Autoantibodies neutralizing type I IFNs underlie ~5% of herpes simplex encephalitis in adults.
Inborn errors of type I interferon (IFN-I) immunity account for ∼7-8% of herpes simplex encephalitis (HSE) cases in young children, but the pathogenesis of HSE in adults is largely unknown. We report that IFN-I autoantibodies (auto-Abs) in serum/plasma samples drawn before, during, or after HSE in 16/339 Danish adults neutralized 0.1-10 ng/ml of IFN-I. Neutralization was IgG-mediated and was also detected in cerebrospinal fluid in several patients. Patients' serum impaired the ability of exogenous IFN-I to protect fibroblasts against herpes simplex virus (HSV)-1 infection in vitro. Among patients with neutralizing IFN-I auto-Abs, a larger fraction were HSV-1 IgG seronegative, suggesting that these auto-Abs confer a greater risk of HSE during primary HSV-1 infection. Neutralization was mainly driven by auto-Abs to IFN-ω, and the risk of HSE in adults with auto-Abs was significantly elevated (odds ratio [OR] = 3.1 for IFN-ω and OR = 2.0 for any IFN-I) compared with the general population. Overall, auto-Abs neutralizing IFN-I accounted for ∼5% of adult HSE cases.
Authors
- Paul Bastard (ORCID: https://orcid.org/0000-0002-5926-8437)
- Renée Marije van der Sluis (ORCID: https://orcid.org/0000-0002-7668-2517)
- Sofie E. Jørgensen (ORCID: https://orcid.org/0000-0002-2700-0882)
- Nanna Mørk (ORCID: https://orcid.org/0009-0003-9848-3425)
- Aurélie Cobat (ORCID: https://orcid.org/0000-0001-7209-6257)
- Morten Kelder Skouboe (ORCID: https://orcid.org/0000-0001-9358-5500)
- Anne Puel (ORCID: https://orcid.org/0000-0003-2603-0323)
- Stefanie Fruhwürth (ORCID: https://orcid.org/0000-0003-4035-7330)
- Marvin Werner (ORCID: https://orcid.org/0000-0003-1200-807X)
- Muyesier Maimaitili (ORCID: https://orcid.org/0009-0006-2049-840X)
- Shen‐Ying Zhang (ORCID: https://orcid.org/0000-0002-9449-3672)
- Merete Storgaard (ORCID: https://orcid.org/0000-0001-6110-5963)
- Henrik Nielsen
- Jean-Laurent Casanova (ORCID: https://orcid.org/0000-0002-7782-4169)
- Julie A. Jensen (ORCID: https://orcid.org/0009-0002-9704-5442)
- Adrian Gervais
- Bettina Bundgaard
- Jacob Bodilsen
- Marie Helleberg
- Trine H Mogensen
- Søren R Paludan
Institutions
- Hôpital Necker-Enfants Malades (FR)
- Howard Hughes Medical Institute (US)
- Inserm (FR)
- Aarhus University (DK)
- Université Paris Cité (FR)
- Aalborg University Hospital (DK)
- Aarhus University Hospital (DK)
- Rigshospitalet (DK)
- Assistance Publique – Hôpitaux de Paris (FR)
- Human Genetic of Infectious Diseases (FR)
- Institut des Maladies Génétiques Imagine (FR)
- The University of Texas Southwestern Medical Center (US)
- University of Gothenburg (SE)
- Aalborg University (DK)
Publication Details
- Journal
- PubMed
- Published
- 2026-10-05
- DOI
- https://doi.org/10.1084/jem.20261020
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00