Tick-borne encephalitis (TBE) virus (TBEV) is transmitted to humans via tick bites. Infection is benign in >90% of the cases but can cause mild (<5%), moderate (<4%), or severe (<1%) encephalitis. We show here that ∼10% of patients hospitalized for severe TBE in cohorts from Austria, Czech Republic, and France carry auto-Abs neutralizing IFN-α2, -β, and/or -ω at the onset of disease, contrasting with only ∼1% of patients with moderate and mild TBE. These auto-Abs were found in two of eight patients who died and none of 13 with silent infection. The odds ratios (OR) for severe TBE in individuals with these auto-Abs relative to those without them in the general population were 4.9 (95% CI: 1.5-15.9, P < 0.0001) for the neutralization of only 100 pg/ml IFN-α2 and/or -ω, and 20.8 (95% CI: 4.5-97.4, P < 0.0001) for the neutralization of 10 ng/ml IFN-α2 and -ω. Auto-Abs neutralizing type I IFNs accounted for ∼10% of severe TBE cases in these three European cohorts.

CHU de Strasbourg Service des Maladies Infectieuses et Tropicales Strasbourg France

Clinical Immunology Department Assistance Publique Hôpitaux de Paris Saint Louis Hospital Paris France

Clinical Research Department Hôpitaux Civils de Colmar Colmar France

Department of Children's Infectious Diseases University Hospital and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic

Department of Infectious Diseases University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pediatrics and Neonatology F Tappeiner Hospital Merano Italy

Department of Pediatrics Necker Hospital for Sick Children AP HP Paris France

Howard Hughes Medical Institute New York NY USA

Imagine Institute Paris Cité University Paris France

Infectious Disease Unit Provincial Hospital of Bolzano Lehrkrankenhaus der Paracelsus Medizinischen Privatuniversität Bolzano Italy

Infectious Diseases Department Hôpitaux Civils Colmar France

Institut de Virologie Strasbourg University Hospital Strasbourg University INSERM Unité Mixte de Recherche S1109 Strasbourg France

Institute for Research in Biomedicine Università della Svizzera italiana Bellinzona Switzerland

Institute of Parasitology Biology Centre of the Czech Academy of Science České Budějovice Czech Republic

Laboratory of Emerging Viral Diseases Veterinary Research Institute Brno Czech Republic

Laboratory of Human Genetics of Infectious Diseases Necker Branch Institut National de la Santé et de la Recherche Médicale U1163 Necker Hospital for Sick Children Paris France

Laboratory of Microbiology and Virology SABES ASDAA Lehrkrankenhaus der Paracelsus Medizinischen Privatuniversität Bolzano Italy

Laboratory of Virology and Infectious Disease The Rockefeller University New York NY USA

Medical University of Vienna Center for Virology Vienna Austria

Neonatal Intensive Care Unit San Matteo Research Hospital Pavia Italy

Pediatric Hematology Immunology and Rheumatology Unit Necker Hospital for Sick Children AP HP Paris France

School of Life Sciences Swiss Federal Institute of Technology Lausanne Switzerland

St Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch Rockefeller University New York NY USA

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