Synergy among non-desmoglein antibodies contributes to the immunopathology of desmoglein antibody-negative pemphigus vulgaris
Synergy among non-desmoglein antibodies contributes to the immunopathology of desmoglein antibody-negative pemphigus vulgaris
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DOI：
10.1074/jbc.ra118.006743
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发表时间：
2019-03-22
影响因子：
4.8
通讯作者：
Grando, Sergei A.
中科院分区：
文献类型：
--
作者：
Chernyavsky, Alex;Amber, Kyle T.;Grando, Sergei A.
寻常天疱疮（PV）是一种潜在致命的皮肤粘膜水疱性疾病，其特征在于IgG自身抗体（AuAb）结合表皮角质形成细胞并诱导这种毁灭性疾病。在这里，我们观察到，非桥粒芯糖蛋白（Dsg）AuAb在Dsg 1/3 AuAb阴性的急性PV患者的血清中是致病的，因为这些人的IgG诱导新生小鼠皮肤起泡引起的基底上棘层松解症。血清抗桥粒胶蛋白3（Dsc 3）、M3毒蕈碱乙酰胆碱受体（M3 AR）和分泌途径Ca 2 +/Mn 2 +-ATP酶亚型1（SPCA 1）的AuAb水平与PV的疾病分期相关。此外，AuAb对重组Dsc 3、M3 AR或SPCA 1的吸收均防止了BALB/c小鼠PV的AuAb模型被动转移中的皮肤起泡，并显著降低了新生小鼠皮肤外植体模型中棘层松解的程度。虽然这些免疫亲和纯化的AuAb中的每一种的棘层溶解活性不能诱导PV样表型，但它们的混合物产生了协同效应，表现为新生小鼠皮肤中的阳性Nikolskiy征。所有致病性非Dsg AuAb的下游信号传导涉及p38丝裂原活化蛋白激酶（MAPK）介导的磷酸化和细胞色素c释放和caspase 9活性的升高。抗Dsc 3和抗SPCA 1的AuAb也激活SRC原癌基因、非受体酪氨酸激酶（SRC）。值得注意的是，尽管一系列非Dsg AuAb明显破坏了表皮完整性，但消除单个致病性AuAb可以防止角质形成细胞脱离和起泡。因此，无抗Dsg 1/3 AuAb的PV可以作为阐明非Dsg抗原特异性AuAb在角质形成细胞-细胞粘附和水疱发育的生理调节中的作用的模型。
Pemphigus vulgaris (PV) is a potentially lethal mucocutaneous blistering disease characterized by IgG autoantibodies (AuAbs) binding to epidermal keratinocytes and inducing this devastating disease. Here, we observed that non-desmoglein (Dsg) AuAbs in the sera of patients with Dsg1/3 AuAb-negative acute PV are pathogenic, because IgGs from these individuals induced skin blistering in neonatal mice caused by suprabasal acantholysis. Serum levels of AuAbs to desmocollin 3 (Dsc3), M3 muscarinic acetylcholine receptor (M3AR), and secretory pathway Ca2+/Mn2+-ATPase isoform 1 (SPCA1) correlated with the disease stage of PV. Moreover, AuAb absorption on recombinant Dsc3, M3AR, or SPCA1 both prevented skin blistering in the passive transfer of AuAbs model of PV in BALB/c mice and significantly decreased the extent of acantholysis in a neonatal mouse skin explant model. Although acantholytic activities of each of these immunoaffinity-purified AuAbs could not induce a PV-like phenotype, their mixture produced a synergistic effect manifested by a positive Nikolskiy sign in the skin of neonatal mice. The downstream signaling of all pathogenic non-Dsg AuAbs involved p38 mitogen-activated protein kinase (MAPK)-mediated phosphorylation and elevation of cytochrome c release and caspase 9 activity. Anti-Dsc3 and anti-SPCA1 AuAbs also activated SRC proto-oncogene, nonreceptor tyrosine kinase (SRC). Of note, although a constellation of non-Dsg AuAbs apparently disrupted epidermal integrity, elimination of a single pathogenic AuAb could prevent keratinocyte detachment and blistering. Therefore, anti-Dsg1/3 AuAb-free PV can be a model for elucidating the roles of non-Dsg antigen-specific AuAbs in the physiological regulation of keratinocyte cell-cell adhesion and blister development.