Role of Apoptosis in Pemphigus

天疱疮是一组以致病性IgG为特征的危及生命的自身免疫性水疱性疾病 抗桥粒芯糖蛋白的自身抗体（Dsg）和表皮内细胞-细胞脱离（棘层松解）。. 落叶型天疱疮（PF）和寻常型天疱疮（PV）是天疱疮的两种典型类型。虽然PF PV由Dsg 1自身抗体介导，PV由Dsg 3自身抗体引起。的发病机制 天疱疮尚未完全了解。在初步研究中，我们已经表明，来自PF的致病性抗体 PV患者被动转移到新生小鼠后，能够诱导表皮细胞凋亡。 值得注意的是，时间进程研究表明，细胞凋亡的发生早于并伴随着细胞凋亡的发生。 棘层松解症在R 03试验项目中，我们将进一步表征小鼠中细胞凋亡的诱导 模型的PF和PV和测试的假设，细胞凋亡有助于天疱疮的发病机制。 在目的1中，我们将证实三种抗角化蛋白诱导天疱疮小鼠模型中角质形成细胞凋亡。 独立的方法。我们还将验证凋亡的诱导是通过抗Dsgl的作用， 和抗Dsg 3自身抗体。在目标2中，我们将定义天疱疮激活的关键凋亡介质 IgG。将进行时程实验以揭示凋亡调节剂的顺序激活 通过免疫组织化学、免疫印迹和酶测定。在目标3中，我们将测试 阻断细胞凋亡可抑制或减轻天疱疮病变。我们会尽力防止 通过使用细胞凋亡抑制剂和具有已知细胞凋亡缺陷的小鼠进行细胞凋亡。由此得出的数据 这项研究有望为桥粒芯糖蛋白在角质形成细胞存活/凋亡中的作用提供新的见解， 提高我们对天疱疮发病机制的认识。这项研究可能会开辟一条新的途径， 治疗干预这项工作可能会导致一个更全面的R 01项目， 天疱疮的凋亡途径及其致病作用。

Pemphigus is a group of life-threatening autoimmune blistering diseases characterized by pathogenic IgG autoantibodies against desmogleins (Dsg) and intraepidermal cell-cell detachment (acantholysis). . Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are two classical forms of pemphigus. While PF is mediated by autoantibodies to Dsg1, PV is caused by autoantibodies against Dsg3. The pathogenesis of pemphigus is not fully understood. In preliminary studies, we have shown that pathogenic antibodies from PF and PV patients were able to induce epidermal cell apoptosis when passively transferred into neonatal mice. Remarkably, time-course study indicated that the onset of apoptosis preceded and accompanied the onset of acantholysis. In this R03 pilot project, we will further characterize the induction of apoptosis in the mouse models of PF and PV and test the hypothesis that apoptosis contributes to the pathogenesis of pemphigus. In Aim 1, we will confirm the induction of keratinocyte apoptosis in the mouse models of pemphigus by three independent methods. We will also verify that the induction of apoptosis is through the action of anti-Dsgl and anti-Dsg3 autoantibodies. In Aim 2, we will define the key apoptotic mediators activated by pemphigus IgG. Time course experiments will be performed to reveal the sequential activation of apoptotic modulators by means of immunohistochemistry, immunoblotting, and enzymatic assays. In Aim 3, we will test whether blocking apoptosis could inhibit or attenuate pemphigus lesions. We will attempt to prevent induced apoptosis by using apoptosis inhibitors and mice with known apoptotic defects. The data derived from this study is expected to provide new insight into the role of desmogleins in keratinocyte survival/apoptosis and advance our understanding of the pathogenesis of pemphigus. This study may open a novel avenue for therapeutic intervention. The work is likely to lead to a more comprehensive R01 project investigating the apoptotic pathways involved in pemphigus and its pathogenic role in pemphigus.