Specific viral antibodies associate with anti-NMDAR encephalitis after herpes simplex encephalitis

Herpes simplex encephalitis (HSE) patients may develop secondary anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (NMDARE), associated with worsened long-term neurological outcome. Immunosuppressive treatment can limit NMDAR autoantibody-mediated pathology, but early predictive biomarkers for the risk of NMDARE are lacking. In a multicenter study, we performed unbiased antibody reactome profiling using Phage ImmunoPrecipitation Sequencing (PhIP-Seq). HSE patients with secondary NMDARE (n = 13) versus those without (n = 10) showed enhanced antibody responses against HSV-1, but not HSV-2, which comprised specific antibodies to five peptides of the HSV-1 UL42 and UL48 proteins. A score of these signature CSF antibodies identified HSE patients with secondary NMDARE with a sensitivity of 75%, a specificity of > 99%, a positive predictive value of 90%, a negative predictive value of > 97% and an odds ratio (OR) of 209 (CI: 28 - 1,582) across all individuals in this study, and with similar performance values in serum (>66%, >99%, >88%, >96%, OR 307 (15 - 6,089)). These signature antibodies represent a promising biomarker to identify HSE patients at risk for NMDARE development. In NMDARE patients without a history of HSE and in MS patients, no disease-associated HSV antibody reactivity patterns were detected. Furthermore, we introduced the Multiplexed Index Calculations of the Antibody Reactome (MICAR) metric to characterize proteomic targets of compartment-specific antibody responses, an approach that is applicable in neuroimmunology and other compartmentalized disease states.

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Publication Details

Journal
Brain Behavior and Immunity
Published
2025-08-11
DOI
https://doi.org/10.1016/j.bbi.2025.106073
Primary Topic
Herpesvirus Infections and Treatments
Type
article
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article

Specific viral antibodies associate with anti-NMDAR encephalitis after herpes simplex encephalitis

Rose Kohlie, Jan Lewerenz, William R. Morgenlander, Sarah Schott et al.
Brain Behavior and Immunity
Herpesvirus Infections and Treatments
article

Specific viral antibodies associate with anti-NMDAR encephalitis after herpes simplex encephalitis

Rose Kohlie, Jan Lewerenz, William R. Morgenlander, Sarah Schott, Klemens Ruprecht, Jakob Kreye, Sahana Jayaraman, Carlos A. Pardo, Franziska Thaler, Isabel Bünger, Erik Lattwein, Hans‐Christian Kornau, H. Benjamin Larman, Peter A. Calabresi, Julia W. Angkeow, Mirjam Korporal‐Kuhnke, Nico Melzer, Carolin Otto, Justina Dargvainiene, Christian G. Bien, Wiebke Hahn, Dietmar Schmitz, Manjusha Thakar, Harald Prüß, Poul M Schulte-Frankenfeld
article en

Abstract

Herpes simplex encephalitis (HSE) patients may develop secondary anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (NMDARE), associated with worsened long-term neurological outcome. Immunosuppressive treatment can limit NMDAR autoantibody-mediated pathology, but early predictive biomarkers for the risk of NMDARE are lacking. In a multicenter study, we performed unbiased antibody reactome profiling using Phage ImmunoPrecipitation Sequencing (PhIP-Seq). HSE patients with secondary NMDARE (n = 13) versus those without (n = 10) showed enhanced antibody responses against HSV-1, but not HSV-2, which comprised specific antibodies to five peptides of the HSV-1 UL42 and UL48 proteins. A score of these signature CSF antibodies identified HSE patients with secondary NMDARE with a sensitivity of 75%, a specificity of > 99%, a positive predictive value of 90%, a negative predictive value of > 97% and an odds ratio (OR) of 209 (CI: 28 - 1,582) across all individuals in this study, and with similar performance values in serum (>66%, >99%, >88%, >96%, OR 307 (15 - 6,089)). These signature antibodies represent a promising biomarker to identify HSE patients at risk for NMDARE development. In NMDARE patients without a history of HSE and in MS patients, no disease-associated HSV antibody reactivity patterns were detected. Furthermore, we introduced the Multiplexed Index Calculations of the Antibody Reactome (MICAR) metric to characterize proteomic targets of compartment-specific antibody responses, an approach that is applicable in neuroimmunology and other compartmentalized disease states.

Brain Behavior and ImmunityVol. 130
Johns Hopkins University (US), Philipps University of Marburg (DE), Universität Ulm (DE), Heidelberg University (DE), Johns Hopkins Medicine (US), LMU Klinikum (DE), Christian-Albrechts-Universität zu Kiel (DE), Humboldt-Universität zu Berlin (DE), Düsseldorf University Hospital (DE), Evangelisches Krankenhaus Bielefeld (DE), Euroimmun Medizinische Labordiagnostika (Germany) (DE), University Hospital Schleswig-Holstein (DE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Heinrich Heine University Düsseldorf (DE), Freie Universität Berlin (DE), Charité - Universitätsmedizin Berlin (DE), Ludwig-Maximilians-Universität München (DE), Bethel University (US), University of Lübeck (DE)
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