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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02715

Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis

  • 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden AND Center for Molecular Medicine (CMM), Sweden
  • 2Department of Pharmacology and Clinical Neuroscience, Umeå University, Sweden
  • 3German Cancer Research Center (DKFZ), Germany
  • 4Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden
  • 5Department of Laboratory Medicine, Karolinska Institutet, Sweden
  • 6Department of Neurology, Skåne University Hospital, Sweden
  • 7Institute of Environmental Medicine, Karolinska Institutet, Sweden
  • 8Department of Clinical Neuroscience, Karolinska Institutet, Sweden
  • 9Department of Microbiology-Infectiology and Immunology, Faculty of Medicine, Laval University, Canada
  • 10Department of Pediatrics, Faculty of Medicine, Fujita Health University, Japan
  • 11Centre for Occupational and Environmental Medicine, Stockholm County Council, Sweden
  • 12Department of Pharmacology and Clinical Neuroscience, Faculty of Medicine, Umeå University, Sweden
  • 13Department of Clinical Neuroscience, Karolinska Institutet, Sweden
  • 14Karolinska Institutet (KI), Sweden

Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses.
A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8742 persons with MS and 7215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further.
The IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9x10-22), and increased risk of future MS (OR = 2.22, p = 2x10-5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6x10-6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6x10-11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the HLA region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04.
In conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.

Keywords: Human Herpesvirus 6A, Human herpesvirus 6B, Multiple Sclerosis, Association, risk, Epstein-Barr virus ( EBV), human leukocyte antigen (HLA), Serology

Received: 16 Aug 2019; Accepted: 05 Nov 2019.

Copyright: © 2019 Engdahl, Gustafsson, Huang, Biström, Lima Bomfim, Stridh, Khademi, Brenner, Butt, Michel, Jons, Hortlund, Alonso-Magdalena, Hedström, Flamand, Ihira, Yoshikawa, Andersen, Hillert, Alfredsson, Waterboer, Sundström, Olsson, Kockum and Fogdell-Hahn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Anna Fogdell-Hahn, Karolinska Institutet (KI), Solna, Sweden, Anna.Fogdell-Hahn@ki.se