多发性硬化症CSF富含滤泡T细胞,显示Th1/Eomes特征。

Jérémy Morille, Marion Mandon, Stéphane Rodriguez, David Roulois, Simon Leonard, Alexandra Garcia, Sandrine Wiertlewski, Emmanuelle Le Page, Laureline Berthelot, Arnaud Nicot, Camille Mathé, Flora Lejeune, Karin Tarte, Céline Delaloy, Patricia Amé, David Laplaud, Laure Michel
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引用次数: 5

摘要

背景和目的:据报道,多发性硬化症(MS)患者脑膜中存在三级淋巴结构和聚集体,特别是在进展期,并且与皮质病变和残疾密切相关。除了B细胞外,这些结构还包括滤泡辅助T细胞(Tfh),它们对支持B细胞分化至关重要。在一些自身免疫性疾病中,Tfh细胞在扩增自身反应性B细胞和促进自身抗体产生中起关键作用,但在MS中很少被发现。在本研究中,我们检测了复发-缓解型MS (RRMS)患者血液和脑脊液中循环cTfh细胞的表型、频率和转录组。方法:用流式细胞术分析39例健康对照和41例未治疗的RRMS患者的血液中cTfh细胞的表型和频率,以及10例未治疗的RRMS患者诊断时的CSF和配对血中cTfh细胞的表型和频率。利用体外血脑屏障模型,我们评估了不同ctfh细胞亚群的跨内皮迁移能力。最后,我们对8例首次脱髓鞘事件患者的配对CSF cTfh细胞和血液cTfh细胞进行了RNA测序分析。结果:RRMS患者血液中cTfh细胞的表型和频率无明显改变。在脑脊液中,我们发现了Tfh1细胞的重要浸润,激活的PD1+细胞比例很高。我们证明了Tfh1细胞的特定亚群在血脑屏障的体外模型中表现出更高的迁移能力。有趣的是,即使在第一次脱髓鞘事件中,CSF中的cTfh细胞也表现出EOMES基因上调和促炎/细胞毒性转录组特征,能够有效地将cTfh细胞与CSF和血液区分开来。最后,相互作用组分析揭示了致病性B细胞和CSF cTfh细胞之间潜在的强串音,指出CSF是合适的支持室,并强调了B细胞辅助性T细胞在MS发病中的早期意义。讨论:总的来说,一旦疾病诊断,激活的Tfh1中的CSF富集,与EOMES的高表达相关,以及预测的与CSF B细胞相互作用的高倾向表明,这些细胞可能有助于疾病的发生和/或活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Multiple Sclerosis CSF Is Enriched With Follicular T Cells Displaying a Th1/Eomes Signature.

Multiple Sclerosis CSF Is Enriched With Follicular T Cells Displaying a Th1/Eomes Signature.

Multiple Sclerosis CSF Is Enriched With Follicular T Cells Displaying a Th1/Eomes Signature.

Multiple Sclerosis CSF Is Enriched With Follicular T Cells Displaying a Th1/Eomes Signature.

Background and objectives: Tertiary lymphoid structures and aggregates are reported in the meninges of patients with multiple sclerosis (MS), especially at the progressive stage, and are strongly associated with cortical lesions and disability. Besides B cells, these structures comprise follicular helper T (Tfh) cells that are crucial to support B-cell differentiation. Tfh cells play a pivotal role in amplifying autoreactive B cells and promoting autoantibody production in several autoimmune diseases, but very few are known in MS. In this study, we examined the phenotype, frequency, and transcriptome of circulating cTfh cells in the blood and CSF of patients with relapsing-remitting MS (RRMS).

Methods: The phenotype and frequency of cTfh cells were analyzed in the blood of 39 healthy controls and 41 untreated patients with RRMS and in the CSF and paired blood of 10 patients with drug-naive RRMS at diagnosis by flow cytometry. Using an in vitro model of blood-brain barrier, we assessed the transendothelial migratory abilities of the different cTfh-cell subsets. Finally, we performed an RNA sequencing analysis of paired CSF cTfh cells and blood cTfh cells in 8 patients sampled at their first demyelinating event.

Results: The blood phenotype and frequency of cTfh cells were not significantly modified in patients with RRMS. In the CSF, we found an important infiltration of Tfh1 cells, with a high proportion of activated PD1+ cells. We demonstrated that the specific subset of Tfh1 cells presents increased migration abilities to cross an in vitro model of blood-brain barrier. Of interest, even at the first demyelinating event, cTfh cells in the CSF display specific characteristics with upregulation of EOMES gene and proinflammatory/cytotoxic transcriptomic signature able to efficiently distinguish cTfh cells from the CSF and blood. Finally, interactome analysis revealed potential strong cross talk between pathogenic B cells and CSF cTfh cells, pointing out the CSF as opportune supportive compartment and highlighting the very early implication of B-cell helper T cells in MS pathogenesis.

Discussion: Overall, CSF enrichment in activated Tfh1 as soon as disease diagnosis, associated with high expression of EOMES, and a predicted high propensity to interact with CSF B cells suggest that these cells probably contribute to disease onset and/or activity.

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