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

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

Elin Engdahl et al. Front Immunol.

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.

Keywords: Epstein-Barr virus; association; human herpesvirus 6A; human herpesvirus 6B; human leukocyte antigen; multiple sclerosis; risk; serology.

Figures

Figure 1
Figure 1
Antibody responses against HHV-6A and 6B proteins in MS cases and controls. Log10-transformed antibody levels measured as median fluorescence intensity (MFI) are visualized with bean plots for established MS cohort [n = 8,742 persons with MS (blue) and n = 7,215 controls (pink)] (A–C) and pre-MS cohort [n = 478 persons with MS (blue) and n = 476 controls (pink)] (D–F) for HHV-6A IE1A IgG (A,D); HHV-6B IE1B IgG (B,E); HHV-6B anti-101K IgG (C,F). The 1st and 3rd quartiles are indicated with dotted lines and solid lines indicate median.
Figure 2
Figure 2
Interaction of antibody response against different herpesviruses in association to MS. Odds ratios (OR) and confidence intervals (CI) for IE1A and EBV (A) and IE1A and CMV (B), were obtained through logistic regression models adjusted for age, sex and cohort type analyzing the Established MS cohort (n = 8,742 persons with MS and n = 7,215 controls). OR were calculated in relation to the group with the lowest MS risk. Plus (+) indicates being a strong responder while minus (–) indicates being a weak responder. Strong IE1A response is defined as having an MFI value being in the upper quartile of measured response, while a low response is having an antibody measurement being in the lower quartile of measured response. Strong EBV/CMV response is defined as having a higher EBV/CMV index than the median among controls, while a weak response is having a lower index compared to the median among controls.
Figure 3
Figure 3
Median MFI response against HHV-6A IE1A protein in different age groups. Median of median fluorescence intensity (MFI) in different age groups for (A) pre-MS cohort (n = 478 persons who later developed MS and n = 476 controls) and (B) established MS cohort (n = 8,394 persons with MS and n = 7,214 controls). Statistics were calculated with linear regression. Significant (p < 0.008) differences in IgG levels between MS cases and controls within each age group are indicated with *.
Figure 4
Figure 4
Manhattan plots visualizing associations between SNPs and anti-HHV-6A/6B protein IgG response levels. GWAS data (n = 6,396 MS cases and n = 5,530 controls from the established MS cohort) obtained through linear regression models showing associations between SNPs and IgG response (Log10 levels) against (A) IE1A, (B) IE1B and, (C) 101K. Red lines indicate GWAS significance level of 5 ×10−8 (–log10 = 7.3 on the y-axis) and blue lines indicate suggestive association (p = 10−5). Analysis was carried out jointly in MS cases and controls and adjusted with age, sex, cohort type, and case status.
Figure 5
Figure 5
Interaction analysis between IE1A and IE1B IgG response and main MS risk HLA alleles. Odds ratios (OR) and confidence intervals (CI) for (A) IE1A and DRB1*15:01, (B) IE1A and A*02:01, (C) IE1B and DRB1*15:01, and (D) IE1B and A*02 were obtained through logistic regression models adjusted for age, sex and cohort type analyzing the Established MS cohort (n = 7,063 MS cases and n = 6,098 controls). OR were calculated in relation to the group with the lowest MS risk. Plus (+) indicates being a strong responder while minus (–) indicates being a weak responder defined as having an MFI value in the upper quartile of measured response. AP = attributable proportion due to interaction, p is p-value for interaction. No adjustment for EBV was done in these figures.
Figure 6
Figure 6
Flow chart depicting identification and selection of patients for inclusion in the Pre-MS cohort. Through crosslinking between the Swedish MS registry and three Swedish microbiological biobanks potential study participants were identified. In the next step all patients that did not have a relapsing onset of MS, had not deposited serum sample before MS debut or were above 40 years old at the time of sampling were excluded. Validation of the information gathered from the Swedish MS registry was performed for 65% of study participants. This, together with some samples missing or having too low volume, resulted in additional patients being excluded.

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References

    1. Ablashi D, Agut H, Alvarez-Lafuente R, Clark DA, Dewhurst S, DiLuca D, et al. . Classification of HHV-6A and HHV-6B as distinct viruses. Arch Virol. (2014) 159:863–70. 10.1007/s00705-013-1902-5 - DOI - PMC - PubMed
    1. Hall CB, Caserta MT, Schnabel KC, Long C, Epstein LG, Insel RA, et al. . Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A. Clin Infect Dis. (1998) 26:132–7. 10.1086/516280 - DOI - PubMed
    1. Dewhurst S, McIntyre K, Schnabel K, Hall CB. Human herpesvirus 6 (HHV-6) variant B accounts for the majority of symptomatic primary HHV-6 infections in a population of U.S. infants. J Clin Microbiol. (1993) 31:416–8. - PMC - PubMed
    1. Hall CB, Long CE, Schnabel KC, Caserta MT, McIntyre KM, Costanzo MA, et al. . Human herpesvirus-6 infection in children. A prospective study of complications and reactivation. N Engl J Med. (1994) 331:432–8. 10.1056/NEJM199408183310703 - DOI - PubMed
    1. Zerr DM, Meier AS, Selke SS, Frenkel LM, Huang ML, Wald A, et al. . A population-based study of primary human herpesvirus 6 infection. N Engl J Med. (2005) 352:768–76. 10.1056/NEJMoa042207 - DOI - PubMed
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