Role of Apoptosis in Pemphigus

描述（由申请人提供）：天疱疮是一组危及生命的自身免疫性水疱疾病，其特征是致病性IgG自身抗体抗粘粒蛋白（Dsg）和表皮内细胞-细胞脱离（棘层溶解）。叶状天疱疮（PF）和寻常型天疱疮（PV）是天疱疮的两种经典形式。PF是由Dsg1自身抗体介导的，而PV是由Dsg3自身抗体引起的。天疱疮的发病机制尚不完全清楚。在初步研究中，我们已经证明来自PF和PV患者的致病抗体在被动转移到新生小鼠体内时能够诱导表皮细胞凋亡。

DESCRIPTION (provided by applicant): 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 pemphigusIgG. 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.