Autoantibodies neutralizing type I IFNs in 40% of patients with WNV encephalitis in seven new cohorts

Mosquito-borne West Nile virus (WNV) infection is a growing global health problem. About 0.5% of infected individuals develop encephalitis. We previously showed that 40% of patients in six cohorts had WNV encephalitis because of circulating autoantibodies (auto-Abs) neutralizing type I IFNs. In seven new cohorts, we found that the prevalence of auto-Abs was highest (40% [17-44%]) in patients with encephalitis and very low in a small sample of individuals with asymptomatic or mild infection. In the 13 European, Middle Eastern, and American cohorts available, odds ratios (OR) for WNV encephalitis in individuals with these auto-Abs relative to those without them in a large sample of the general population untested for WNV infection range from ∼20 (OR = 17.7; 95% CI: 13.8-22.8, P < 10^-16) for auto-Abs neutralizing only 100 pg/ml IFN-α2 and/or IFN-ω to >2,000 (OR = 2,218.4; 95% CI: 125.1-39,337.7, P < 10^-16) for auto-Abs neutralizing high concentrations of IFN-α2 and high or low concentrations of IFN-ω. Preexisting auto-Abs neutralizing type I IFNs are therefore causal for WNV encephalitis in about 40% of patients.