We report that, while the proportion of EBNA-1 positive subjects is not affected by DRB1 status,8
DRB1 positivity is associated with higher EBNA-1 antibody response among those who are EBNA-1 positive (p
=0.005) after adjusting for MS/CIS status, age at sampling, race and ethnicity. In contrast, DRB1 positivity is not associated with higher VCA, EA, CMV or HSV-1 antibody response among those who are positive for seroconversion against the virus. This is an intriguing finding as VCA IgG seroconversion represents remote EBV infection whereas EBNA-1 IgG seroconversion oftentimes represents evidence of EBV latency. This may be related to DRB1 being a co-receptor for EBV entry in B-cells, but it is then unclear why this association is not found for VCA and EA. Whether the interactions between MS status and DRB1 status in the EBNA-1 and possibly EA models can be confirmed in larger studies or are clinically relevant remains to be determined.
Similar findings of higher EBNA-1 antibody response in DRB1 positive individuals were reported in adult controls but were not statistically significant in adult MS cases although this latter group was smaller and thus, the 95% CI did not exclude 1.0 (OR 1.47, 95% CI 0.74 to 2.93).6
An association of HLA class I polymorphisms respectively with EBV titers, number of EBV copies and risk of infectious mononucleosis has been reported in healthy individuals,13
suggesting a role for genetic background as a regulator of viral infection rate and clinical expression. Another study recently reported that three gene variants, HLA-DR15, HLA-A and CTLA4 altered the association between higher anti-EBNA response and risk of first demyelinating event in adults.14
That HLA-DRB1 is associated with EBNA-1 antibody response regardless of MS status suggests that DRB1 status or the status for a nearby gene (or a gene in linkage disequilibrium) influences the humoral response to EBNA-1, but not to VCA or EA. The reasons for this selectivity are elusive. It is also unclear whether and how the effect of DRB1 on the humoral response to EBNA-1 contributes to MS pathogenesis. Processes such as cross-reactivity between EBV and myelin protein,15
EBV activation of superantigens, and EBV activation of autoreactive B cells have been proposed as potentially underlying these results. Higher EBNA-1 titers were recently reported in smokers, and the risk of adult MS associated with high EBNA-1 titers was stronger in smokers.16
In this study, little modification by HLA-DR15 was observed.
We also report that pediatric MS patients have similar antibody concentrations against EBV (EBNA-1, VCA, EA), CMV and HSV-1 compared with seropositive neurologic disease controls. This finding is in contrast with previous studies which have reported higher antibody response to EBNA-1 in pediatric MS patients.17,18
However, differences exists between these studies and ours possibly explaining the discrepancy. One study used healthy and non demyelinating controls while the other averaged the response for all individuals including those EBV negative.19
Limitations of this study include the small number and type of controls who had other neurological conditions, some of which are inflammatory in nature such as acute disseminated encephalomyelitis, neurosarcoid or neuromyelitis optica. This could have biased our findings toward the null hypothesis. Although a few patients were on disease-modifying therapy at the time of blood sampling, our results based on analyses adjusted for the use of such therapies were very similar. We have not measured total IgG serum levels but considering the fact that antibody responses were similar for VCA, EA, CMV and HSV-1, we doubt that differences in IgG levels between controls and cases explain our findings. We have only studied HLA-DRB1*1501/1503 status. Future studies including healthy controls will have to confirm these observation and study full, high resolution HLA genotyping and how it relates to antibody response to various viruses associated with MS risk. Furthermore, other relevant viruses such as HHV-6 (Human Herpes Virus) should also be studied.
The role of EBV in MS pathogenesis is still overall poorly understood. It is unclear whether the virus plays a direct (molecular interaction) or indirect (promotion of smoldering inflammation) role in processes leading to disease onset, and whether this role is specific to MS or also applies to other autoimmune disorders. Although the two strongest risk factors for MS include EBV and DRB1, and HLA-type II molecules are necessary for EBV infection, very few reports are available that suggest gene-environment interactions between these two factors in MS. Our data suggest that the effect of DRB1, although restricted to EBNA-1, and not other viruses under study, may in fact not be disease specific, as found in both cases and controls.
Understanding factors that regulate antibody response to specific viral antigens may prove helpful to understand the multiple processes at play in MS onset.