Saskia Räuber, Andreas Schulte-Mecklenbeck, Alice Willison, Ramona Hagler, Marius Jonas, Duygu Pul, Lars Masanneck, Christina B Schroeter, Kristin S Golombeck, Stefanie Lichtenberg, Christine Strippel, Marco Gallus, Andre Dik, Ruth Kerkhoff, Sumanta Barman, Katharina J Weber, Stjepana Kovac, Melanie Korsen, Marc Pawlitzki, Norbert Goebels, Tobias Ruck, Catharina C Gross, Werner Paulus, Guido Reifenberger, Michael Hanke, Oliver Grauer, Marion Rapp, Michael Sabel, Heinz Wiendl, Sven G Meuth, Nico Melzer
{"title":"流式细胞术可确定中枢神经系统自身免疫性疾病和原发性中枢神经系统恶性肿瘤中外周和鞘内淋巴细胞模式的变化。","authors":"Saskia Räuber, Andreas Schulte-Mecklenbeck, Alice Willison, Ramona Hagler, Marius Jonas, Duygu Pul, Lars Masanneck, Christina B Schroeter, Kristin S Golombeck, Stefanie Lichtenberg, Christine Strippel, Marco Gallus, Andre Dik, Ruth Kerkhoff, Sumanta Barman, Katharina J Weber, Stjepana Kovac, Melanie Korsen, Marc Pawlitzki, Norbert Goebels, Tobias Ruck, Catharina C Gross, Werner Paulus, Guido Reifenberger, Michael Hanke, Oliver Grauer, Marion Rapp, Michael Sabel, Heinz Wiendl, Sven G Meuth, Nico Melzer","doi":"10.1186/s12974-024-03269-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Immune dysregulation is a hallmark of autoimmune diseases of the central nervous system (CNS), characterized by an excessive immune response, and primary CNS tumors (pCNS-tumors) showing a highly immunosuppressive parenchymal microenvironment.</p><p><strong>Methods: </strong>Aiming to provide novel insights into the pathogenesis of CNS autoimmunity and cerebral tumor immunity, we analyzed the peripheral blood (PB) and cerebrospinal fluid (CSF) of 81 autoimmune limbic encephalitis (ALE), 148 relapsing-remitting multiple sclerosis (RRMS), 33 IDH-wildtype glioma, 9 primary diffuse large B cell lymphoma of the CNS (CNS-DLBCL), and 110 controls by flow cytometry (FC). Additionally, an in-depth immunophenotyping of the PB from an independent cohort of 20 RRMS and 18 IDH-wildtype glioblastoma patients compared to 19 controls was performed by FC combined with unsupervised computational approaches.</p><p><strong>Results: </strong>We identified alterations in peripheral and intrathecal adaptive immunity, mainly affecting the T cell (Tc) but also the B cell (Bc) compartment in ALE, RRMS, and pCNS-tumors compared to controls. ALE, RRMS, and pCNS-tumors featured higher expression of the T cell activation marker HLA-DR, which was even more pronounced in pCNS-tumors than in ALE or RRMS. Glioblastoma patients showed signs of T cell exhaustion that were not visible in RRMS patients. In-depth characterization of the PB revealed differences mainly in the T effector and memory compartment between RRMS and glioblastoma patients and similar alterations in the Bc compartment, including atypical Bc, CD19<sup>+</sup>CD20<sup>-</sup> double negative Bc, and plasma cells. PB and CSF mFC together with CSF routine parameters could reliably differentiate ALE and RRMS from pCNS-tumors facilitating early diagnosis and treatment.</p><p><strong>Conclusions: </strong>ALE, RRMS, and pCNS-tumors show distinct but partially overlapping changes mainly in HLA-DR<sup>+</sup> Tc, memory Tc, exhausted Tc, and Bc subsets providing insights into disease pathogenesis. Moreover, mFC shows diagnostic potential facilitating early diagnosis and treatment.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536547/pdf/","citationCount":"0","resultStr":"{\"title\":\"Flow cytometry identifies changes in peripheral and intrathecal lymphocyte patterns in CNS autoimmune disorders and primary CNS malignancies.\",\"authors\":\"Saskia Räuber, Andreas Schulte-Mecklenbeck, Alice Willison, Ramona Hagler, Marius Jonas, Duygu Pul, Lars Masanneck, Christina B Schroeter, Kristin S Golombeck, Stefanie Lichtenberg, Christine Strippel, Marco Gallus, Andre Dik, Ruth Kerkhoff, Sumanta Barman, Katharina J Weber, Stjepana Kovac, Melanie Korsen, Marc Pawlitzki, Norbert Goebels, Tobias Ruck, Catharina C Gross, Werner Paulus, Guido Reifenberger, Michael Hanke, Oliver Grauer, Marion Rapp, Michael Sabel, Heinz Wiendl, Sven G Meuth, Nico Melzer\",\"doi\":\"10.1186/s12974-024-03269-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Immune dysregulation is a hallmark of autoimmune diseases of the central nervous system (CNS), characterized by an excessive immune response, and primary CNS tumors (pCNS-tumors) showing a highly immunosuppressive parenchymal microenvironment.