The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis impact of immunotherapies

Jamie van Langelaar; Annet F Wierenga-Wolf; Johnny P A Samijn; Caroline J M Luijks; Theodora A Siepman; Pieter A van Doorn; Andrew Bell; Menno C van Zelm; Joost Smolders; Marvin M van Luijn

doi:10.1002/eji.202048739

The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis impact of immunotherapies

Jamie van Langelaar, Annet F Wierenga-Wolf, Johnny P A Samijn, Caroline J M Luijks, Theodora A Siepman, Pieter A van Doorn, Andrew Bell, Menno C van Zelm, Joost Smolders, Marvin M van Luijn

Netherlands Institute for Neuroscience (NIN)

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

Abstract

Epstein-Barr virus (EBV) infection of B cells is associated with increased multiple sclerosis (MS) susceptibility. Recently, we found that CXCR3-expressing B cells preferentially infiltrate the central nervous system of MS patients. In chronic virus-infected mice, these types of B cells are sustained and show increased antiviral responsiveness. How EBV persistence in B cells influences their development remains unclear. First, we analyzed ex vivo B-cell subsets from MS patients who received autologous bone marrow transplantation (n=9), which is often accompanied by EBV reactivation. The frequencies of non-class-switched and class-switched memory B cells were reduced at 3-7 months, while only class-switched B cells returned back to baseline at 24-36 months post-transplantation. At these time points, EBV DNA load positively correlated to the frequency of CXCR3+ , and not CXCR4+ or CXCR5+ , class-switched B cells. Second, for CXCR3+ memory B cells trapped within the blood of MS patients treated with natalizumab (anti-VLA-4 antibody n=15), latent EBV infection corresponded to enhanced in vitro formation of anti-EBNA1 IgG-secreting plasma cells under germinal center-like conditions. These findings imply that EBV persistence in B cells potentiates brain-homing and antibody-producing CXCR3+ subsets in MS. This article is protected by copyright. All rights reserved.

Original language	English
Journal	European Journal of Immunology
DOIs	https://doi.org/10.1002/eji.202048739
Publication status	E-pub ahead of print - 2021

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van Langelaar, J., Wierenga-Wolf, A. F., Samijn, J. P. A., Luijks, C. J. M., Siepman, T. A., van Doorn, P. A., Bell, A., van Zelm, M. C., Smolders, J., & van Luijn, M. M. (2021). The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis impact of immunotherapies. European Journal of Immunology. https://doi.org/10.1002/eji.202048739

van Langelaar, Jamie ; Wierenga-Wolf, Annet F ; Samijn, Johnny P A ; Luijks, Caroline J M ; Siepman, Theodora A ; van Doorn, Pieter A ; Bell, Andrew ; van Zelm, Menno C ; Smolders, Joost ; van Luijn, Marvin M. / The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis impact of immunotherapies. In: European Journal of Immunology. 2021.

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title = "The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis impact of immunotherapies",

abstract = "Epstein-Barr virus (EBV) infection of B cells is associated with increased multiple sclerosis (MS) susceptibility. Recently, we found that CXCR3-expressing B cells preferentially infiltrate the central nervous system of MS patients. In chronic virus-infected mice, these types of B cells are sustained and show increased antiviral responsiveness. How EBV persistence in B cells influences their development remains unclear. First, we analyzed ex vivo B-cell subsets from MS patients who received autologous bone marrow transplantation (n=9), which is often accompanied by EBV reactivation. The frequencies of non-class-switched and class-switched memory B cells were reduced at 3-7 months, while only class-switched B cells returned back to baseline at 24-36 months post-transplantation. At these time points, EBV DNA load positively correlated to the frequency of CXCR3+ , and not CXCR4+ or CXCR5+ , class-switched B cells. Second, for CXCR3+ memory B cells trapped within the blood of MS patients treated with natalizumab (anti-VLA-4 antibody n=15), latent EBV infection corresponded to enhanced in vitro formation of anti-EBNA1 IgG-secreting plasma cells under germinal center-like conditions. These findings imply that EBV persistence in B cells potentiates brain-homing and antibody-producing CXCR3+ subsets in MS. This article is protected by copyright. All rights reserved.",

