Increased CMV response at disease onset protective in long-term prognosis of Multiple Sclerosis

Recent research in Barcelona published in the Journal of Neurology, Neurosurgery & Psychiatry suggests that elevated immune responses against HCMV at disease onset have protective effects on long-term disability and inflammation disease outcomes, and that increased immune responses against EBV in early phases may influence long term disease prognosis.

The association between infection by the Epstein-Barr virus (EBV) and multiple sclerosis (MS) development has been known for many years and recently there is strong evidence for a causal relationship between EBV and MS based on the finding that individuals who seroconverted during the study had a 32-fold risk increased for MS, whereas infection with other viruses including the human cytomegalovirus (HCMV), which shows similar epidemiology to EBV, was not associated with an increased MS risk.

Humoral immune responses against Epstein-Barr virus (EBV)-encoded nuclear antigen EBNA1, viral capsid antigen (VCA) and early antigen, and toward cytomegalovirus (HCMV), human herpesvirus 6 and measles were investigated by Comabella et al in a cohort of 143 patients with MS for their association with long-term disability and inflammation disease outcomes.

They found that the immune responses against EBV-encoded antigens maintained a long-term prognostic role but mainly on inflammation-related outcomes. Increased immune responses against EBNA1 antigen at disease onset were associated with an increased relapse rate. To a lesser degree, EBNA1-specific IgG levels were also slightly increased at disease onset in patients who reached an Expanded Disability Status Scale (EDSS) of 3.0 and received second-line therapies, and slightly correlated with disease severity.

Immune responses against the lytic EBV antigen VCA at disease onset, played a more important prognostic role in long-term outcomes. Elevated VCA-specific immune responses, indicative for increased viral reactivation and replication, were associated with an increased risk for treatment with first-line and second-line therapies, and with shorter time to treatment onset. Unexpectedly, immune responses to another lytic antigen, EBV-EA, seemed to play a modest long-term prognostic role and were only associated with lower relapse rate during follow-up at the univariable level.

They also found that elevated immune responses against HCMV at disease onset had protective effects on a number of outcomes mostly related with disability such as the time to EDSS 4.0 and the time to develop a secondary progressive MS (SPMS) disease course. HCMV seroprevalence in patients at disease onset was 60%, HCMV establishes latency in bone marrow-derived myeloid progenitor cells and monocytes seem to be the major reservoir of HCMV persistence in peripheral blood mononuclear cells. HCMV-driven expansion of NKG2C+NK cells was associated with a lower risk of disability progression in patients with MS. Furthermore, HCMV infection was found associated with a reduced proinflammatory cytokine profile in B cells from patients with progressive MS, which may also contribute to the protective role found for this virus in MS.

Their results suggest that HCMV IgG antibody levels should be measured at the time of the first demyelinating event, insomuch as they may have protective effects on long-term disability and inflammation outcomes. Also, EBV infection was not only associated with an increased risk for MS but may also influence long-term disease prognosis.

Reference: Manuel Comabella et al; Journal of Neurology, Neurosurgery and Psychiatryhttp://dx.doi.org/10.1136/jnnp-2022-330205