Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, 469 Joe H. Reynolds Medical Sciences Building, 1114 TAMU, College Station, TX 77843, USA; Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, 3107 Medical Research & Education Building, 8447 State Hwy 47, Bryan, TX 77807, USA.
Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, 469 Joe H. Reynolds Medical Sciences Building, 1114 TAMU, College Station, TX 77843, USA; Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, 3107 Medical Research & Education Building, 8447 State Hwy 47, Bryan, TX 77807, USA; Biomedical Engineering Graduate Program, University of Texas Southwestern Medical Center, 5232 Harry Hines Boulevard, Dallas, TX 75390, USA.
J Autoimmun. 2018 Jan;86:104-115. doi: 10.1016/j.jaut.2017.09.002. Epub 2017 Sep 28.
Myelin oligodendrocyte glycoprotein (MOG) is exposed on the outer surface of the myelin sheath, and as such, represents a possible target antigen for antibodies in multiple sclerosis (MS) and other demyelinating diseases. However, despite extensive analyses, whether MOG-specific antibodies contribute to pathogenesis in human MS remains an area of uncertainty. In the current study we demonstrate that antibodies derived from adult MS patients exacerbate experimental autoimmune encephalomyelitis (EAE) in 'humanized' mice that transgenically express human FcγRs (hFcγRs). Importantly, this exacerbation is dependent on MOG recognition by the human-derived antibodies. The use of mice that express hFcγRs has allowed us to also investigate the contribution of these receptors to disease in the absence of confounding effects of cross-species differences. Specifically, by engineering the Fc region of MOG-specific antibodies to modulate FcγR and complement (C1q) binding, we reveal that FcγRs but not complement activation contribute to EAE pathogenesis. Importantly, selective enhancement of the affinities of these antibodies for specific FcγRs reveals that FcγRIIA is more important than FcγRIIIA in mediating disease exacerbation. These studies not only provide definitive evidence for the contribution of MOG-specific antibodies to MS, but also reveal mechanistic insight that could lead to new therapeutic targets.
髓鞘少突胶质细胞糖蛋白（MOG）暴露在髓鞘的外表面，因此，它代表了多发性硬化症（MS）和其他脱髓鞘疾病中抗体的一个可能的靶抗原。然而，尽管进行了广泛的分析，MOG 特异性抗体是否有助于人类 MS 的发病机制仍然是一个不确定的领域。在目前的研究中，我们证明来自成人 MS 患者的抗体在转染人 FcγR（hFcγR）的“人源化”小鼠中加重实验性自身免疫性脑脊髓炎（EAE）。重要的是，这种加重依赖于人类来源的抗体对 MOG 的识别。使用表达 hFcγR 的小鼠使我们能够在没有跨物种差异的混杂影响的情况下，研究这些受体对疾病的贡献。具体而言，通过对 MOG 特异性抗体的 Fc 区进行工程改造以调节 FcγR 和补体（C1q）结合，我们发现 FcγR 而不是补体激活有助于 EAE 的发病机制。重要的是，这些抗体对特定 FcγR 的亲和力的选择性增强表明，FcγRIIA 比 FcγRIIIA 在介导疾病加重方面更为重要。这些研究不仅为 MOG 特异性抗体对 MS 的贡献提供了明确的证据，而且还揭示了可能导致新的治疗靶点的机制见解。
