Intrathecal CD8 T-cells of multiple sclerosis patients recognize lytic Epstein-Barr virus proteins

Nierop, Gijsbert P. van; Mautner, Josef; Mitterreiter, Johanna G.; Hintzen, Rogier Q.; Verjans, Georges M. G. M.

doi:10.1177/1352458515588581

Cited by 51 publications

(51 citation statements)

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“…In addition, in inflamed cerebral meninges of post‐mortem MS brain tissue, infiltrates of effector and cytotoxic CD8 + T cells and innate immune responses characterized by interferon‐ α production have been detected in proximity to EBV‐infected plasma cells . Therefore, the observed increase of CD8 + T cells specific for EBV lytic antigens in the peripheral blood and cerebrospinal fluid (CSF) of patients with MS during relapses suggests a close association between replication of EBV in the CNS and inflammatory disease activity . Also, the evidence for active replication of EBV in patients with MS indicates that the virus has the capacity to escape immune control by cytotoxic lymphocytes .…”

Section: Introductionmentioning

confidence: 99%

“…8,10 Therefore, the observed increase of CD8 + T cells specific for EBV lytic antigens in the peripheral blood and cerebrospinal fluid (CSF) of patients with MS during relapses suggests a close association between replication of EBV in the CNS and inflammatory disease activity. [11][12][13] Also, the evidence for active replication of EBV in patients with MS indicates that the virus has the capacity to escape immune control by cytotoxic lymphocytes. 11 However, the results from other studies examining the involvement of EBV infection in the MS pathological process diverged.…”

Section: Introductionmentioning

confidence: 99%

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Programmed death 1 is highly expressed on CD8⁺CD57⁺ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein–Barr virus

et al. 2017

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Summary Growing evidence points to a deregulated response to Epstein–Barr virus (EBV) in the central nervous system of patients with multiple sclerosis (MS) as a possible cause of disease. We have investigated the response of a subpopulation of effector CD8+ T cells to EBV in 36 healthy donors and in 35 patients with MS in active and inactive disease. We have measured the expression of markers of degranulation, the release of cytokines, cytotoxicity and the regulation of effector functions by inhibitory receptors, such as programmed death 1 (PD‐1) and human inhibitor receptor immunoglobulin‐like transcript 2 (ILT2). We demonstrate that polyfunctional cytotoxic CD8+ CD57+ T cells are able to kill EBV‐infected cells in healthy donors. In contrast, an anergic exhaustion‐like phenotype of CD8+ CD57+ T cells with high expression of PD‐1 was observed in inactive patients with MS compared with active patients with MS or healthy donors. Detection of CD8+ CD57+ T cells in meningeal inflammatory infiltrates from post‐mortem MS tissue confirmed the association of this cell phenotype with the disease pathological process. The overall results suggest that ineffective immune control of EBV in patietns with MS during remission may be one factor preceding and enabling the reactivation of the virus in the central nervous system and may cause exacerbation of the disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Programmed death 1 is highly expressed on CD8⁺CD57⁺ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein–Barr virus

et al. 2017

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“…This protein is ordinarily not expressed in human lymphoid tissues; however, perhaps due to the stress of EBV infection, infected B cells express CRYAB, along with presentation of CRYAB peptides on HLA-DR to CD4 + T cells, promoting an inflammatory response. Curiously, in a constructed system of antigen presentation on HLA-I molecules, the expression of CRYAB within the antigen-presenting cells did not result in CD8 + T cell recognition or activation (van Nierop et al, 2016). This implies a more restricted T cell response to CRYAB epitopes in the form of memory CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Antibodies from multiple sclerosis brain identified Epstein-Barr virus nuclear antigen 1 & 2 epitopes which are recognized by oligoclonal bands

Wang¹,

Kennedy

Dupree

et al. 2020

Preprint

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Background Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), the etiology of which is poorly understood. The most common laboratory abnormality associated with MS is increased intrathecal IgG synthesis and the presence of oligoclonal bands (OCBs) in the brain and cerebrospinal fluid (CSF). However, the major antigenic targets of these antibody responses are unknown. The risk of MS is increased after infectious mononucleosis (IM) due to EBV infection, and MS patients have higher serum titers of anti-EBV antibodies than control populations. Objectives To identify disease-relevant epitopes of IgG antibodies in MS. Methods We screened phage-displayed random peptide libraries (12-mer) with total IgG antibodies purified from the brain of a patient with acute MS. We identified and characterized the phage peptides for binding specificity to intrathecal IgG from patients with MS and from controls by ELISA, phage-mediated Immuno-PCR, and isoelectric focusing. Results Two phage peptides were identified that share sequence homologies with EBV nuclear antigens 1 and 2 (EBNA1 and EBNA2), respectively. The specificity of the EBV epitopes found by panning with MS brain IgG was confirmed by ELISA and competitive inhibition assays. Using a highly sensitive phage-mediated immuno-PCR assay, we determined specific bindings of the two EBV epitopes to IgG from CSF from 46 MS and 5 inflammatory control (IC) patients. MS CSF IgG have significantly higher bindings to EBNA1 epitope than to EBNA2 epitope, whereas EBNA1 and EBNA2 did not significantly differ in binding to IC CSF IgG. Further, the EBNA1 epitope was recognized by OCBs from multiple MS CSF as shown in blotting assays with samples separated by isoelectric focusing. Conclusions The EBNA1 epitope is reactive to MS intrathecal antibodies corresponding to oligoclonal bands. This reinforces the potential role of EBV in the etiology of MS.

