Anti-Human Herpesvirus 6A/B IgG Correlates with Relapses and Progression in Multiple Sclerosis

Abstract

ObjectiveTo analyze the titers of the IgG and IgM antibodies against human herpesvirus 6A/B (HHV-6A/B) in multiple sclerosis (MS) patients treated with different disease modified therapies (DMTs) along two-years of follow-up.MethodsWe collected 2163 serum samples from 596 MS; for 301 MS patients a 2-years follow-up was performed. Serum samples of 337 healthy controls were also analyzed. Anti-HHV-6A/B IgG and IgM were analyzed by ELISA (Panbio).ResultsWe found that 129/187 (69.0%) MS patients with a decrease of the anti-HHV-6A/B IgG titers after 2-years with DMTs were free of relapses and progression vs. 46/113 (40.7%) of MS patients with an increase of the anti-HHV-6A/B IgG titers (p = 0.0000015); the higher significance was found for natalizumab. Furthermore, we found that anti-HHV-6A/B IgG titers reached their highest value two weeks before the relapse (p = 0.0142), while the anti-HHV-6A/B IgM titers reached their highest value one month before the relapse (p = 0.0344).ConclusionThe measurement of the anti-HHV-6A/B IgG titers could be a good biomarker of clinical response to the different DMTs. The increase of the anti-HHV-6A/B IgG and IgM titers predicts the upcoming clinical relapses. However, further longitudinal studies are needed to validate these results.

HLA-A∗02, gender and tobacco smoking, but not multiple sclerosis, affects the IgG antibody response against human herpesvirus 6

“…As we do not have a validated cutoff for determining positivity the exact % seropositive individuals should be interpreted with caution. However, as seen in Table 2, the combined seropositivities for all three epitopes measured in study V are in the range of 75-100% that has previously been reported as HHV-6A/6B IgG seropositivity in the general population [9,11,[60][61][62][63]. As seen in Figure 20, the IgG responses against the two HHV-6B epitopes IE1B and 101K do not correlate, indicating that individuals generally do not seem to have antibodies specific for both IE1 and 101K at the same time.…”

“…Both studies performed by us (Study IV) and others [9,11,[60][61][62][63] have detected IgG antibodies against HHV-6A/6B in >75% of the general population. The problem with antibody assays used, at least until now, is that they have not been able to distinguish between antibodies against HHV-6A and HHV-6B.…”

“…When studying the role of HHV-6A and HHV-6B during disease, Alvarez-Lafuente et al [99,104] have in several studies demonstrated a role of HHV-6A in disease activity as they observed higher HHV-6A viral DNA load in serum, and messenger RNA load in blood, during MS relapse compared to remission. The same group has also recorded an increase in anti-HHV-6A/6B IgM prior to relapse [61]. Since IgM antibodies are regarded as markers of recent reactivation or primary infection, the increased anti-HHV-6A/6B IgM prior to relapse suggests that the observed HHV-6A reactivation during relapses may have had a trigging effect on the relapse onset rather than being a consequence of it.…”

Evidence linking HHV-6 with multiple sclerosis: an update

“…A 2012 study of a Tasmanian cohort found HHV-6 IgG titer to be a significant predictor of relapse risk [27]. This was echoed in a 2014 study of a Spanish MS cohort, which reported that a decrease in HHV-6 antibody titers correlated with fewer relapses and less disease progression [28]. Interestingly, the authors noted that IgG titers reached their highest value two weeks, and IgM titers one month, before relapse [28].…”

“…This was echoed in a 2014 study of a Spanish MS cohort, which reported that a decrease in HHV-6 antibody titers correlated with fewer relapses and less disease progression [28]. Interestingly, the authors noted that IgG titers reached their highest value two weeks, and IgM titers one month, before relapse [28]. A 2011 study of a Latvian MS cohort reported HHV-6 DNA in the plasma of a majority of RRMS and SPMS patients during relapse, which was confirmed by enhancing MRI lesions, and correlated with higher serum concentrations of the inflammatory cytokines IL-12 and TNF-alpha relative to periods of remission [29].…”