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

• Published in: Frontiers in immunology Vol. 10; p. 2715
• Main Authors: Engdahl, Elin, Gustafsson, Rasmus, Huang, Jesse, Biström, Martin, Lima Bomfim, Izaura, Stridh, Pernilla, Khademi, Mohsen, Brenner, Nicole, Butt, Julia, Michel, Angelika, Jons, Daniel, Hortlund, Maria, Alonso-Magdalena, Lucia, Hedström, Anna Karin, Flamand, Louis, Ihira, Masaru, Yoshikawa, Tetsushi, Andersen, Oluf, Hillert, Jan, Alfredsson, Lars, Waterboer, Tim, Sundström, Peter, Olsson, Tomas, Kockum, Ingrid, Fogdell-Hahn, Anna
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 2019
• Subjects: Adult; Antibodies, Viral - metabolism; Antibody Formation - genetics; association; Clinical Medicine; Cohort Studies; Epstein-Barr virus; Epstein-Barr Virus Infections - immunology; Female; Haplotypes; Herpesvirus 4, Human - physiology; Herpesvirus 6, Human - physiology; HLA-DQ alpha-Chains - genetics; HLA-DRB1 Chains - genetics; human herpesvirus 6A; human herpesvirus 6B; human leukocyte antigen; Humans; Immediate-Early Proteins - immunology; Immunoglobulin G - metabolism; Immunology; Klinisk medicin; Male; Medicin och hälsovetenskap; Middle Aged; multiple sclerosis; Multiple Sclerosis - immunology; Phosphoproteins - immunology; Risk; Roseolovirus Infections - immunology; serology; Young Adult; human leukocyte antigen; multiple sclerosis; serology; association; Epstein-Barr virus; risk; human herpesvirus 6A; human herpesvirus 6B
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2019.02715

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,
= 9 × 10
), and increased risk of future MS (OR = 2.22,
= 2 × 10
). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24,
= 6 × 10
). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74,
= 6 × 10
). 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.