Temporal relationship between environmental influenza A and Epstein–Barr viral infections and high multiple sclerosis relapse occurrence

Abstract

Our findings suggest that influenza A and EBV viral infections in the general population are associated with a higher occurrence of exacerbations in MS patients, and thus environmental infection data should be included in epidemiological models on MS relapses.

Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis

“…Notably, several studies that examined the effects of upperrespiratory infection on MS relapse included "flu-like symptoms" and "fever over 38°C" as criteria for occurrence of infection, indicating that influenza may have been the culprit underlying disease exacerbation in a few of these patients (14,21,24). That influenza is associated with exacerbation of MS symptoms is further eluded to by epidemiological data that link the incidence of MS hospitalizations to influenza epidemics (22). Moreover, De Keyser et al have shown that influenza infection increases relapse risk whereas patients vaccinated against influenza had a lower risk of relapse (24).…”

“…To model the effects of upper-respiratory infection on relapse and/or disease progression in MS patients, we infected autoimmune-prone T-cell receptor transgenic (2D2) mice with mouse-adapted human influenza A virus. This strategy was chosen because, although ∼90% of CD4 + T-cells in 2D2 mice express a T-cell receptor (TCR) with specificity for myelin oligodendrocyte glycoprotein (MOG ) and neurofilament-m (NF-M [18][19][20][21][22][23][24][25][26][27][28][29][30] ), few (4%) develop spontaneous classic experimental autoimmune encephalomyelitis (EAE) (25). Additionally, the presence of circulating autoreactive cells enabled us to bypass the need to polarize and activate T-cells before injection.…”

“…Additionally, the presence of circulating autoreactive cells enabled us to bypass the need to polarize and activate T-cells before injection. Finally, influenza A virus can induce glial activation (4,5) and has been associated with increased relapse risk in MS patients (22,24,26). Here, we report that upper-respiratory infection with influenza virus is capable of causing neurological disease in 2D2 mice.…”

“…Importantly, both relapse rate and intervals between relapses are predictors of disability outcome and relapses contribute to the development of permanent neurological dysfunction (19). Interestingly, within 5 weeks of contracting an upper-respiratory infection an estimated 27-41% of patients will suffer disease exacerbation (13,15,16,(20)(21)(22). In addition, some reports suggest that relapses occurring around the time of infection are associated with sustained neurological deficits, increased relapse severity, and an increased number of gadolinium-enhancing lesions as measured by MRI (21).…”

Multiple Sclerosis: Modulation of Toll-Like Receptor (TLR) Expression by Interferon-β Includes Upregulation of TLR7 in Plasmacytoid Dendritic Cells

“…It therefore seems conceivable that upregulation of TLR7 in pDCs by interferon-β and a subsequently enhanced antiviral innate immune response may reduce the risk of virus-triggered MS relapses. As one example in accordance with this hypothesis, there is a temporal relationship between infections with influenza A virus and MS relapses [33], and single-stranded RNA derived from influenza A virus is a known TLR7 ligand [34]. One could therefore speculate that an enhanced immune response against influenza A virus in patients with MS treated with interferon-β could reduce the risk of influenza A virus-triggered relapses.…”