Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses.
Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses.
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DOI：
10.1093/braincomms/fcaa124
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发表时间：
2020
影响因子：
4.8
通讯作者：
Munitic I
中科院分区：
文献类型：
--
作者：
Béland LC;Markovinovic A;Jakovac H;De Marchi F;Bilic E;Mazzini L;Kriz J;Munitic I
肌萎缩侧索硬化症是一种以运动神经元为靶点的快速致死性神经退行性疾病，尽管存在广泛的遗传、环境和临床异质性，但神经炎症是一种常见的发现。它以局部胶质细胞活化、T细胞浸润和全身免疫系统活化为标志。免疫系统在各种慢性疾病的发病机制中起着重要作用，因此其中一些疾病，包括某些类型的癌症，可以通过免疫方法成功靶向。然而，肌萎缩侧索硬化症的各种抗炎或免疫抑制疗法都失败了。这促使人们对肌萎缩侧索硬化症的免疫介导过程进行更多的研究。也许最大的难题是肌萎缩侧索硬化症的发病机制表现出三个不同的免疫功能障碍的特点过度炎症，自身免疫和免疫反应效率低下。流行病学和全基因组关联研究表明，肌萎缩侧索硬化症和自身免疫性疾病之间只有很小的重叠，因此过度炎症通常被认为是继发于蛋白质聚集、线粒体损伤或其他应激。相比之下，最近表征的几种肌萎缩性侧索硬化症相关突变，包括TBK 1，OPTN，CYLD和C9 orf 72中的突变，可能导致免疫应答效率低下和/或损伤堆积，这表明先天性免疫缺陷也可能是这种疾病的触发因素和/或修饰因素。在这种情况下，非选择性免疫抑制将进一步限制神经保护性免疫反应。在这里，我们讨论了肌萎缩侧索硬化症免疫介导的神经保护和神经毒性的多层。特别关注直接或间接影响免疫系统的个体患者突变，以及这些突变影响疾病进展的机制。肌萎缩侧索硬化症的免疫问题是及时和相关的，因为它是这种异质性疾病中为数不多的常见和潜在的可塑性因素之一。重要的是，肌萎缩侧索硬化症的进展最近已经与患者的T细胞和单核细胞谱以及细胞因子和趋化因子受体的多态性错综复杂地联系在一起。因此，基于免疫表型的精确患者分层对于有效治疗至关重要。免疫系统是肌萎缩侧索硬化症发病机制的重要驱动力。在这里，我们探讨不同的分子，细胞和系统的过程，导致这种疾病的免疫失衡。值得注意的是，最近的遗传学证据表明，过度的炎症和无效的免疫反应都可能导致运动神经元功能障碍和死亡。
Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions—excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, non-selective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies. The immune system is an important driver of disease pathogenesis in amyotrophic lateral sclerosis. Here we explore diverse molecular, cellular and systemic processes leading to dysbalanced immunity in this disease. Notably, recent genetic evidence suggests that both excessive inflammation and inefficient immune responses may lead to motoneuron dysfunction and death.
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影响因子：
5.1
作者：
Bilic, E.;Bilic, E.;Zagar, M.
通讯作者：
Zagar, M.
影响因子：
9.9
作者：
Berger, MM;Kopp, N;Lina, B
通讯作者：
Lina, B
跨种族荟萃分析确定 GPX3-TNIP1 基因座与肌萎缩侧索硬化症的关联
影响因子：
16.6
作者：
Benyamin B;He J;Zhao Q;Gratten J;Garton F;Leo PJ;Liu Z;Mangelsdorf M;Al-Chalabi A;Anderson L;Butler TJ;Chen L;Chen XD;Cremin K;Deng HW;Devine M;Edson J;Fifita JA;Furlong S;Han YY;Harris J;Henders AK;Jeffree RL;Jin ZB;Li Z;Li T;Li M;Lin Y;Liu X;Marshall M;McCann EP;Mowry BJ;Ngo ST;Pamphlett R;Ran S;Reutens DC;Rowe DB;Sachdev P;Shah S;Song S;Tan LJ;Tang L;van den Berg LH;van Rheenen W;Veldink JH;Wallace RH;Wheeler L;Williams KL;Wu J;Wu X;Yang J;Yue W;Zhang ZH;Zhang D;Noakes PG;Blair IP;Henderson RD;McCombe PA;Visscher PM;Xu H;Bartlett PF;Brown MA;Wray NR;Fan D
通讯作者：
Fan D
影响因子：
3.4
作者：
Berry JD;Paganoni S;Atassi N;Macklin EA;Goyal N;Rivner M;Simpson E;Appel S;Grasso DL;Mejia NI;Mateen F;Gill A;Vieira F;Tassinari V;Perrin S
通讯作者：
Perrin S
DOI：
10.1126/science.1252945
发表时间：
2014-10-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baruch K;Deczkowska A;David E;Castellano JM;Miller O;Kertser A;Berkutzki T;Barnett-Itzhaki Z;Bezalel D;Wyss-Coray T;Amit I;Schwartz M
通讯作者：
Schwartz M