PDF(Pubmed)
Abstract：
Conventional rodent neuromyelitis optica spectrum disorder (NMOSD) models using patient-derived immunoglobulin G (IgG) are potentially affected by the differences between the human and rodent aquaporin-4 (AQP4) extracellular domains (ECDs). We hypothesized that the humanization of AQP4 ECDs would make the rodent model lesions closer to human NMOSD pathology. Humanized-AQP4-expressing (hAQP4) rats were generated using genome-editing technology, and the human AQP4-specific monoclonal antibody (mAb) or six patient-derived IgGs were introduced intraperitoneally into hAQP4 rats and wild-type Lewis (WT) rats after immunization with myelin basic protein and complete Freund\'s adjuvant. Human AQP4-specific mAb induced astrocyte loss lesions specifically in hAQP4 rats. The patient-derived IgGs also induced NMOSD-like tissue-destructive lesions with AQP4 loss, demyelination, axonal swelling, complement deposition, and marked neutrophil and macrophage/microglia infiltration in hAQP4 rats; however, the difference in AQP4 loss lesion size and infiltrating cells was not significant between hAQP4 and WT rats. The patient-derived IgGs bound to both human and rat AQP4 M23, suggesting their binding to the shared region of human and rat AQP4 ECDs. Anti-AQP4 titers positively correlated with AQP4 loss lesion size and neutrophil and macrophage/microglia infiltration. Considering that patient-derived IgGs vary in binding sites and affinities and some of them may not bind to rodent AQP4, our hAQP4 rat is expected to reproduce NMOSD-like pathology more accurately than WT rats.
摘要：
使用患者衍生的免疫球蛋白G（IgG）的常规啮齿动物视神经脊髓炎谱系障碍（NMOSD）模型可能受到人和啮齿动物水通道蛋白4（AQP4）胞外域（ECD）之间差异的影响。我们假设AQP4ECD的人源化将使啮齿动物模型病变更接近人类NMOSD病理学。使用基因组编辑技术产生表达人源AQP4(hAQP4)的大鼠,在用髓鞘碱性蛋白和完全弗氏佐剂免疫后，将人AQP4特异性单克隆抗体（mAb）或6种患者来源的IgG腹膜内导入hAQP4大鼠和野生型Lewis（WT）大鼠。人AQP4特异性mAb在hAQP4大鼠中诱导星形胶质细胞丢失损伤。患者来源的IgGs还诱导了NMOSD样组织破坏性病变，并伴有AQP4丢失，脱髓鞘,轴突肿胀,补体沉积,和明显的中性粒细胞和巨噬细胞/小胶质细胞浸润在hAQP4大鼠;然而,在hAQP4和WT大鼠之间，AQP4损失病变大小和浸润细胞的差异无统计学意义。患者来源的IgG与人和大鼠AQP4M23结合，表明它们与人和大鼠AQP4ECD的共享区域结合。抗AQP4滴度与AQP4丢失病灶大小、中性粒细胞和巨噬细胞/小胶质细胞浸润呈正相关。考虑到患者来源的IgG在结合位点和亲和力方面存在差异，并且其中一些可能不与啮齿动物AQP4结合，因此我们的hAQP4大鼠有望比WT大鼠更准确地再现NMOSD样病理。
