当前位置: X-MOL 学术Mol. Pharmaceutics › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Autoantigen Tetramer Silences Autoreactive B Cell Populations.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-09-09 , DOI: 10.1021/acs.molpharmaceut.0c00665
Matthew A Christopher 1 , Stephanie N Johnson 1 , J Daniel Griffin 1, 2 , Cory J Berkland 1, 2, 3
Affiliation  

Many autoimmune therapies focus on immune suppression to reduce symptom severity and halt disease progression; however, currently approved treatments lack specificity for the autoantigen and rely on more global immune suppression. Multivalent antigen arrays can disarm pathogenic autoimmune B cell populations that specifically recognize the antigen of interest via their B cell receptor (BCR). Disarmament may be achieved by BCR engagement, cross-linking, and sustained receptor occupancy as a result of multivalent, high avidity BCR binding. To engage and explore this mechanism, a tetramer display of the encephalogenic proteolipid peptide (PLP139–151), referred to as 4-arm PLP139–151, was synthesized by copper-catalyzed azide–alkyne cycloaddition chemistry. Subcutaneous administration of 4-arm PLP139–151 completely ameliorated symptoms of paralysis in a mouse model of multiple sclerosis known as experimental autoimmune encephalomyelitis. Competitive binding of 4-arm PLP139–151 to PLP139–151-specific IgG in the mouse serum demonstrated the enhanced avidity associated with the multivalent array compared to the free peptide. Furthermore, key PLP139–151-reactive B cells were depleted following 4-arm PLP139–151 treatment, resulting in significant reduction of proinflammatory cytokines. Together, these data demonstrate the potential of 4-arm PLP139–151 to silence autoreactive B cell populations and limit the downstream activation of effector cells.

中文翻译:

自身抗原四聚体沉默自身反应性 B 细胞群。

许多自身免疫疗法侧重于免疫抑制,以减轻症状严重程度并阻止疾病进展;然而,目前批准的治疗缺乏对自身抗原的特异性,并依赖于更多的整体免疫抑制。多价抗原阵列可以解除通过其 B 细胞受体 (BCR) 特异性识别目标抗原的致病性自身免疫性 B 细胞群。由于多价、高亲和力的 BCR 结合,可以通过 BCR 参与、交联和持续的受体占据来实现解除武装。为了参与和探索这种机制,脑源性蛋白肽 (PLP 139–151 )的四聚体展示,称为 4 臂 PLP 139–151,是通过铜催化的叠氮化物 - 炔烃环加成化学合成的。皮下注射 4 臂 PLP 139-151完全改善了多发性硬化症小鼠模型(称为实验性自身免疫性脑脊髓炎)的瘫痪症状。小鼠血清中 4 臂 PLP 139-151与 PLP 139-151特异性 IgG 的竞争性结合证明,与游离肽相比,与多价阵列相关的亲和力增强。此外,在 4 臂 PLP 139-151治疗后,关键的 PLP 139-151反应性 B 细胞被耗尽,导致促炎细胞因子显着减少。总之,这些数据证明了 4 臂 PLP 139-151 的潜力 沉默自身反应性 B 细胞群并限制效应细胞的下游激活。
更新日期:2020-11-02
down
wechat
bug