Olivry T, Mirsky M L, Singleton W, Dunston S M, Borrillo A K, Xu L, Traczyk T, Rosolia D L, Chan L S
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA.
Arch Dermatol Res. 2000 Jan;292(1):37-45. doi: 10.1007/pl00007459.
Bullous pemphigoid (BP) is an IgG-mediated autoimmune blistering disease targeting the hemidesmosomal proteins bullous pemphigoid antigens 1 and 2. Currently, there is no active animal model in which to dissect the immunopathogenic mechanism. We noticed that cutaneous blistering arose spontaneously in 12 adult Yucatan minipigs. Skin lesions consisted of turgid, isolated or clustered vesicles that occasionally evolved from erythematous and pruritic patches. Histopathological examination revealed subepidermal vesicles rich in intact and degranulated eosinophils. Antigen mapping and transmission electron microscopy confirmed that dermoepidermal separation took place in the lamina lucida of the epidermal basement membrane zone. Direct immunofluorescence revealed the presence of IgG deposited linearly at the dermoepidermal junction in seven of nine skin specimens examined. Indirect immunofluorescence testing confirmed the presence, in the serum from eight of eight affected pigs, of circulating basement membrane-specific IgG autoantibodies (titers 1 : 50 to 1 : 250). Using uncleaved and salt-split lip substrates, the autoantibodies were shown to target antigens situated not only at the basal, but also at the lateral and apical aspects of stratum basale keratinocytes. Immunoelectron microscopy confirmed that circulating IgG autoantibodies recognized hemidesmosomal antigen(s). ELISA, immunoblotting and immunoadsorption demonstrated that five of eight serum samples exhibited high immunoreactivity against BPAG2-NC16A peptides. This novel porcine acquired blistering dermatosis could be proposed as a valuable model to conduct immunomechanistic studies on the natural progression of BP, correlation of autoreactive T cells or autoantibodies with disease activity, and the role of eosinophils in the blistering process, as these diseases cannot be modeled easily in human patients or in murine passive transfer models.
大疱性类天疱疮（BP）是一种由IgG介导的自身免疫性水疱病，其靶抗原为半桥粒蛋白大疱性类天疱疮抗原1和2。目前，尚无用于剖析免疫致病机制的活性动物模型。我们注意到12只成年尤卡坦小型猪自发出现皮肤水疱。皮肤病变表现为肿胀、孤立或成簇的水疱，偶尔由红斑和瘙痒性斑块演变而来。组织病理学检查显示表皮下水疱富含完整和脱颗粒的嗜酸性粒细胞。抗原定位和透射电子显微镜证实真皮表皮分离发生在表皮基底膜带的透明层。直接免疫荧光显示，在所检查的9个皮肤标本中有7个在真皮表皮交界处有线性沉积的IgG。间接免疫荧光检测证实，8只患病猪的血清中均存在循环的基底膜特异性IgG自身抗体（滴度为1:50至1:250）。使用未切割和盐裂的脂质底物，显示自身抗体不仅靶向位于基底细胞角质形成细胞基底方面的抗原，还靶向其侧面和顶端方面的抗原。免疫电子显微镜证实循环IgG自身抗体识别半桥粒抗原。ELISA、免疫印迹和免疫吸附表明，8份血清样本中有5份对BPAG2-NC16A肽表现出高免疫反应性。这种新型猪获得性水疱性皮肤病可作为一种有价值的模型，用于开展关于BP自然病程、自身反应性T细胞或自身抗体与疾病活动的相关性以及嗜酸性粒细胞在水疱形成过程中的作用的免疫机制研究，因为这些疾病在人类患者或小鼠被动转移模型中不易建模。
