Autoantibodies neutralizing type I IFNs underlie West Nile virus encephalitis in ∼40% of patients

Gervais, A.; Rovida, F.; Avanzini, M. A.; Croce, S.; Marchal, A.; Lin, S. C.; Ferrari, A.; Thorball, C. W.; Constant, O.; Le Voyer, T.; Philippot, Q.; Rosain, J.; Angelini, M.; Pérez Lorenzo, M.; Bizien, L.; Achille, C.; Trespidi, F.; Burdino, E.; Cassaniti, I.; Lilleri, D.; Fornara, C.; Sammartino, J. C.; Cereda, D.; Marrocu, C.; Piralla, A.; Valsecchi, C.; Ricagno, S.; Cogo, P.; Neth, O.; Marín-Cruz, I.; Pacenti, M.; Sinigaglia, A.; Trevisan, M.; Volpe, A.; Marzollo, A.; Conti, F.; Lazzarotto, T.; Pession, A.; Viale, P.; Fellay, J.; Ghirardello, S.; Aubart, M.; Ghisetti, V.; Aiuti, A.; Jouanguy, E.; Bastard, P.; Percivalle, E.; Baldanti, F.; Puel, A.; Macdonald, M. R.; Rice, C. M.; Rossini, G.; Murray, K. O.; Simonin, Y.; Nagy, A.; Barzon, L.; Abel, L.; Diamond, M. S.; Cobat, A.; Zhang, S. Y.; Casanova, J. L.; Borghesi, A.

doi:10.1084/jem.20230661

Gervais et al. show that auto-Abs neutralizing type I IFNs and pre-existing infection underlie & SIM;40% of cases of West Nile virus (WNV) encephalitis. Blood and cerebrospinal fluid auto-Abs neutralize the protective activity of type I IFNs against WNV in vitro.Mosquito-borne West Nile virus (WNV) infection is benign in most individuals but can cause encephalitis in <1% of infected individuals. We show that & SIM;35% of patients hospitalized for WNV disease (WNVD) in six independent cohorts from the EU and USA carry auto-Abs neutralizing IFN-& alpha; and/or -& omega;. The prevalence of these antibodies is highest in patients with encephalitis (& SIM;40%), and that in individuals with silent WNV infection is as low as that in the general population. The odds ratios for WNVD in individuals with these auto-Abs relative to those without them in the general population range from 19.0 (95% CI 15.0-24.0, P value <10(-15)) for auto-Abs neutralizing only 100 pg/ml IFN-& alpha; and/or IFN-& omega; to 127.4 (CI 87.1-186.4, P value <10(-15)) for auto-Abs neutralizing both IFN-& alpha; and IFN-& omega; at a concentration of 10 ng/ml. These antibodies block the protective effect of IFN-& alpha; in Vero cells infected with WNV in vitro. Auto-Abs neutralizing IFN-& alpha; and/or IFN-& omega; underlie & SIM;40% of cases of WNV encephalitis.

Autoantibodies neutralizing type I IFNs underlie West Nile virus encephalitis in ∼40% of patients / Gervais, A., Rovida, F., Avanzini, M.A., Croce, S., Marchal, A., Lin, S.C., Ferrari, A., Thorball, C.W., Constant, O., Le Voyer, T., Philippot, Q., Rosain, J., Angelini, M., Pérez Lorenzo, M., Bizien, L., Achille, C., Trespidi, F., Burdino, E., Cassaniti, I., Lilleri, D., et al.. - In: JOURNAL OF EXPERIMENTAL MEDICINE. - ISSN 0022-1007. - 220:9(2023). [10.1084/jem.20230661]