HSV-1-SPECIFIC IGG3 TITERS AND NEUTRALIZING ACTIVITY ARE REDUCED IN AD PATIENTS

Abstract

Human Herpes Simplex Virus type 1 (HSV-1) infection is suggested to play a role in the development of Alzheimer's disease (AD). Thus, the presence of an inverse correlation between HSV-1-specific antibodies (Ab) titers and brain atrophy as evaluated by magnetic resonance was recently described in AD, suggesting a protective role of the HSV-1-specific humoral response (Agostini et al., 2017). HSV-1 can evade immune responses by interfering with activities mediated by immunoglobulin G (IgG) antibodies, as it expresses a receptor that binds the Fc portion of all IgG subclasses with the exception of IgG3. We analyzed whether IgG-mediated serum neutralization activity against HSV-1 differs when individuals with a diagnosis of either AD or Mild Cognitive Impairment (MCI) are compared to age-matched healthy controls (HC). 135 individuals were enrolled in the study: 48 AD, 50 MCI and 37 HC. Serum HSV-1 IgG Ab titers and subclasses were measured by ELISA. IgG neutralizing activity was performed on HSV-1 infected Vero cells and neutralizing antibody (NAb) titers was measured in all sera. Whereas HSV-1-specific IgG1, IgG2 and IgG4 titers were comparable in all groups of individuals, the presence of IgG3 were significantly increased in MCI (86.2 %) compared to AD (71.6%; p=0.05) and to HC (60.6 %; p=0.002). The analysis of IgG neutralizing capacity showed that low IgG3 levels correspond with low neutralizing capacity (NAb titer <100) in all the three groups of the study, without any significant differences. Surprisingly, in AD patients the neutralizing capacity remained low even with the presence of high IgG3 levels (NAb <100), contrary to MCI and HC subjects, where, as expected, high IgG3levels correspond with high neutralizing capacity (NAb titer =120). HSV-1-specific IgG3 titers and neutralizing activity are significantly reduced in AD. As IgG3 plays a key role to challenge the HSV1 immune-evasion, these results reinforce the hypothesis of a pathogenetic role of HSV-1 in AD.