Non-pathogenic pemphigus foliaceus (PF) IgG acts synergistically with a directly pathogenic PF IgG to increase blistering by p38MAPK-dependent desmoglein 1 clustering.
Non-pathogenic pemphigus foliaceus (PF) IgG acts synergistically with a directly pathogenic PF IgG to increase blistering by p38MAPK-dependent desmoglein 1 clustering.
复制标题
DOI：
10.1016/j.jdermsci.2016.12.010
复制
发表时间：
2017-03
影响因子：
4.6
通讯作者：
Ishiko A
中科院分区：
文献类型：
--
作者：
Yoshida K;Ishii K;Shimizu A;Yokouchi M;Amagai M;Shiraishi K;Shirakata Y;Stanley JR;Ishiko A
落叶型天疱疮（PF）是由抗桥粒芯糖蛋白1（Dsg1）的自身抗体（Abs）引起的自身免疫性水疱性疾病。PF血清含有多克隆抗体，其是致病性和非致病性抗体的异质混合物，如通过分离单克隆抗体（mAb）所示。为了探讨致病性和非致病性抗Dsg1抗体有助于水疱形成PF。使用器官培养的人皮肤，我们比较了一个单一的致病性抗Dsg1 IgG单克隆抗体，一个单一的非致病性抗Dsg1 IgG单克隆抗体，以及它们的混合物对水疱形成的影响，通过组织学分析，亚细胞定位的IgG存款和桥粒蛋白的共聚焦显微镜，桥粒结构的电子显微镜。此外，我们测量角质形成细胞粘附的体外解离试验。注射后24 h，单个致病性抗Dsg1 IgG引起角膜下水疱，IgG和Dsg1线性定位于角质形成细胞的细胞表面。一个单一的非致病性抗Dsg1 IgG线性结合的角质形成细胞，但不诱导水泡。一起注射的致病性和非致病性IgG mAb导致下表皮中IgG和Dsg1的异常颗粒模式，并在浅表表皮中形成水疱。电子显微镜观察表明，混合物的单克隆抗体缩短桥粒长度超过一个单一的单克隆抗体在基底层和棘层。此外，虽然Dsg1聚类需要通过非致病性IgG加上致病性抗体交联Dsg1分子，但后者可以是单价单链可变片段的形式，这表明Dsg1的反式相互作用的丧失是聚类所需的。最后，p38MAPK抑制剂阻断Dsg1聚集。当通过解离测定测量致病强度时，致病性和非致病性IgG mAb的混合物比单一致病性mAb更能破坏角质形成细胞粘附。p38 MAPK抑制剂仅部分抑制了这种致病作用。这些发现表明，抗Dsg1 IgG抗体的多克隆混合物增强了与p38 MAPK依赖性Dsg1聚类相关的水疱形成的致病活性，并且不仅致病性抗体而且非致病性抗体协同地有助于PF中水疱的形成。
Pemphigus foliaceus (PF) is an autoimmune blistering disease caused by autoantibodies (Abs) against desmoglein 1 (Dsg1). PF sera contain polyclonal Abs which are heterogeneous mixture of both pathogenic and non-pathogenic Abs, as shown by isolation of monoclonal Abs (mAbs). To investigate how pathogenic and non-pathogenic anti-Dsg1 Abs contribute to blister formation in PF. Using organ-cultured human skin, we compared the effect of a single pathogenic anti-Dsg1 IgG mAb, a single non-pathogenic anti-Dsg1 IgG mAb, and their mixture on blister formation as analyzed by histology, subcellular localization of IgG deposits and desmosomal proteins by confocal microscopy, and desmosomal structure by electron microscopy. In addition, we measured keratinocyte adhesion by an in vitro dissociation assay. 24 h after injection, a single pathogenic anti-Dsg1 IgG caused a subcorneal blister with IgG and Dsg1 localized linearly on the cell surface of keratinocytes. A single non-pathogenic anti-Dsg1 IgG bound linearly on the keratinocytes but did not induce blisters. A pathogenic and a non-pathogenic IgG mAb injected together caused an aberrant granular pattern of IgG and Dsg1 in the lower epidermis with blister formation in the superficial epidermis. Electron microscopy demonstrated that the mixture of mAbs shortened desmosomal lengths more than a single mAb in the basal and spinous layers. Furthermore, although Dsg1 clustering required both cross-linking of Dsg1 molecules by the non-pathogenic IgG plus a pathogenic antibody, the latter could be in the form of a monovalent single chain variable fragment, suggesting that loss of trans-interaction of Dsg1 is required for clustering. Finally, a p38MAPK inhibitor blocked Dsg1 clustering. When pathogenic strength was measured by the dissociation assay, a mixture of pathogenic and non-pathogenic IgG mAbs disrupted keratinocyte adhesion more than a single pathogenic mAb. This pathogenic effect was only partially suppressed by the p38MAPK inhibitor. These findings indicate that a polyclonal mixture of anti-Dsg1 IgG antibodies enhances pathogenic activity for blister formation associated with p38MAPK-dependent Dsg1 clustering and that not only pathogenic antibodies but also non-pathogenic antibodies coordinately contribute to blister formation in PF.
登录
查看更多内容
影响因子：
6.5
作者：
Kawasaki, Hiroshi;Tsunoda, Kazuyuki;Amagai, Masayuki
通讯作者：
Amagai, Masayuki
DOI：
10.1016/b978-0-12-394311-8.00005-4
发表时间：
2013
影响因子：
--
作者：
Kowalczyk, Andrew P.;Green, Kathleen J.
通讯作者：
Green, Kathleen J.
影响因子：
4.8
作者：
Rader, C;Popkov, M;Barbas, CF
通讯作者：
Barbas, CF
影响因子：
15.9
作者：
Payne, AS;Ishii, K;Siege, DL
通讯作者：
Siege, DL
影响因子：
13.3
作者：
Waschke, Jens;Spindler, Volker
通讯作者：
Spindler, Volker