Schmidt E, Reimer S, Kruse N, Jainta S, Bröcker E B, Marinkovich M P, Giudice G J, Zillikens D
Department of Dermatology, University of Würzburg, Würzburg, Germany.
J Invest Dermatol. 2000 Nov;115(5):842-8. doi: 10.1046/j.1523-1747.2000.00141.x.
Bullous pemphigoid is an inflammatory subepidermal blistering disease that is associated with auto- antibodies to the keratinocyte surface protein, BP180. In addition to the binding of autoantibodies, the infiltration of inflammatory cells is necessary for blister formation. Cytokines, including interleukin-6 and interleukin-8, have been implicated in the disease process of both human and experimental murine bullous pemphigoid. This study was aimed at testing the hypothesis that the binding of anti-BP180 antibodies to their target antigen triggers a signal transduction event that results in the secretion of these pro-inflammatory cytokines. Consistent with this hypothesis, treatment of cultured normal human epidermal keratinocytes with bullous pemphigoid IgG, but not control IgG, led to increased levels of interleukin-6 and interleukin-8, but not interleukin-1alpha, interleukin-1beta, tumor necrosis factor-alpha, interleukin-10, or monocyte chemoattractant protein-1, in the culture medium. This effect was concentration- and time-dependent and was abolished by depleting the bullous pemphigoid IgG of reactivity to two distinct epitopes on the BP180 NC16A domain. Upregulation of interleukin-6 and interleukin-8 was found at both protein and mRNA levels. In addition, bullous pemphigoid IgG did not induce the release of interleukin-6 and interleukin-8 from BP180-deficient keratinocytes obtained from a patient with generalized atrophic benign epidermolysis bullosa. These data indicate that bullous pemphigoid-associated autoantibodies to the human BP180 ectodomain trigger a signal transducing event that leads to expression and secretion of interleukin-6 and interleukin-8 from human keratinocytes.
大疱性类天疱疮是一种炎症性表皮下大疱性疾病，与针对角质形成细胞表面蛋白BP180的自身抗体有关。除自身抗体的结合外，炎症细胞的浸润对于水疱形成也是必需的。细胞因子，包括白细胞介素-6和白细胞介素-8，已被认为参与了人类和实验性小鼠大疱性类天疱疮的疾病过程。本研究旨在检验以下假设：抗BP180抗体与其靶抗原的结合触发信号转导事件，导致这些促炎细胞因子的分泌。与该假设一致，用大疱性类天疱疮IgG而非对照IgG处理培养的正常人表皮角质形成细胞，导致培养基中白细胞介素-6和白细胞介素-8水平升高，但白细胞介素-1α、白细胞介素-1β、肿瘤坏死因子-α、白细胞介素-10或单核细胞趋化蛋白-1水平未升高。这种效应具有浓度和时间依赖性，并且通过去除大疱性类天疱疮IgG对BP180 NC16A结构域上两个不同表位的反应性而被消除。在蛋白质和mRNA水平均发现白细胞介素-6和白细胞介素-8上调。此外，大疱性类天疱疮IgG不会诱导从泛发性萎缩性良性大疱性表皮松解症患者获得的BP180缺陷角质形成细胞释放白细胞介素-6和白细胞介素-8。这些数据表明，针对人BP180胞外结构域的大疱性类天疱疮相关自身抗体触发信号转导事件，导致人角质形成细胞表达和分泌白细胞介素-6和白细胞介素-8。
