Induction of T regulatory cells by the superagonistic anti‐CD28 antibody D665 leads to decreased pathogenic IgG autoantibodies against desmoglein 3 in a HLA‐transgenic mouse model of pemphigus vulgaris
Induction of T regulatory cells by the superagonistic anti‐CD28 antibody D665 leads to decreased pathogenic IgG autoantibodies against desmoglein 3 in a HLA‐transgenic mouse model of pemphigus vulgaris
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DOI：
10.1111/exd.12919
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发表时间：
2016-04
影响因子：
3.6
通讯作者：
T. Schmidt;S. Willenborg;T. Hünig;C. Deeg;G. Sønderstrup;M. Hertl;R. Eming
中科院分区：
文献类型：
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作者：
T. Schmidt;S. Willenborg;T. Hünig;C. Deeg;G. Sønderstrup;M. Hertl;R. Eming
寻常型天疱疮（Pemphigus vulgaris， PV）是一种潜在危及生命的皮肤和粘膜自身免疫性疾病。其发病机制是基于IgG自身抗体，该抗体靶向桥粒钙粘蛋白、桥粒蛋白3 （Dsg3）和桥粒蛋白1 (Dsg1)，并诱导表皮内粘附丧失。尽管PV的发病机制已经被很好地理解，但治疗选择仍然局限于免疫抑制药物，特别是与显著副作用相关的皮质类固醇。Dsg3反应性T调节细胞（Treg）先前在PV和健康的PV相关HLA II类等位基因携带者中被发现。在体外，Dsg3特异性Treg细胞下调致病性Dsg3特异性T - helper (Th) 2细胞的激活。在本研究中，在HLA - DRB1*04:02转基因PV小鼠模型中，分别使用Treg -耗尽或扩增单克隆抗体调节外周Treg细胞。我们的研究结果表明，在体内，尽管没有统计学意义，Treg细胞对Dsg3驱动的T细胞反应有明显的下调作用，因此，Dsg3特异性IgG抗体的形成。这些观察结果证实了Treg细胞强大的免疫调节功能，并确定Treg细胞是PV的潜在治疗调节剂。
Pemphigus vulgaris (PV) is a potentially life‐threatening autoimmune disease of the skin and mucous membranes. Its pathogenesis is based on IgG autoantibodies that target the desmosomal cadherins, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1) and induce intra‐epidermal loss of adhesion. Although the PV pathogenesis is well‐understood, therapeutic options are still limited to immunosuppressive drugs, particularly corticosteroids, which are associated with significant side effects. Dsg3‐reactive T regulatory cells (Treg) have been previously identified in PV and healthy carriers of PV‐associated HLA class II alleles. Ex vivo, Dsg3‐specific Treg cells down‐regulated the activation of pathogenic Dsg3‐specific T‐helper (Th) 2 cells. In this study, in a HLA‐DRB1*04:02 transgenic mouse model of PV, peripheral Treg cells were modulated by the use of Treg‐depleting or expanding monoclonal antibodies, respectively. Our findings show that, in vivo, although not statistically significant, Treg cells exert a clear down‐regulatory effect on the Dsg3‐driven T‐cell response and, accordingly, the formation of Dsg3‐specific IgG antibodies. These observations confirm the powerful immune regulatory functions of Treg cells and identify Treg cells as potential therapeutic modulators in PV.