</p><p><strong>Methods: </strong>Aiming to provide novel insights into the pathogenesis of CNS autoimmunity and cerebral tumor immunity, we analyzed the peripheral blood (PB) and cerebrospinal fluid (CSF) of 81 autoimmune limbic encephalitis (ALE), 148 relapsing-remitting multiple sclerosis (RRMS), 33 IDH-wildtype glioma, 9 primary diffuse large B cell lymphoma of the CNS (CNS-DLBCL), and 110 controls by flow cytometry (FC). Additionally, an in-depth immunophenotyping of the PB from an independent cohort of 20 RRMS and 18 IDH-wildtype glioblastoma patients compared to 19 controls was performed by FC combined with unsupervised computational approaches.</p><p><strong>Results: </strong>We identified alterations in peripheral and intrathecal adaptive immunity, mainly affecting the T cell (Tc) but also the B cell (Bc) compartment in ALE, RRMS, and pCNS-tumors compared to controls. ALE, RRMS, and pCNS-tumors featured higher expression of the T cell activation marker HLA-DR, which was even more pronounced in pCNS-tumors than in ALE or RRMS. Glioblastoma patients showed signs of T cell exhaustion that were not visible in RRMS patients. In-depth characterization of the PB revealed differences mainly in the T effector and memory compartment between RRMS and glioblastoma patients and similar alterations in the Bc compartment, including atypical Bc, CD19<sup>+</sup>CD20<sup>-</sup> double negative Bc, and plasma cells. PB and CSF mFC together with CSF routine parameters could reliably differentiate ALE and RRMS from pCNS-tumors facilitating early diagnosis and treatment.</p><p><strong>Conclusions: </strong>ALE, RRMS, and pCNS-tumors show distinct but partially overlapping changes mainly in HLA-DR<sup>+</sup> Tc, memory Tc, exhausted Tc, and Bc subsets providing insights into disease pathogenesis. 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引用次数: 0
摘要
背景:免疫失调是中枢神经系统(CNS)自身免疫性疾病的一个特征,其特点是过度的免疫反应,而原发性中枢神经系统肿瘤(pCNS-tumors)则显示出高度免疫抑制的实质微环境:为了深入了解中枢神经系统自身免疫和脑肿瘤免疫的发病机制,我们通过流式细胞术(FC)分析了81例自身免疫性边缘脑炎(ALE)、148例复发缓解型多发性硬化(RRMS)、33例IDH-野生型胶质瘤、9例中枢神经系统原发性弥漫大B细胞淋巴瘤(CNS-DLBCL)和110例对照组的外周血(PB)和脑脊液(CSF)。此外,我们还通过流式细胞术结合无监督计算方法,对独立队列中的20名RRMS和18名IDH-野生型胶质母细胞瘤患者的PB与19名对照组进行了深入的免疫分型:我们发现,与对照组相比,ALE、RRMS 和 pCNS 肿瘤患者的外周和鞘内适应性免疫发生了改变,主要影响 T 细胞 (Tc),但也影响 B 细胞 (Bc)。ALE、RRMS和中枢神经系统肿瘤的T细胞活化标志物HLA-DR的表达量较高,中枢神经系统肿瘤中的表达量甚至比ALE或RRMS中的表达量更高。胶质母细胞瘤患者表现出T细胞衰竭的迹象,而在RRMS患者中却不明显。PB的深入表征显示,RRMS和胶质母细胞瘤患者的T效应细胞和记忆细胞主要存在差异,Bc细胞也发生了类似的改变,包括非典型Bc、CD19+CD20-双阴性Bc和浆细胞。PB和CSF mFC以及CSF常规参数能可靠地区分ALE和RRMS与中枢神经系统肿瘤,从而有助于早期诊断和治疗:ALE、RRMS和中枢神经系统肿瘤主要在HLA-DR+ Tc、记忆Tc、衰竭Tc和Bc亚群中表现出不同但部分重叠的变化,为疾病的发病机制提供了见解。此外,mFC 还具有诊断潜力,有助于早期诊断和治疗。
Flow cytometry identifies changes in peripheral and intrathecal lymphocyte patterns in CNS autoimmune disorders and primary CNS malignancies.
Background: Immune dysregulation is a hallmark of autoimmune diseases of the central nervous system (CNS), characterized by an excessive immune response, and primary CNS tumors (pCNS-tumors) showing a highly immunosuppressive parenchymal microenvironment.
Methods: Aiming to provide novel insights into the pathogenesis of CNS autoimmunity and cerebral tumor immunity, we analyzed the peripheral blood (PB) and cerebrospinal fluid (CSF) of 81 autoimmune limbic encephalitis (ALE), 148 relapsing-remitting multiple sclerosis (RRMS), 33 IDH-wildtype glioma, 9 primary diffuse large B cell lymphoma of the CNS (CNS-DLBCL), and 110 controls by flow cytometry (FC). Additionally, an in-depth immunophenotyping of the PB from an independent cohort of 20 RRMS and 18 IDH-wildtype glioblastoma patients compared to 19 controls was performed by FC combined with unsupervised computational approaches.
Results: We identified alterations in peripheral and intrathecal adaptive immunity, mainly affecting the T cell (Tc) but also the B cell (Bc) compartment in ALE, RRMS, and pCNS-tumors compared to controls. ALE, RRMS, and pCNS-tumors featured higher expression of the T cell activation marker HLA-DR, which was even more pronounced in pCNS-tumors than in ALE or RRMS. Glioblastoma patients showed signs of T cell exhaustion that were not visible in RRMS patients. In-depth characterization of the PB revealed differences mainly in the T effector and memory compartment between RRMS and glioblastoma patients and similar alterations in the Bc compartment, including atypical Bc, CD19+CD20- double negative Bc, and plasma cells. PB and CSF mFC together with CSF routine parameters could reliably differentiate ALE and RRMS from pCNS-tumors facilitating early diagnosis and treatment.
Conclusions: ALE, RRMS, and pCNS-tumors show distinct but partially overlapping changes mainly in HLA-DR+ Tc, memory Tc, exhausted Tc, and Bc subsets providing insights into disease pathogenesis. Moreover, mFC shows diagnostic potential facilitating early diagnosis and treatment.
期刊介绍:
The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes.
Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems.
The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.