Novel B cell-dependent multiple sclerosis model using extracellular domains of myelin proteolipid protein
Novel B cell-dependent multiple sclerosis model using extracellular domains of myelin proteolipid protein
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DOI：
10.1038/s41598-020-61928-w
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发表时间：
2020-03-19
影响因子：
4.6
通讯作者：
Karandikar, Nitin J.
中科院分区：
文献类型：
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作者：
Boyden, Alexander W.;Brate, Ashley A.;Karandikar, Nitin J.
B 细胞靶向方法在多发性硬化症 (MS) 中的治疗成功加强了对这些细胞在脱髓鞘疾病中的致病和调节作用的研究。剖析 MS 小鼠模型实验性自身免疫性脑脊髓炎 (EAE) 中 B 细胞的功能主要限于用髓磷脂少突胶质细胞糖蛋白表位 MOG35-55 或全长重组人 MOG 蛋白进行诱导，后者代表最常用的 B 细胞依赖性 EAE 模型。显然需要研究其他髓磷脂抗原背景下的 B 细胞功能。与 MOG35-55 不同，MOG35-55 缺乏 B 细胞会导致更严重的疾病，我们在此表明，免疫显性髓鞘蛋白脂质蛋白表位 (PLP178-191) 在 WT 和 mu MT 小鼠中引发相同的 EAE，表明该肽不存在 B 细胞参与。我们假设较长的 PLP 抗原可能更好地与 B 细胞结合，并设计了一种包含 PLP 胞外结构域 (ECD) 的肽。我们在此证明，PLPECD 免疫的 B 细胞缺陷小鼠未能表现出 EAE。相比之下，PLPECD 不仅在 WT 小鼠中诱导 EAE，而且在无法分泌抗体的 B 细胞充足的小鼠中也诱导 EAE，这表明 PLPECD 具有主要的抗原呈递作用。这些结果建立了一种新颖、有效的 B 细胞依赖性 EAE 模型。
Therapeutic success of B cell-targeting approaches in multiple sclerosis (MS) has intensified research into the pathogenic and regulatory roles these cells play in demyelinating disease. Dissecting the function of B cells in the MS mouse model experimental autoimmune encephalomyelitis (EAE) is largely confined to induction with either the myelin oligodendrocyte glycoprotein epitope MOG35-55 or the fulllength recombinant human MOG protein, the latter representing the most-used B cell-dependent EAE model. There is a clear need to investigate B cell function in additional myelin antigen contexts. Unlike MOG35-55, where lack of B cells yields more severe disease, we show here that the immunodominant myelin proteolipid protein epitope (PLP178-191) elicited identical EAE in WT and mu MT mice, suggesting an absence of B cell engagement by this peptide. We hypothesized that a longer PLP antigen may better engage B cells and designed a peptide encompassing the extracellular domains (ECD) of PLP. We demonstrate here that PLPECD-immunized B cell-deficient mice failed to exhibit EAE. In contrast, PLPECD induced EAE not only in WT mice, but in B cell-sufficient mice incapable of secreting antibodies, suggesting a predominant antigen presentation role. These results establish a novel, efficient B celldependent EAE model.