Increased Serological Response Against Human Herpesvirus 6A Is Associated With Risk for Multiple Sclerosis

Elin Engdahl, Rasmus Gustafsson, Jesse Huang, Martin Biström, Izaura Lima Bomfim, Pernilla Stridh, Mohsen Khademi, Nicole Brenner, Julia Butt, Angelika Michel, Daniel Jons, Maria Hortlund, Lucia Alonso-Magdalena, Anna Karin Hedström, Louis Flamand, Masaru Ihira, Tetsushi Yoshikawa, Oluf Andersen, Jan Hillert, Lars AlfredssonTim Waterboer, Peter Sundström, Tomas Olsson, Ingrid Kockum, Anna Fogdell-Hahn

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Abstract

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 (8,742 persons with MS and 7,215 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 = 9 × 10−22), and increased risk of future MS (OR = 2.22, p = 2 × 10−5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6 × 10−6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6 × 10−11). 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 Human Leukocyte Antigen (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.

Original languageEnglish
Article number2715
JournalFrontiers in Immunology
Volume10
DOIs
Publication statusPublished - 26-11-2019

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Engdahl, E., Gustafsson, R., Huang, J., Biström, M., Lima Bomfim, I., Stridh, P., Khademi, M., Brenner, N., Butt, J., Michel, A., Jons, D., Hortlund, M., Alonso-Magdalena, L., Hedström, A. K., Flamand, L., Ihira, M., Yoshikawa, T., Andersen, O., Hillert, J., ... Fogdell-Hahn, A. (2019). Increased Serological Response Against Human Herpesvirus 6A Is Associated With Risk for Multiple Sclerosis. Frontiers in Immunology, 10, [2715]. https://doi.org/10.3389/fimmu.2019.02715