Tight junction defects in patients with atopic dermatitis.
Tight junction defects in patients with atopic dermatitis.
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DOI：
10.1016/j.jaci.2010.10.018
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发表时间：
2011-03
影响因子：
14.2
通讯作者：
Beck, Lisa A
中科院分区：
文献类型：
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作者：
De Benedetto, Anna;Rafaels, Nicholas M;McGirt, Laura Y;Ivanov, Andrei I;Georas, Steve N;Cheadle, Chris;Berger, Alan E;Zhang, Kunzhong;Vidyasagar, Sadasivan;Yoshida, Takeshi;Boguniewicz, Mark;Hata, Tissa;Schneider, Lynda C;Hanifin, Jon M;Gallo, Richard L;Novak, Natalija;Weidinger, Stephan;Beaty, Terri H;Leung, Donald Y M;Barnes, Kathleen C;Beck, Lisa A
特应性皮炎（AD）的特征在于皮肤干燥和对过敏原的高反应性免疫应答，这两个主要特征部分地由表皮屏障缺陷引起。紧密连接（TJ）位于角质层下方，调节细胞旁途径的选择性渗透性。我们评估了TJ蛋白、紧密连接蛋白-1在AD和非特应性（NA）受试者上皮中的表达/功能，并筛选了两个美国人群CLDN 1中的SNP。使用Illumina的BeadChips生成来自外源性AD、NA和银屑病受试者的非病变上皮的表达谱。通过组织染色和qPCR验证失调的细胞间蛋白。在尤辛室中测量了上皮细胞的生物电特性。在原代人角质形成细胞（PHK）中使用敲低方法评估密蛋白-1的功能相关性。在两个独立的AD人群中筛选CLDN 1中的27个单倍型标记SNP。我们仅在AD中观察到TJ蛋白claudin-1和claudin-23的表达显著降低，这在mRNA和蛋白质水平上得到了验证。Claudin-1表达与Th 2生物标志物呈负相关。我们观察到AD表皮的生物电屏障功能显著受损。在体外，我们证实了沉默人角质形成细胞中的claudin-1表达减少了TJ功能，同时增强了角质形成细胞增殖。最后，CLDN 1单倍型标记单核苷酸多态性揭示了与两个北美人群中的AD的关联。总之，这些数据表明，受损的表皮TJ是在AD中观察到的皮肤屏障功能障碍和免疫失调的新特征，并且CLDN 1可能是这种疾病的新易感基因。
Atopic dermatitis (AD) is characterized by dry skin and a hyperreactive immune response to allergens, two cardinal features that are caused in part by epidermal barrier defects. Tight junctions (TJ) reside immediately below the stratum corneum and regulate the selective permeability of the paracellular pathway. We evaluated the expression/function of the TJ protein, claudin-1 in epithelium from AD and nonatopic (NA) subjects and screened two American populations for SNPs in CLDN1. Expression profiles of nonlesional epithelium from extrinsic AD, NA and psoriasis subjects were generated using Illumina’s BeadChips. Dysregulated intercellular proteins were validated by tissue staining and qPCR. Bioelectric properties of epithelium were measured in Ussing chambers. Functional relevance of claudin-1 was assessed using a knockdown approach in primary human keratinocytes (PHK). Twenty seven haplotype-tagging SNPs in CLDN1 were screened in two independent AD populations. We observed strikingly reduced expression of the TJ proteins claudin-1 and -23 only in AD, which were validated at the mRNA and protein levels. Claudin-1 expression inversely correlated with Th2 biomarkers. We observed a remarkable impairment of the bioelectric barrier function in AD epidermis. In vitro, we confirmed that silencing claudin-1 expression in human keratinocytes diminishes TJ function while enhancing keratinocyte proliferation. Finally, CLDN1 haplotype-tagging single nucleotide polymorphisms revealed associations with AD in two North American populations. Taken together, these data suggest that an impaired epidermal TJ is a novel feature of skin barrier dysfunction and immune dysregulation observed in AD, and that CLDN1 may be a new susceptibility gene in this disease.