Attenuated immune control of Epstein-Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA-DR15.
- Zdimerova H Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
- Murer A Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
- Engelmann C Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
- Raykova A Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
- Deng Y Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
- Gujer C Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
- Rühl J Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
- McHugh D Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
- Caduff N Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
- Naghavian R Neuroimmunology and MS Research Section, Neurology Clinic, University Hospital Zurich, University Zurich, Zurich, Switzerland.
- Pezzino G Laboratory of Immunology and Biotherapy, Department of Human Pathology, University of Messina, Messina, Italy.
- Capaul R Institute of Medical Virology, University of Zürich, Zürich, Switzerland.
- Zbinden A Institute of Medical Virology, University of Zürich, Zürich, Switzerland.
- Ferlazzo G Laboratory of Immunology and Biotherapy, Department of Human Pathology, University of Messina, Messina, Italy.
- Lünemann JD Department of Neurology with Institute of Translational Neurology, Medical Faculty, University of Münster, Münster, Germany.
- Martin R Neuroimmunology and MS Research Section, Neurology Clinic, University Hospital Zurich, University Zurich, Zurich, Switzerland.
- Chatterjee B Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
- Münz C Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
- 2020-09-19
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.
- Language
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- English
- Open access status
- bronze
- Identifiers
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- DOI 10.1002/eji.202048655
- PMID 32949466
- Persistent URL
- https://sonar.ch/global/documents/234661
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