Attenuated immune control of Epstein-Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA-DR15.
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Zdimerova H
Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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Murer A
Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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Engelmann C
Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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Raykova A
Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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Deng Y
Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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Gujer C
Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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Rühl J
Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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McHugh D
Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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Caduff N
Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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Naghavian R
Neuroimmunology and MS Research Section, Neurology Clinic, University Hospital Zurich, University Zurich, Zurich, Switzerland.
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Pezzino G
Laboratory of Immunology and Biotherapy, Department of Human Pathology, University of Messina, Messina, Italy.
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Capaul R
Institute of Medical Virology, University of Zürich, Zürich, Switzerland.
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Zbinden A
Institute of Medical Virology, University of Zürich, Zürich, Switzerland.
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Ferlazzo G
Laboratory of Immunology and Biotherapy, Department of Human Pathology, University of Messina, Messina, Italy.
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Lünemann JD
Department of Neurology with Institute of Translational Neurology, Medical Faculty, University of Münster, Münster, Germany.
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Martin R
Neuroimmunology and MS Research Section, Neurology Clinic, University Hospital Zurich, University Zurich, Zurich, Switzerland.
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Chatterjee B
Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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Münz C
Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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Published in:
- European journal of immunology. - 2020
English
Immune responses to Epstein-Barr virus (EBV) infection synergize with the main genetic risk factor HLA-DRB1*15:01 (HLA-DR15) to increase the likelihood to develop the autoimmune disease multiple sclerosis (MS) at least sevenfold. In order to gain insights into this synergy, we investigated HLA-DR15 positive human immune compartments after reconstitution in immune-compromised mice (humanized mice) with and without EBV infection. We detected elevated activation of both CD4+ and CD8+ T cells in HLA-DR15 donor-reconstituted humanized mice at steady state, even when compared to immune compartments carrying HLA-DRB1*04:01 (HLA-DR4), which is associated with other autoimmune diseases. Increased CD8+ T cell expansion and activation was also observed in HLA-DR15 donor-reconstituted humanized mice after EBV infection. Despite this higher immune activation, EBV viral loads were less well controlled in the context of HLA-DR15. Indeed, HLA-DR15-restricted CD4+ T cell clones recognized EBV-transformed B cell lines less efficiently and demonstrated cross-reactivity toward allogeneic target cells and one MS autoantigen. These findings suggest that EBV as one of the main environmental risk factors and HLA-DR15 as the main genetic risk factor for MS synergize by priming hyperreactive T-cell compartments, which then control the viral infection less efficiently and contain cross-reactive CD4+ T cell clones.
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Open access status
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bronze
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Persistent URL
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https://folia.unifr.ch/global/documents/234661
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