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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\u201310 ng\/ml of IFN-I. Neutralization was IgG-mediated and was also detected in cerebrospinal fluid in several patients. Patients\u2019 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-\u03c9, and the risk of HSE in adults with auto-Abs was significantly elevated (odds ratio [OR] = 3.1 for IFN-\u03c9 and OR = 2.0 for any IFN-I) compared with the general population. Overall, auto-Abs neutralizing IFN-I accounted for \u223c5% of adult HSE cases.<\/jats:p>","DOI":"10.1084\/jem.20261020","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:20:59Z","timestamp":1788416459000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Autoantibodies neutralizing type I IFNs underlie ~5% of herpes simplex encephalitis in adults"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9704-5442","authenticated-orcid":true,"given":"Julie A.","family":"Jensen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/040r8fr65","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University Hospital 1 Department of Infectious Diseases, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 2 Department of Biomedicine, , 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