IgG4 is the least potent human IgG subclass for the FcγR-mediated antibody effector function and is considered anti-inflammatory in the context of prolonged inflammation and allergic responses. Paradoxically, IgG4 is also the dominant IgG subclass of pathogenic autoantibodies in IgG4-mediated diseases. Here we show that the IgG subclass and Fc-FcγR interaction have a distinct impact on the pathogenic function of autoantibodies in different IgG4-mediated diseases. While IgG4 and its weak Fc-FcγR interaction have an ameliorative role in the pathogenicity of anti-ADAMTS13 autoantibodies isolated from thrombotic thrombocytopenic purpura (TTP) patients, they have an unexpected exacerbating effect on anti-Dsg1 autoantibody pathogenicity in pemphigus foliaceus (PF) models. Strikingly, a non-pathogenic anti-Dsg1 antibody variant optimized for FcγR-mediated effector function can attenuate the skin lesions induced by pathogenic anti-Dsg1 antibodies by promoting the clearance of dead keratinocytes. These studies suggest that IgG effector function contributes to the clearance of autoantibody-Ag complexes, which is harmful in TTP, but beneficial in PF and may provide new therapeutic opportunity.

中文翻译：

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IgG亚类和Fc-FcγR相互作用对不同IgG4介导的疾病自身抗体致病性的不同影响

IgG4是FcγR介导的抗体效应子功能最弱的人IgG亚类，在长时间的炎症和过敏反应中被认为是抗炎药。矛盾的是，IgG4还是IgG4介导的疾病中致病性自身抗体的主要IgG亚类。在这里，我们显示IgG亚类和Fc-FcγR相互作用对不同IgG4介导的疾病中自身抗体的致病功能产生了明显影响。尽管IgG4及其弱Fc-FcγR相互作用在从血栓性血小板减少性紫癜（TTP）患者分离的抗ADAMTS13自身抗体的致病性中具有改善作用，但它们对天疱疮（PF）模型中的抗Dsg1自身抗体致病性具有意想不到的加剧作用。惊人地 针对FcγR介导的效应子功能优化的非致病性抗Dsg1抗体变异体可以通过促进死亡角质形成细胞的清除来减轻由致病性抗Dsg1抗体诱导的皮肤损伤。这些研究表明，IgG效应子功能有助于清除自身抗体-Ag复合物，这在TTP中是有害的，但对PF有好处，并可能提供新的治疗机会。