Liu Z, Shipley J M, Vu T H, Zhou X, Diaz L A, Werb Z, Senior R M
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
J Exp Med. 1998 Aug 3;188(3):475-82. doi: 10.1084/jem.188.3.475.
Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease characterized by deposition of autoantibodies at the basement membrane zone. In an experimental BP model in mice, the subepidermal blistering is mediated by antibodies directed against the hemidesmosomal protein BP180 (collagen XVII, BPAG2), and depends on complement activation and neutrophil infiltration. Gelatinase B is present in BP blister fluid and can cleave BP180. In this study we investigated the role of gelatinase B in the immunopathogenesis of experimental BP using mice containing targeted disruption of the gelatinase B (MMP-9, 92 kD gelatinase) gene. Gelatinase B-deficient mice were resistant to the blistering effect of intracutaneous anti-mBP180 antibodies, although these mice showed deposition of autoantibodies at the basement membrane zone and neutrophil recruitment to the skin comparable to that observed in the control mice. Interleukin 8 given intradermally concomitantly with pathogenic anti-mBP180 elicited a significant neutrophil recruitment into the skin in gelatinase B-deficient mice, but blistering did not occur. However, gelatinase B-deficient mice reconstituted with neutrophils from normal mice developed blistering in response to anti-mBP180 antibodies. These results implicate neutrophil-derived gelatinase B in the pathogenesis of experimental BP and might lead to novel therapeutic strategies for BP.
大疱性类天疱疮（BP）是一种自身免疫性表皮下疱病，其特征是自身抗体沉积于基底膜带。在小鼠实验性BP模型中，表皮下疱形成由针对半桥粒蛋白BP180（胶原蛋白XVII，BPAG2）的抗体介导，并依赖补体激活和中性粒细胞浸润。明胶酶B存在于BP疱液中，可裂解BP180。在本研究中，我们使用明胶酶B（MMP-9，92kD明胶酶）基因靶向破坏的小鼠，研究了明胶酶B在实验性BP免疫发病机制中的作用。明胶酶B缺陷小鼠对皮内注射抗mBP180抗体的疱形成效应具有抗性，尽管这些小鼠在基底膜带显示自身抗体沉积，且皮肤中性粒细胞募集与对照小鼠相当。与致病性抗mBP180同时皮内注射白细胞介素8可在明胶酶B缺陷小鼠中引起显著的中性粒细胞募集至皮肤，但未发生疱形成。然而，用正常小鼠的中性粒细胞重建的明胶酶B缺陷小鼠对抗mBP180抗体产生了疱形成反应。这些结果表明中性粒细胞衍生的明胶酶B参与实验性BP的发病机制，并可能为BP带来新的治疗策略。
