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Cell:体内唾液酸化作用可将有害抗体变为有益抗炎抗体

2017-12-27 佚名 “细胞”微信号

来自美国麻省总医院(MGH)和哈佛医学院的研究人员已经找到一种方法,能将体内有害的自身抗体(autoantibody)直接转变成抗炎抗体(anti-inflammatory antibody),初步测试显示,这种技术在自身抗体诱导性疾病小鼠模型中成功减轻了炎症。这项技术由MGH风湿病、过敏症及免疫学部免疫学和炎症性疾病中心Robert Anthony博士实验室开发,涉及利用酶将半乳糖和唾液酸连接到

来自美国麻省总医院(MGH)和哈佛医学院的研究人员已经找到一种方法,能将体内有害的自身抗体(autoantibody)直接转变成抗炎抗体(anti-inflammatory antibody),初步测试显示,这种技术在自身抗体诱导性疾病小鼠模型中成功减轻了炎症。这项技术由MGH风湿病、过敏症及免疫学部免疫学和炎症性疾病中心Robert Anthony博士实验室开发,涉及利用酶将半乳糖和唾液酸连接到有害免疫球蛋白G(IgG)的尾部,触发抗炎活性。

Anthony博士表示,通过特异性修饰连接至抗体的糖分子,我们能够将导致自身免疫性疾病的抗体转化为抗炎抗体。尽管还需要做更多的工作,但我们希望这种抗炎抗体转化方法能够为罹患自身免疫性疾病和炎症性疾病的患者产生有益的影响。

这项研究已于近日发表于顶级期刊《细胞》(Cell),文章题名为:Engineered Sialylation of Pathogenic Antibodies In Vivo Attenuates Autoimmune Disease(唾液酸化的致病性抗体在体内减轻自身免疫性疾病疾病病情)

作者解释称,IgG抗体作为连接适应性免疫系统和先天免疫系统通路之间的桥梁,在免疫系统中扮演着一个关键角色,对于清除病原微生物必不可少。然而,机体内也会产生有害的IgG抗体,从而引发自身免疫性疾病,包括系统性红斑狼疮和类风湿性关节炎。IgG抗体也已被用于治疗用途。例如,由来源于健康供体的抗体制备而成的低剂量多克隆静脉注射免疫球蛋白(IVIG)可输注给缺乏某些抗体的患者,而高剂量IVIG在临床上应用于治疗炎症和自身免疫性疾病已经超过40年。

之前的研究表明,高剂量IVIG的抗炎活性是由IgG的可结晶片段区域(即Fc区,是IgG抗体分子Y型结构的尾巴部分)糖链的糖分子所决定,而且这种活性特别需要糖链的唾液酸化作用。糖链(Glycan)通常通过修饰蛋白分子的细胞内机制被连接于抗体分子上,但近期研究表明,糖链也能在细胞外进行修饰。这一发现为Anthony博士的团队提供了一个工程化转移酶的出发点,可能能够通过修饰Fc糖链将炎症性抗体转变为抗炎性抗体。

将唾液酸连接到Fc糖链需要另一种糖,即半乳糖。因此,Anthony博士的团队创造了2种酶,B4Fc和ST6Fc,这2种酶能分别介导半乳糖和唾液酸的连接。当联合应用时,这2种酶在类风湿性关节炎小鼠模型种触发了抗炎作用,同时在狼疮性肾炎小鼠模型中减轻了肾损伤。文章作者表示,当这2种酶以预防性或治疗性方式使用时,明显减轻了小鼠体内的自身免疫性炎症。

进一步的分析表明,这些酶只在炎症部位影响自身抗体,因此没有脱靶效应(off-target effects)。该团队的研究还表明,血小板激活是抗炎作用所必需的,正是激活的血小板提供了唾液酸和半乳糖。该团队称,将这2种酶联合应用,似乎并不影响血液循环系统中的IgG或血液循环系统中的其他糖蛋白的唾液酸化作用,这可能是由于血小板只在炎症部位释放半乳糖和唾液酸底物。

与现有的IVIG治疗相比,由Anthony团队所开发的这种新技术能够更有效地治疗炎症和自身免疫性疾病。此外,现有的高剂量IVIG治疗成本高昂、耗时、供货短缺,而该团队的这种技术在比高剂量IVIG低400倍的剂量下仍有效,并且可通过操作机体内的酶,消除长期输注IVIG的需求。

调节IgG唾液酸化作用的能力也可能被用来帮助提高疫苗的免疫效果,也可帮助临床医生控制IgG治疗。作者表示,这些研究结果强调了体内糖工程化的治疗潜力。这种体内唾液酸化作用的潜力不仅仅局限于自身免疫性疾病和炎症性疾病。事实上,这种方法还可应用于目前由高剂量IVIG治疗的各种疾病。体内唾液酸化作用是一种新颖有力的方法,能通过将内源性抗体进行糖基工程化,将其转化为抗炎介质,来有效减轻有害的自身抗体所接到的炎症作用。

原始出处:

Jose D. Pagan, Maya Kitaoka, Robert M. Anthony.Engineered Sialylation of Pathogenic Antibodies In Vivo Attenuates Autoimmune Disease.Cell.December 21, 2017.

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