Extensive Characterization of HSV1 Antibody Responses in Herpes Encephalitis Reveals Compartmentalization in CSF and Predicts Development of Post-herpes Autoimmune Encephalitis
Laura Marmolejo Alcaide1, Chiara Milano2, Jesus Planaguma1, Esther Aguilar1, Raquel Bello-Morales3, Josep Dalmau1, Thais Armangue4, Marianna Spatola2
11Neuroimmunology 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, 21Neuroimmunology 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 2Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy, 33Universidad Autonoma de Madrid, Spain, 41Neuroimmunology 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 4Pediatric Neuroimmunology Unit, Neurology Service, Sant Joan de Déu (SJD) Children's Hospital, University of Barcelona, Barcelona, Spain
Objective:
Characterize the HSV1-antibody responses 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 of HSV1-infected cultured neurons treated with IgG from HSE, periphHSV or healthy controls (with/out innate cells) was 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. Effects of innate effector cells will also be presented.
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, likely contributing to antigen release and development of neuronal autoimmunity.
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