Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis

Author:

Thomas Olivia G.1ORCID,Bronge Mattias1ORCID,Tengvall Katarina23ORCID,Akpinar Birce1,Nilsson Ola B.1,Holmgren Erik1ORCID,Hessa Tara1,Gafvelin Guro1ORCID,Khademi Mohsen2ORCID,Alfredsson Lars24ORCID,Martin Roland15ORCID,Guerreiro-Cacais André Ortlieb2ORCID,Grönlund Hans1ORCID,Olsson Tomas2ORCID,Kockum Ingrid2ORCID

Affiliation:

1. Therapeutic Immune Design, Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institute, 171 76 Stockholm, Sweden.

2. Neuroimmunology Unit, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, 171 76 Stockholm, Sweden.

3. Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 75123 Uppsala, Sweden.

4. Institute of Environmental Medicine, Karolinska Institute, 171 77 Stockholm, Sweden.

5. Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, for which Epstein-Barr virus (EBV) infection is a likely prerequisite. Due to the homology between Epstein-Barr nuclear antigen 1 (EBNA1) and alpha-crystallin B (CRYAB), we examined antibody reactivity to EBNA1 and CRYAB peptide libraries in 713 persons with MS (pwMS) and 722 matched controls (Con). Antibody response to CRYAB amino acids 7 to 16 was associated with MS (OR = 2.0), and combination of high EBNA1 responses with CRYAB positivity markedly increased disease risk (OR = 9.0). Blocking experiments revealed antibody cross-reactivity between the homologous EBNA1 and CRYAB epitopes. Evidence for T cell cross-reactivity was obtained in mice between EBNA1 and CRYAB, and increased CRYAB and EBNA1 CD4 + T cell responses were detected in natalizumab-treated pwMS. This study provides evidence for antibody cross-reactivity between EBNA1 and CRYAB and points to a similar cross-reactivity in T cells, further demonstrating the role of EBV adaptive immune responses in MS development.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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