文献简介

出版社:Clinical Reviews in Allergy & Immunology

作  者:Robert Pollmann1 & Thomas Schmidt & Rüdiger Eming & Michael Hertl

编  号:

关键字:天疱疮;寻常型天疱疮;抗体;发病机制;诊断;治疗

年  份:2018   点击量:88

文献摘要 全文翻译

Pemphigus is a group of rare, potentially devastating autoimmune diseases of the skin and mucous membranes with high morbidity and potentially lethal outcome. The major clinical variant, pemphigus vulgaris (PV) is caused by a loss of intercellular adhesion of epidermal keratinocytes which is induced by IgG autoantibodies against components of desmosomes. Specifically, IgG against the desmosomal adhesion proteins, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1), preferentially target their ectodomains which are presumably critical for the transinteraction and signalling function of these adhesion molecules. There is a close immunogenetic association of PV with the human leukocyte antigen (HLA) class II alleles, HLA-DRB1*0402 and HLA-DQB1*0503. These have been shown to be critical for the presentation of immunodominant peptides to autoreactive CD4+ T helper cells. The importance of autoaggressive T-B cell interaction in the induction of pathogenic IgG autoantibodies which directly cause epidermal loss of adhesion has been demonstrated both clinically (by the use of the anti-CD20 monoclonal antibody rituximab) and experimentally (in PV mouse models). The strong association of clinically active pemphigus with autoantibodies of the IgG4 and IgE subclasses strongly suggests that T helper 2 cells are critical regulators of the immune pathogenesis of pemphigus. Novel therapeutic approaches target autoreactive T and B cells to specifically interfere with the T cell-dependent activation of B cells leading to the generation of autoantibody-producing plasma cells. Our improved understanding of the autoantibody-driven effect or phase of pemphigus has led to the introduction of novel therapies that target pathogenic autoantibodies such as immunoadsorption and drugs that block pathogenic autoantibody-induced cell signalling events.

天疱疮是一种罕见的、对皮肤和粘膜具有潜在破坏性的自身免疫性疾病,发病率高,有致命性。主要临床变体--寻常型天疱疮(PV)是由针对桥粒的IgG自身抗体诱导的表皮角质形成细胞细胞间粘附丧失所致。具体来说,针对桥粒粘附蛋白、桥粒芯糖蛋白3(Dsg3)和桥粒芯糖蛋白1(Dsg1)的IgG优先靶向它们的胞外域,它们可能对这些粘附分子的相互作用和信号传导功能起关键作用。PV与人类白细胞抗原(HLA) II类等位基因,HLA-DRB1*0402 和HLA-DQB1*0503存在密切的免疫遗传学联系。已证明这些对将提呈免疫优势肽呈递给自身反应性CD4 +辅助性T细胞是至关重要的。临床(通过使用抗CD20单克隆抗体的利妥昔单抗)和实验(在PV小鼠模型中)均证明了T-B细胞相互作用在诱导病原性IgG自身抗体(直接导致表皮粘连丧失)中的重要性。天疱疮临床活性与IgG4自身抗体和IgE亚型强烈关联表明Th2辅助细胞是天疱疮免疫发病机制的关键调控因子。新的治疗方法靶向自身反应性T和B细胞,特异性干扰B细胞的T细胞依赖性激活,导致产生自身抗体的浆细胞产生。通过对自身抗体驱动效应或天疱疮分期的进一步了解,我们提出了针对致病性自身抗体的新疗法,如免疫吸附和阻断致病性自身抗体诱导的细胞信号事件的药物。