Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis.
Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis.
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鉴定CNS-定殖T细胞作为预防多发性硬化进展的潜在治疗靶点。
DOI：
10.1016/j.medj.2021.01.006
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发表时间：
2021-03-12
期刊：
影响因子：
--
通讯作者：
Friese MA
中科院分区：
文献类型：
--
作者：
Kaufmann M;Evans H;Schaupp AL;Engler JB;Kaur G;Willing A;Kursawe N;Schubert C;Attfield KE;Fugger L;Friese MA
多发性硬化症（MS）是一种中枢神经系统（CNS）的自身免疫性疾病，在早期阶段可以抑制，但最终会在临床上进展，对治疗无反应。在这里，我们研究进展性MS的治疗抵抗是否可归因于血脑屏障（BBB）后的慢性免疫细胞积累。我们系统地跟踪了31名MS患者和31名匹配的健康人外周血中的cns归巢免疫细胞，对71个样本的497,705个单细胞转录组和355,433个表面蛋白谱进行了综合分析。通过空间RNA测序，我们在6名进展性MS患者的死后脑组织中定位了这些细胞，并与4名对照大脑（20个样本，85,000个点转录组）进行了对比。我们确定了一种特定的致病性CD161+/淋巴毒素β (LTB)+ T细胞群存在于进行性MS患者的大脑中。有趣的是，我们的数据表明，这些T细胞在中枢神经系统的定植可能在疾病过程的早期就开始了，因为它们可以在复发缓解型MS患者中通过使用整合素阻断抗体natalizumab被动员到血液中。因此，我们为一种治疗策略奠定了基础，即在中枢神经系统归巢的T细胞能够促进治疗抵抗性进展之前耗尽它们。这项研究得到了汉堡-埃彭多夫大学医学中心、德国科学基金会、橡树基金会、英国医学研究委员会和惠康基金会的资助。多发性硬化症（MS）以攻击大脑和脊髓的流氓免疫系统为特征，导致年轻患者严重残疾。在进展性MS患者中，Th17/Tfh为脑常驻细胞的Th17/Tfh的靶向表面标记包括AQP3、TNFRSF25、ICOS和VLA4。在疾病的早期阶段，免疫调节疗法仍然可以抑制复发。后来，许多患者进入缓慢进展阶段，大部分对现有药物产生耐药性，原因尚不清楚。根据一个长期存在的理论，治疗抵抗可能是由于血液免疫细胞在血脑屏障后面的浸润和持久驻留，超出了大多数治疗方法的范围。在目前的研究中，来自汉堡大学和牛津大学的研究人员联手研究了多发性硬化症中中枢神经系统的这种暗示免疫细胞定植。结果，他们确定了居住在进行性多发性硬化症患者大脑中的特定免疫细胞群，并为在疾病过程的早期靶向治疗奠定了基础。Kaufmann等人通过血液免疫细胞的大规模多模态单细胞谱和脑组织的空间RNA测序，鉴定了MS患者大脑中的致病性CD161+/LTB+ T细胞。他们描述了可靶向的表面标记物和MS早期通过vla4阻断向血液的动员是治疗靶向的先决条件。
Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), can be suppressed in its early stages but eventually becomes clinically progressive and unresponsive to therapy. Here, we investigate whether the therapeutic resistance of progressive MS can be attributed to chronic immune cell accumulation behind the blood-brain barrier (BBB). We systematically track CNS-homing immune cells in the peripheral blood of 31 MS patients and 31 matched healthy individuals in an integrated analysis of 497,705 single-cell transcriptomes and 355,433 surface protein profiles from 71 samples. Through spatial RNA sequencing, we localize these cells in post mortem brain tissue of 6 progressive MS patients contrasted against 4 control brains (20 samples, 85,000 spot transcriptomes). We identify a specific pathogenic CD161+/lymphotoxin beta (LTB)+ T cell population that resides in brains of progressive MS patients. Intriguingly, our data suggest that the colonization of the CNS by these T cells may begin earlier in the disease course, as they can be mobilized to the blood by usage of the integrin-blocking antibody natalizumab in relapsing-remitting MS patients. As a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression. This study was supported by funding from the University Medical Center Hamburg-Eppendorf, the Stifterverband für die Deutsche Wissenschaft, the OAK Foundation, Medical Research Council UK, and Wellcome. Multimodal single-cell profiling of blood and spatial RNA sequencing of brain tissue VLA4 blockage mobilizes CD161+/LTB+ Th17/Tfh cells to the blood early in MS Identification of these Th17/Tfh as brain-resident cells in progressive MS patients Targetable surface markers on Th17/Tfh include AQP3, TNFRSF25, ICOS, and VLA4 Multiple sclerosis (MS) is characterized by a rogue immune system that attacks the brain and spinal cord, leading to severe disability in young patients. During early phases of the disease, relapses can still be suppressed by immunomodulatory therapies. Later on, many patients develop a slowly progressive phase that is mostly resistant to available drugs for reasons remaining largely unclear. According to one long-standing theory, the therapeutic resistance might arise due to infiltration and lasting residence of blood immune cells behind the blood-brain barrier, beyond the reach of most therapeutics. In the present study, researchers from the Universities of Hamburg and Oxford joined forces to study this insinuated immune cell colonization of the central nervous system in MS. As a result, they identified a specific immune cell population resident in the brains of progressive MS patients and lay the groundwork to target it therapeutically earlier in the disease course. Kaufmann et al. identified pathogenic CD161+/LTB+ T cells resident in brains of MS patients with large-scale multimodal single-cell profiling of blood immune cells and spatial RNA sequencing of brain tissue. They describe targetable surface markers and mobilization to the blood by VLA4-blockage early in MS as prerequisites for therapeutic targeting.
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影响因子：
120.7
作者：
Brown, J. William L.;Coles, Alasdair;Zwanikken, Cees
通讯作者：
Zwanikken, Cees
影响因子：
7.3
作者：
Martinelli S;Chen EJ;Clarke F;Lyck R;Affentranger S;Burkhardt JK;Niggli V
通讯作者：
Niggli V
影响因子：
3.7
作者：
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通讯作者：
Berberich-Siebelt F
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影响因子：
48
作者：
He, Anna;Merkel, Bernd;Kalincik, Tomas
通讯作者：
Kalincik, Tomas
影响因子：
9.3
作者：
McGinnis, Christopher S.;Murrow, Lyndsay M.;Gartner, Zev J.
通讯作者：
Gartner, Zev J.