author = "{van Langelaar}, Jamie and Wierenga-Wolf, {Annet F} and Samijn, {Johnny P A} and Luijks, {Caroline J M} and Siepman, {Theodora A} and {van Doorn}, {Pieter A} and Andrew Bell and {van Zelm}, {Menno C} and Joost Smolders and {van Luijn}, {Marvin M}",

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doi = "10.1002/eji.202048739",

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journal = "European Journal of Immunology",

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The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis impact of immunotherapies. / van Langelaar, Jamie; Wierenga-Wolf, Annet F; Samijn, Johnny P A; Luijks, Caroline J M; Siepman, Theodora A; van Doorn, Pieter A; Bell, Andrew; van Zelm, Menno C; Smolders, Joost; van Luijn, Marvin M.

In: European Journal of Immunology, 2021.

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

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AU - van Langelaar, Jamie

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AU - Luijks, Caroline J M

AU - Siepman, Theodora A

AU - van Doorn, Pieter A

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AU - van Zelm, Menno C

AU - Smolders, Joost

AU - van Luijn, Marvin M

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N2 - Epstein-Barr virus (EBV) infection of B cells is associated with increased multiple sclerosis (MS) susceptibility. Recently, we found that CXCR3-expressing B cells preferentially infiltrate the central nervous system of MS patients. In chronic virus-infected mice, these types of B cells are sustained and show increased antiviral responsiveness. How EBV persistence in B cells influences their development remains unclear. First, we analyzed ex vivo B-cell subsets from MS patients who received autologous bone marrow transplantation (n=9), which is often accompanied by EBV reactivation. The frequencies of non-class-switched and class-switched memory B cells were reduced at 3-7 months, while only class-switched B cells returned back to baseline at 24-36 months post-transplantation. At these time points, EBV DNA load positively correlated to the frequency of CXCR3+ , and not CXCR4+ or CXCR5+ , class-switched B cells. Second, for CXCR3+ memory B cells trapped within the blood of MS patients treated with natalizumab (anti-VLA-4 antibody n=15), latent EBV infection corresponded to enhanced in vitro formation of anti-EBNA1 IgG-secreting plasma cells under germinal center-like conditions. These findings imply that EBV persistence in B cells potentiates brain-homing and antibody-producing CXCR3+ subsets in MS. This article is protected by copyright. All rights reserved.

AB - Epstein-Barr virus (EBV) infection of B cells is associated with increased multiple sclerosis (MS) susceptibility. Recently, we found that CXCR3-expressing B cells preferentially infiltrate the central nervous system of MS patients. In chronic virus-infected mice, these types of B cells are sustained and show increased antiviral responsiveness. How EBV persistence in B cells influences their development remains unclear. First, we analyzed ex vivo B-cell subsets from MS patients who received autologous bone marrow transplantation (n=9), which is often accompanied by EBV reactivation. The frequencies of non-class-switched and class-switched memory B cells were reduced at 3-7 months, while only class-switched B cells returned back to baseline at 24-36 months post-transplantation. At these time points, EBV DNA load positively correlated to the frequency of CXCR3+ , and not CXCR4+ or CXCR5+ , class-switched B cells. Second, for CXCR3+ memory B cells trapped within the blood of MS patients treated with natalizumab (anti-VLA-4 antibody n=15), latent EBV infection corresponded to enhanced in vitro formation of anti-EBNA1 IgG-secreting plasma cells under germinal center-like conditions. These findings imply that EBV persistence in B cells potentiates brain-homing and antibody-producing CXCR3+ subsets in MS. This article is protected by copyright. All rights reserved.

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