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“…Primary effector preparations were made by direct expansion of the activated CD8+ T cells that dominate the blood picture in IM, and earlier work using defined HLA/EBV peptide tetramers has shown that such ex vivo-expanded IM effectors accurately reflect the in vivo response [12]. By contrast, the small population of EBV-specific memory cells in the blood of healthy carriers need to be selectively reactivated in vitro before expansion; not surprisingly, the only published attempt at direct memory cell expansion ex vivo revealed very few detectable EBV-specific reactivities despite screening on a wide target panel [31]. To avoid the bias inherent in using LCL cells to reactivate memory, we adapted an approach first developed for HSV [3] whereby monocyte-derived dendritic cells cross-present the whole spectrum of virus-coded lytic antigens to the CD8 memory pool.…”

Section: Discussionmentioning

confidence: 99%

Proteome-Wide Analysis of Cd8+ T Cell Responses to Ebv Reveals Differences Between Primary and Persistent Infection

Forrest

Hislop

Rickinson

et al. 2018

Preprint

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words)Human herpesviruses are antigenically rich agents that induce strong CD8+T cell responses in primary infection yet persist for life, continually challenging T cell memory through recurrent lytic replication and potentially influencing the spectrum of antigen-specific responses. Here we describe the first lytic proteome-wide analysis of CD8+ T cell responses to the Epstein-Barr gamma1-herpesvirus (EBV), and the first such proteome-wide analysis of primary versus memory CD8 responses to any human herpesvirus. Primary effector preparations were generated directly from activated CD8+ T cells in the blood of infectious mononucleosis (IM) patients by in vitro mitogenic expansion. For memory preparations, EBV-specific cells in the blood of long-term virus carriers were first re-stimulated in vitro by autologous dendritic cells loaded with a lysate of lytically-infected cells, then expanded as for IM cells. Preparations from 7 donors of each type were screened against each of 70 EBV lytic cycle proteins in combination with the donor's individual HLA class I alleles. Multiple reactivities against immediate early (IE), early (E) and late (L) lytic cycle proteins, including many hitherto unrecognised targets, were detected in both contexts. Interestingly however, the two donor cohorts showed a different balance between IE, E and L reactivities. Primary responses targeted IE and a small group of E proteins preferentially, seemingly in line with their better presentation on the infected cell surface before later-expressed viral evasins take full hold. By contrast, target choice equilibrates in virus carriage with responses to key IE and E antigens still present but with responses to a select subset of L proteins now often prominent. We infer that, for EBV at least, long-term virus carriage with its low level virus replication and lytic antigen release is associated with a re-shaping of the virus-specific response.3 Author Summary (156 words) Epstein-Barr virus (EBV) is a herpesvirus and an important human pathogen that normally persists for life and induces strong CD8+T cell responses. Primary EBV infection can cause mononucleosis (IM) disease and EBV is associated with malignant lymphocytes cancers and epithelial cells. Here for the first time, we described proteome-wide analysis of CD8+ T cell responses to EBV lytic antigens, and compare the CD8 T cell responses between primary and memory CD8 responses to EBV. The EBV primary CD8 T cells responses targeted IE and a small group of E proteins preferentially. By contrast, the memory CD8 T cells responses from EBV persistent infection are dominated by L proteins. This study can help to understand how human CD8 T cells respond evolves with the long-term virus infection. For EBV at least, we infer that long-term EBV virus carriage with its low level virus replication and lytic antigen release is associated with a re-shaping of the virus-specific response.4

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Intrathecal CD8 T-cells of multiple sclerosis patients recognize lytic Epstein-Barr virus proteins

Cited by 51 publications

References 35 publications

Programmed death 1 is highly expressed on CD8⁺CD57⁺ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein–Barr virus

Programmed death 1 is highly expressed on CD8⁺CD57⁺ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein–Barr virus

Antibodies from multiple sclerosis brain identified Epstein-Barr virus nuclear antigen 1 & 2 epitopes which are recognized by oligoclonal bands

Proteome-Wide Analysis of Cd8+ T Cell Responses to Ebv Reveals Differences Between Primary and Persistent Infection

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Intrathecal CD8 T-cells of multiple sclerosis patients recognize lytic Epstein-Barr virus proteins

Cited by 51 publications

References 35 publications

Programmed death 1 is highly expressed on CD8+CD57+ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein–Barr virus

Programmed death 1 is highly expressed on CD8+CD57+ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein–Barr virus

Antibodies from multiple sclerosis brain identified Epstein-Barr virus nuclear antigen 1 &amp; 2 epitopes which are recognized by oligoclonal bands

Proteome-Wide Analysis of Cd8+ T Cell Responses to Ebv Reveals Differences Between Primary and Persistent Infection

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Programmed death 1 is highly expressed on CD8⁺CD57⁺ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein–Barr virus

Programmed death 1 is highly expressed on CD8⁺CD57⁺ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein–Barr virus

Antibodies from multiple sclerosis brain identified Epstein-Barr virus nuclear antigen 1 & 2 epitopes which are recognized by oligoclonal bands