Department of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, Germany.
Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
J Invest Dermatol. 2024 Dec;144(12):2671-2681.e1. doi: 10.1016/j.jid.2024.02.038. Epub 2024 Apr 29.
Intravenous Ig (IVIg) is used to treat mucous membrane pemphigoid, although its therapeutic effectivity is not sufficiently supported by randomized controlled clinical trials, and its mode of action is only insufficiently understood. We have examined the effect of IVIg in a mouse model of anti-laminin 332 mucous membrane pemphigoid and found that IVIg ameliorates both cutaneous and mucosal inflammatory lesions. Our investigation into the modes of action of IVIg in mucous membrane pemphigoid indicated effective anti-inflammatory mechanisms beyond the enhanced degradation of IgG mediated through inhibition of the FcRn. Our results suggest that IVIg curbs the activation of neutrophils at several levels. This includes a direct, immediate inhibitory effect on neutrophil activation by immune complexes but not C5a, which blunts the release of ROS and leukotriene B from neutrophils. IVIg also suppresses the formation of neutrophil extracellular traps in response to calcium ion ionophore. In vivo treatment with IVIg altered the transcriptome of blood leukocytes and bone marrow neutrophils toward less proinflammatory phenotypes. Collectively, our results support the effectivity of IVIg in the treatment of mucous membrane pemphigoid and indicate that effects on neutrophils at multiple levels may significantly contribute to its therapeutic effects.
静脉注射免疫球蛋白（IVIg）用于治疗黏膜性类天疱疮，尽管随机对照临床试验并未充分证实其治疗效果，且其作用机制也知之甚少。我们在抗层粘连蛋白 332 黏膜性类天疱疮的小鼠模型中研究了 IVIg 的作用，发现 IVIg 可改善皮肤和黏膜炎症性病变。我们对 IVIg 在黏膜性类天疱疮中的作用机制的研究表明，除了通过抑制 FcRn 增强 IgG 的降解而介导的有效抗炎机制之外。我们的结果表明，IVIg 在多个水平上抑制中性粒细胞的激活。这包括通过免疫复合物直接、立即抑制中性粒细胞的激活，但不抑制 C5a，从而阻止中性粒细胞释放 ROS 和白三烯 B。IVIg 还抑制钙离子载体诱导的中性粒细胞细胞外陷阱的形成。体内用 IVIg 治疗可使血液白细胞和骨髓中性粒细胞的转录组向炎症表型减少的方向变化。总之，我们的结果支持 IVIg 在治疗黏膜性类天疱疮中的有效性，并表明其对中性粒细胞的多种作用可能对其治疗效果有重要贡献。
