B Cells Influence Encephalitogenic T Cell Frequency to Myelin Oligodendrocyte Glycoprotein (MOG)38-49 during Full-length MOG Protein-Induced Demyelinating Disease.

Q3 Medicine
Michael A Faust, Lisa Gibbs, Juan M Oviedo, Douglas H Cornwall, Keke C Fairfax, Zemin Zhou, Tracey J Lamb, Brian D Evavold
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Abstract

Although T cells are encephalitogenic during demyelinating disease, B cell-depleting therapies are a successful treatment for patients with multiple sclerosis. Murine models of demyelinating disease utilizing myelin epitopes, such as myelin oligodendrocyte glycoprotein (MOG)35-55, induce a robust CD4 T cell response but mitigate the contribution of pathological B cells. This limits their efficacy for investigating how B cell depletion affects T cells. Furthermore, induction of experimental autoimmune encephalomyelitis with a single CD4 T cell epitope does not reflect the breadth of epitopes observed in the clinic. To better model the adaptive immune response, mice were immunized with the full-length MOG protein or the MOG1-125 extracellular domain (ECD) and compared with MOG35-55. Mature MOG-reactive B cells were generated only by full-length MOG or ECD. The CNS-localized T cell response induced by full-length MOG is characterized by a reduction in frequency and the percentage of low-affinity T cells with reactivity toward the core epitope of MOG35-55. B cell depletion with anti-CD20 before full-length MOG-induced, but not ECD-induced, demyelinating disease restored T cell reactivity toward the immunodominant epitope of MOG35-55, suggesting the B cell-mediated control of encephalitogenic epitopes. Ultimately, this study reveals that anti-CD20 treatment can influence T cell epitopes found in the CNS during demyelinating disease.

在全长 MOG 蛋白诱导的脱髓鞘疾病中,B 细胞影响致脑 T 细胞对髓鞘少突胶质细胞蛋白 (MOG)38-49 的频率。
虽然在脱髓鞘疾病期间 T 细胞具有致脑病性,但 B 细胞清除疗法是治疗多发性硬化症患者的一种成功方法。利用髓鞘表位(如髓鞘少突胶质细胞糖蛋白(MOG)35-55)的脱髓鞘疾病小鼠模型可诱导强大的 CD4 T 细胞反应,但会减轻病理 B 细胞的作用。这限制了它们在研究 B 细胞耗竭如何影响 T 细胞方面的功效。此外,用单一的 CD4 T 细胞表位诱导实验性自身免疫性脑脊髓炎并不能反映临床上观察到的表位的广泛性。为了更好地模拟适应性免疫反应,用全长 MOG 蛋白或 MOG1-125 细胞外结构域(ECD)免疫小鼠,并与 MOG35-55 进行比较。只有全长 MOG 或 ECD 才能产生成熟的 MOG 反应性 B 细胞。全长 MOG 诱导的中枢神经系统定位 T 细胞反应的特点是对 MOG35-55 核心表位有反应性的低亲和性 T 细胞的频率和百分比降低。在全长 MOG 诱导的脱髓鞘疾病(而非 ECD 诱导的脱髓鞘疾病)之前,用抗 CD20 清除 B 细胞可恢复 T 细胞对 MOG35-55 免疫显性表位的反应性,这表明 B 细胞介导了对致脑表位的控制。最终,这项研究揭示了抗 CD20 治疗可影响脱髓鞘疾病期间中枢神经系统中发现的 T 细胞表位。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
3.70
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0.00%
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审稿时长
4 weeks
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