Giudice G J, Liu Z, Diaz L A
Department of Dermatology, Medical College of Wisconsin, Milwaukee 53226, USA.
Proc Assoc Am Physicians. 1995 Jul;107(2):237-41.
BP is an organ-specific autoimmune disease characterized by blistering of the skin due to a detachment of the epidermis from the underlying connective tissue layer and by the production of autoantibodies directed against the cutaneous basement membrane zone. A 180-kD epidermal protein, BP180, has been identified as one of the major antigenic targets of these autoantibodies and, interestingly, has been localized to the epidermal hemidesmosome, a cellular structure involved in anchoring basal epithelial cells to the basement membrane. An immunodominant and potentially pathogenic epitope associated with BP has recently been mapped by our laboratory to a site on the extracellular domain of the human BP180 antigen. This antigenic site, designated the MCW-1 epitope, has been shown to be recognized by the majority of sera from patients with either BP or HG, a pregnancy-associated subepidermal bullous disease. Unfortunately, the MCW-1 epitope is absent from the murine BP180 molecule; therefore, human autoantibodies directed against this site could not be tested directly for pathogenicity using the conventional passive transfer mouse model. As an alternative approach, rabbit antibodies were prepared against the segment of murine BP180 that is homologous with the MCW-1 epitope region and were tested for pathogenicity by passive transfer experiments. Remarkably, neonatal mice injected with these antibodies developed a subepidermal blistering disease that faithfully reproduced all of the key immunopathological features of BP and HG--deposition of lgG and complement at the dermal-epidermal junction, inflammatory infiltration of the upper dermis, and frank, subepidermal blistering. These results strongly suggest that the autoimmune response against the human BP180 MCW-1 epitope is relevant in the pathogenesis of blister formation in BP and HG patients. This animal model is currently being used to further dissect the pathophysiology of these autoimmune disorders.
大疱性类天疱疮（BP）是一种器官特异性自身免疫性疾病，其特征是由于表皮与下方结缔组织层分离导致皮肤出现水疱，以及产生针对皮肤基底膜带的自身抗体。一种180-kD的表皮蛋白BP180已被确定为这些自身抗体的主要抗原靶点之一，有趣的是，它定位于表皮半桥粒，这是一种将基底上皮细胞锚定到基底膜的细胞结构。我们实验室最近已将与BP相关的一个免疫显性且可能致病的表位定位到人BP180抗原细胞外结构域的一个位点。这个抗原位点被命名为MCW-1表位，已证明它能被BP或妊娠相关的表皮下大疱性疾病妊娠疱疹（HG）患者的大多数血清识别。不幸的是，小鼠BP180分子中不存在MCW-1表位；因此，不能使用传统的被动转移小鼠模型直接测试针对该位点的人自身抗体的致病性。作为一种替代方法，制备了针对与MCW-1表位区域同源的小鼠BP180片段的兔抗体，并通过被动转移实验测试其致病性。值得注意的是，注射这些抗体的新生小鼠发生了一种表皮下大疱性疾病，忠实地再现了BP和HG的所有关键免疫病理特征——在真皮-表皮交界处有IgG和补体沉积、真皮上层有炎症浸润以及明显的表皮下水疱形成。这些结果强烈表明，针对人BP180 MCW-1表位的自身免疫反应与BP和HG患者水疱形成的发病机制相关。目前正在使用这个动物模型进一步剖析这些自身免疫性疾病的病理生理学。
