DISTINCT CSF-COMPARTMENTALIZED ANTIBODY FUCTIONALITIES DURING HSV1 INFECTION ASSOCIATE WITH SITE OF INFECTION, DISEASE SEVERITY AND PREDICT POST-HERPES AUTOIMMUNE ENCEPHALITIS

Herpes-simplex-virus-1 (HSV1) can cause recurrent cold sore (periphHSV) or encephalitis (HSE), which may be complicated by autoimmune encephalitis (postHSE-AE). The immunological mechanisms underlying HSE and postHSE-AE remain unclear.
We deeply characterized HSV1-antibody responses in paired serum/CSF of 45 HSE patients (12 who developed postHSE-AE, 33 who did not; at onset and 1 month), and in serum of 12 periphHSV. Profiles included Ig classes/sublasses, Fc receptor binding, and Antibody-Dependent Cellular/Neutrophil Phagocytosis (ADCP/ADNP), Complement Deposition (ADCD) and NK-cells activation (ADNKA). Antibody features were compared across groups and compartments, and correlated with disease severity and development of postHSE-AE. Neuronal death was quantified in HSV1-infected cultures treated with IgG from HSE, periphHSV or healthy controls.
In HSE, HSV1-specific responses in CSF were low at onset, but significantly increased at 1 month, while serum responses remained elevated. LASSO/PLSDA analyses identified ADCD in serum and ADCP in CSF as features that differed most across compartments. Higher CSF-ADCP correlated with HSE severity. Compared to HSE, periphHSV patients showed higher serum ADNKA and FcgR3A binding despite similarly high IgG titers. Patients who developed PostHSE-AE exhibited higher titers, ADCD, ADNP and FcgR binding.
IgG from HSE patients caused increased neuronal death in-vitro compared to IgG from periphHSV or healthy controls.
Our results indicate that, during HSE, HSV1-responses are compartmentalized and characterized by phagocytosis-activating antibodies in CSF that correlate with HSE severity and predict PostHSE-AE. NK-activating antibodies in periphHSV may protect the brain from HSE. Antibodies from HSE cause increased neuronal death, which likely promotes the development of autoimmune encephalitis.