2026 American Academy of Neurology Autoimmune Abstract Website

Chiara Milano¹, Laura Marmolejo Alcaide¹, Jesus Planaguma¹, Esther Aguilar¹, Josep Dalmau², Thais Armangue³, Marianna Spatola⁴
¹Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAS), University of Barcelona, Spain and Caixa Research Institute (CRI), Barcelona, Spain, ²Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAS), University of Barcelona, Spain; Caixa Research Institute (CRI), Barcelona, Spain and 26Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA, ³Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAS), University of Barcelona, Spain and Caixa Research Institute (CRI), Barcelona, Spain and Pediatric Neuroimmunology Unit, Neurology Service, Sant Joan de Déu (SJD) Children's Hospital, University of Barcelona, Barcelona, ⁴Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAS), University of Barcelona, Spain; Caixa Research Institute (CRI), Barcelona, Spain and Institute of Neurosciences, University of Barcelona, Spain

Objective:

Characterize the innate immunity HSV1-antibody cross-talk in periphHSV, HSE and postHSE-AE.

Background:

Herpes-simplex-virus-1 (HSV1) can cause recurrent cold sore (periphHSV) or encephalitis (HSE). HSE can be complicated by autoimmune encephalitis (postHSE-AE). The mechanisms of HSE and postHSE-AE remain unclear.

Design/Methods:

We extensively profiled HSV1-antibody responses in serum and CSF of 45 HSE (12 who developed, 33 who did not develop postHSE-AE, at onset and 1month), and in serum of 12 periphHSV. We analyzed Ig classes/sublasses (IgA, IgG1-4, IgM), capacity to bind Fc receptors (FcgR2A/2B/3A/3B) and mediate Antibody-Dependent Cellular/Neurotrophil Phagocytosis (ADCP/ADNP), Complement Deposition (ADCD) and NK-cells activation (ADNKA). Antibody features were compared across groups and compartments (serum and CSF) and correlated with disease severity. Neuronal death and infection of HSV1-infected cultured neurons treated with IgG from HSE, periphHSV or healthy controls (with/out innate cells) were quantified by confocal microscopy.

Results:

Despite lower CSF responses at HSE onset, at 1 month CSF responses significantly increased (p<0.001), whereas serum responses remained stable. PLSDA/LASSO analyses identified ADCD in serum and ADCP in CSF as the most different features across compartments. Higher CSF-ADCP correlated with HSE severity (Spearman-coefficient=0.49, p=0.03).

Compared to HSE, periphHSV showed higher serum ADNKA and FcgR3A-binding (p<0.01), despite similar IgG titers. Instead, serum ADCP was increased in HSE (p<0.05).

Patients who developed PostHSE-AE showed higher serum/CSF titers, ADCD, ADNP and FcgR binding (p<0.01), compared to those who did not develop PostHSE-AE.

HSV1-infected neurons treated with HSE-derived IgG (but not from periphHSV or healthy controls, p<0.01) caused increased neuronal death and infectivity.

Conclusions:

During HSE, CSF-HSV1-responses are characterized by phagocytosis-activating antibodies, which correlates with HSE severity and predicts PostHSE-AE. Enrichment of NK-activating antibodies in periphHSV suggests a role for NK in protecting the brain from HSE. Antibodies from HSE cause increased neuronal death and infectivity, likely contributing to antigen release and development of neuronal autoimmunity.