和EBA是否可以在单个个体中共存在很大程度上是未知的。在这里，我们描述了一例罕见的DDEB并发EBA。我们在新泻大学医院看到了一个患有DDEB的三代日本家庭(图1a)。家庭中所有三个受影响的人在童年早期都出现了手脚上的水泡，而其他皮肤区域和口腔粘膜没有受到影响。皮肤症状随着年龄的增长而改善，并导致疤痕形成和指甲营养不良(图1床)。在获得机构对实验的批准和患者的书面知情同意后，我们进行了直接测序分析，并在所有三个受影响的个体的COL7A1基因中发现了一个重复的杂合错义突变c.7868G>；A(p.Gly2623Asp)(在线补充材料和方法)(图1e)。根据先前报道的DDEB具有相同突变(Varki等人，2007年)或2623位氨基酸的其他错义突变(Christian ano等人，1995；Sawamura等人，2006；Varki等人，2007)，我们预计该家族中受影响的个体有良好的预后。然而，令我们惊讶的是，家庭中年龄最大的患者(I-1；图1a)最终显示出大疱性疱疹和随后在她全身形成的疤痕，包括63岁时的口腔粘膜(图1feh)。左臂皮肤活检显示真皮下大疱性形成，淋巴细胞、嗜酸性粒细胞和中性粒细胞密集渗透(图1I)。虽然血液检测中未发现针对180 kDa大疱性类天疱疮抗原NC16a区的循环自身抗体，但我们推测她可能患有自身免疫性水泡病。为了验证这一假设，我们对患者的皮肤和血清样本进行了一系列分析(补充材料和方法)。该患者皮肤切片的直接免疫荧光显示，免疫球蛋白和补体C3在DEJ处呈线性沉积(图1j；数据未显示)。此外，用1MNaC l的间接免疫荧光将正常人皮肤切片和患者血清清楚地显示出免疫球蛋白在DEJ真皮一侧呈线性沉积(图1k)，表明该抗原被Auto-…识别。
Dystrophic epidermolysis bullosa (DEB) is a congenital inherited blistering disorder caused by mutations in COL7A1, the gene encoding collagen VII (COL7), which is a major structural component of anchoring fibrils of the hemidesmosome. COL7 protein comprises a central triple helical domain flanked by a 145 kDa noncollagenous amino-terminal domain (NC1) and a 30 kDa carboxylterminal domain (Burgeson, 1993). DEB shows either autosomal dominant (DDEB; OMIM# 131750) or recessive (RDEB; OMIM# 226600) inheritance (Fine et al., 2014). In contrast, epidermolysis bullosa acquista (EBA) is a chronic, autoimmune, subepidermal blistering skin disease with circulating IgG antibodies against COL7 (Kim and Kim, 2013). In skin of patients with EBA, linear deposition of IgG and C3 along the dermal-epidermal junction (DEJ) is evident with direct immunofluorescence; additionally, indirect immunofluorescence with patient sera shows linear deposition of IgG along the dermal side of the DEJ on 1 M NaCl split skin of normal control individuals. In most cases of EBA, epitopes of the auto-antibodies are within the NC1 domain of COL7 (Lapiere et al., 1993). Interestingly, anti-COL7 antibodies can be generated in patients with RDEB (Pendaries et al., 2010; Tampoia et al., 2013; Woodley et al., 2014), or DEB pruriginosa, which is an allelic disorder of DDEB (OMIM# 604129)(Jedlickova et al., 2012). Besides these findings, whether DEB and EBA can coexist in a single individual is largely unknown. Here, we describe a rare case of DDEB complicated by EBA. We have seen a three-generation Japanese family with DDEB at Niigata University Hospital (Figure 1 a). All three affected individuals in the family showed blister formations on their hands and feet during early childhood, whereas other skin areas and oral mucosa were unaffected. The skin symptoms improved with aging and resulted in scar formation and dystrophic nails (Figure 1 bed). After obtaining institutional approval of experiments and written informed consent from the patients, we performed direct sequencing analysis and identified a recurrent heterozygous missense mutation c. 7868G> A (p. Gly2623Asp) in the COL7A1 gene of all three affected individuals (Supplementary Materials and Methods online)(Figure 1 e). On the basis of previous reports of DDEB with the identical mutation (Varki et al., 2007) or other missense mutations at the amino acid position 2623 (Christiano et al., 1995; Sawamura et al., 2006; Varki et al., 2007), we expected a good prognosis for the affected individuals in this family. To our surprise, however, the eldest patient in the family (I-1; Figure 1 a) eventually showed bullae and subsequent scar formation all over her body, including oral mucosa at the age of 63 (Figure 1 feh). Skin biopsy from her left arm revealed subepidermal bulla formation with dense infiltration of lymphocytes, eosinophils, and neutrophils (Figure 1 i). Although circulating autoantibodies against the NC16a domain of 180 kDa bullous pemphigoid antigen were not evident in blood test, we postulated that she might suffer from an autoimmune blistering disease. To test this hypothesis, we conducted a series of analyses with samples of this patient’s skin and serum (Supplementary Materials and Methods). Direct immunofluorescence with skin sections from this patient revealed linear deposition of IgG and C3 at the DEJ (Figure 1 j; data not shown). In addition, indirect immunofluorescence with 1 M NaCl split normal human skin sections and the patient’s serum clearly demonstrated linear deposition of IgG at the dermal side of the DEJ (Figure 1 k), suggesting that the antigen recognized by the auto …