Frontiers in Immunology (Nov 2019)

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

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

DOI
https://doi.org/10.3389/fimmu.2019.02715
Journal volume & issue
Vol. 10

Abstract

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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.

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