Vu T N, Lee T X, Ndoye A, Shultz L D, Pittelkow M R, Dahl M V, Lynch P J, Grando S A
Department of Dermatology, University of California-Davis Medical Center, Sacramento, USA.
Arch Dermatol. 1998 Aug;134(8):971-80. doi: 10.1001/archderm.134.8.971.
To determine whether nondesmoglein (non-Dsg) autoantibodies are pathogenic and whether they recognize keratinocyte cholinergic receptors that control cell adhesion because antikeratinocyte autoimmunity in patients with pemphigus vulgaris is not limited to the development of autoantibodies to Dsg.
To determine whether non-DSg autoantibodies are pathogenic, we sought to induce pemphigus in genetically engineered neonatal mice lacking Dsg 3 using pemphigus vulgaris IgGs that did not cross-react with Dsg 1. To determine whether pemphigus autoimmunity involves keratinocyte cholinergic receptors, the latter were separated from cell membranes of human keratinocytes, tagged with the covalent label [3H]propylbenzilylcholine mustard, and used as an antigen in a radioimmunoprecipitation assay of 34 pemphigus vulgaris and 6 pemphigus foliaceus serum samples.
The dermatologic clinics of the University of Minnesota, Minneapolis; the Mayo Clinic, Rochester, Minn; and the University of California-Davis Medical Center, Sacramento.
Serum samples were collected from 34 patients with pemphigus vulgaris and 6 patients with pemphigus foliaceus (aged 31-89 years) and from 7 age-similar patients of both sexes with nonpemphigus blistering or the following immune-mediated conditions: pemphigoid gestation, bullous drug eruption, lupus erythematosus, erythema nodosum, urticaria, acute contact dermatitis, and skin ulcers.
Clinical, laboratory, and histopathologic findings.
Extensive skin blistering accompanied by the Nikolsky sign and suprabasilar acantholysis was induced in the Dsg3null mice that received pemphigus, but not normal human IgGs. In the radioimmunoprecipitation assays for reactivity with cholinergic receptors, the mean radioactivity precipitated by pemphigus serum samples significantly exceeded both normal- and disease-control levels (P = .001-.02). The mean individual levels of radioactivity precipitated by 34 pemphigus vulgaris and pemphigus foliaceus serum samples (85%) exceeded control values by a mean of approximately 2.6 times.
Autoantibodies to keratinocyte cell-surface molecules other than Dsg 1 and Dsg 3 can induce clinical features of pemphigus vulgaris. Patients with pemphigus vulgaris and those with pemphigus foliaceus develop IgG antibodies that precipitate radiolabeled cholinergic receptors. Because these receptors control keratinocyte adhesion and motility, their inactivation by autoantibodies may elicit intracellular signals that cause disassembly of desmosomes, leading to acantholysis and blistering.
寻常型天疱疮患者的抗角质形成细胞自身免疫并不局限于产生针对桥粒芯糖蛋白（Dsg）的自身抗体，本研究旨在确定非桥粒芯糖蛋白（non-Dsg）自身抗体是否具有致病性，以及它们是否识别控制细胞黏附的角质形成细胞胆碱能受体。
为了确定非Dsg自身抗体是否具有致病性，我们试图用与Dsg 1无交叉反应的寻常型天疱疮免疫球蛋白G（IgG），在缺乏Dsg 3的基因工程新生小鼠中诱发天疱疮。为了确定天疱疮自身免疫是否涉及角质形成细胞胆碱能受体，将后者从人角质形成细胞的细胞膜中分离出来，用共价标记物[3H]丙基苯甲酰胆碱芥子气进行标记，并用作34份寻常型天疱疮和6份落叶型天疱疮血清样本的放射免疫沉淀试验中的抗原。
明尼阿波利斯市明尼苏达大学皮肤科诊所；明尼苏达州罗切斯特市梅奥诊所；加利福尼亚大学戴维斯分校医学中心，萨克拉门托市。
收集了34例寻常型天疱疮患者和6例落叶型天疱疮患者（年龄31 - 89岁）以及7例年龄相仿的非天疱疮性水疱或以下免疫介导疾病患者（包括妊娠类天疱疮、大疱性药疹、红斑狼疮、结节性红斑、荨麻疹、急性接触性皮炎和皮肤溃疡）的血清样本。
临床、实验室和组织病理学检查结果。
接受天疱疮免疫球蛋白G的Dsg3基因敲除小鼠出现广泛皮肤水疱，伴有尼氏征和基底上层棘层松解，但接受正常人IgG的小鼠未出现。在与胆碱能受体反应性的放射免疫沉淀试验中，天疱疮血清样本沉淀的平均放射性显著超过正常对照和疾病对照水平（P = 0.001 - 0.02）。34份寻常型天疱疮和落叶型天疱疮血清样本沉淀的平均个体放射性水平（85%）超过对照值，平均约为2.6倍。
除Dsg 1和Dsg 3之外，针对角质形成细胞表面分子的自身抗体可诱发寻常型天疱疮的临床特征。寻常型天疱疮和落叶型天疱疮患者会产生沉淀放射性标记胆碱能受体的IgG抗体。由于这些受体控制角质形成细胞的黏附和运动，自身抗体使其失活可能引发细胞内信号，导致桥粒解体，进而引起棘层松解和水疱形成。
