Department of Dermatology, University of Iowa, Iowa City, IA 52242, USA.
J Immunol. 2011 Jul 1;187(1):553-60. doi: 10.4049/jimmunol.1001753. Epub 2011 Jun 6.
Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by IgE and IgG class autoantibodies specific for 180-kDa BP Ag 2 (BP180), a protein involved in cell-substrate attachment. Although some direct effects of BP IgG have been observed on keratinocytes, no study to date has examined direct effects of BP IgE. In this study, we use primary cultures of human keratinocytes to demonstrate Ag-specific binding and internalization of BP IgE. Moreover, when BP IgE and BP IgG were compared, both isotypes stimulated FcR- independent production of IL-6 and IL-8, cytokines critical for BP pathology, and elicited changes in culture confluence and viability. We then used a human skin organ culture model to test the direct effects of these Abs on the skin, whereas excluding the immune inflammatory processes that are triggered by these Abs. In these experiments, physiologic concentrations of BP IgE and BP IgG exerted similar effects on human skin by stimulating IL-6 and IL-8 production and decreasing the number of hemidesmosomes localized at the basement membrane zone. We propose that the Ab-mediated loss of hemidesmosomes could weaken attachment of basal keratinocytes to the basement membrane zone of affected skin, thereby contributing to blister formation. In this article, we identify a novel role for IgE class autoantibodies in BP mediated through an interaction with BP180 on the keratinocyte surface. In addition, we provide evidence for an FcR-independent mechanism for both IgE and IgG class autoantibodies that could contribute to BP pathogenesis.
大疱性类天疱疮（BP）是一种表皮下水疱性疾病，其特征是针对 180kDa BP 抗原 2（BP180）的 IgE 和 IgG 类自身抗体，BP180 是一种参与细胞-基底附着的蛋白。尽管已经观察到 BP IgG 对角质形成细胞有一些直接作用，但迄今为止尚无研究检查 BP IgE 的直接作用。在这项研究中，我们使用人角质形成细胞原代培养物证明了 BP IgE 的特异性结合和内化。此外，当比较 BP IgE 和 BP IgG 时，两种同种型都刺激了 FcR 非依赖性产生白细胞介素 6 和白细胞介素 8，这两种细胞因子对于 BP 病理学至关重要，并引起培养物汇合和活力的变化。然后，我们使用人皮肤器官培养模型来测试这些 Abs 对皮肤的直接作用，同时排除了这些 Abs 引发的免疫炎症过程。在这些实验中，BP IgE 和 BP IgG 的生理浓度通过刺激白细胞介素 6 和白细胞介素 8 的产生并减少位于基底膜带的半桥粒数量，对人皮肤产生相似的作用。我们提出，Ab 介导的半桥粒丧失可能会削弱基底角质形成细胞与受影响皮肤的基底膜带的附着，从而导致水疱形成。在本文中，我们确定了 IgE 类自身抗体在 BP 中的一种新作用，这种作用是通过与角质形成细胞表面的 BP180 相互作用介导的。此外，我们为 IgE 和 IgG 类自身抗体提供了证据，证明了一种 FcR 非依赖性机制，这可能有助于 BP 的发病机制。
