Animal model of HSV-induced-NMDAR Autoimmune Encephalitis affects predominantly female mice
Alexander Sandweiss1, Yike Jiang2, Kristy Murray2, Shannon Ronca2
1Division of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine and Texas Children's Hospital, 2Pediatrics, Tropical Medicine, Baylor College of Medicine
Objective:
Our objective was to characterize HSV-1 encephalitis seroconversion into the production of anti-NMDAR antibodies.
Background:
Anti-NMDA receptor autoimmune encephalitis (NMDARAE) is a cell surface autoimmune CNS disorder that decouples the pharmacological action of NMDA receptors from their neuronal networks causing seizures, neuropsychiatric symptoms, movement disorders, and autonomic dysfunction. There are few animal models employed as surrogates for the clinical entity; most involve passive transfer of antibody or active immunization with antigen but lack the ability to interrogate the underlying immune-mediated pathophysiology. Evaluating autoantibody seroconversion of HSV encephalitis may provide clues for the idiopathic encephalitides as well.
Design/Methods:
We modified a previously reported mouse model of HSV-induced-NMDARAE to include both sexes and two common laboratory mouse strains. We infected 4 groups of mice (male C57Bl/6, female C57Bl/6, male Balb/c, female Balb/c; n=8 in each group) with ) 1x106 pfu/mouse HSV-1 (strain 17). Each group was treated with 2mg/mL acyclovir in drinking water for 2 weeks starting 48 hours after HSV infection. Blood was collected weekly for 14 weeks and assessed for the presence of anti-NMDAR antibodies via cell-based assay.
Results:
The first production of anti-NMDAR antibody was in one female C57Bl/6 mouse at week 1 (1/16, 6.25%); more female mice produced antibody each week, peaking at week 10 post HSV infection (6/8 female C57Bl/6, 75% and 7/8 female Balb/c, 87.5%) with fewer animals trending to produce antibody in weeks 11-14. No male Balb/c mice produced detectable anti-NMDAR antibody at any time point, but 1 male C57bl/6 mouse produced antibody per week between weeks 8-10.
Conclusions:
In this modified murine model of HSV-induced-NMDARAE, we demonstrated more female mice produce anti-NMDAR antibodies than males, amplifying the female predisposition and thus providing a meaningful animal model to interrogate the underlying immune-mediated mechanisms of autoantibody seroconversion.