HSV-1-Specific IgG Subclasses Distribution and Serum Neutralizing Activity in Alzheimer's Disease and in Mild Cognitive Impairment

Human Herpes Simplex Virus type 1 (HSV-1) infection is suggested to play a role in the development of Alzheimer's disease (AD). Immunoglobulin G (IgG) neutralize HSV-1 activity, but the virus can evade IgG-mediated immune responses by expressing receptor that efficiently binds the Fc portion of all IgG subclasses with the exception of IgG₃. We analyzed HSV-1-specific IgG subclasses and IgG-mediated serum neutralization activity against HSV-1 in individuals with a diagnosis of either AD or mild cognitive impairment (MCI), comparing the results with those obtained in age-matched healthy controls (HC). 186 individuals were enrolled in the study: 67 AD, 58 MCI, and 61 HC. HSV-1 IgG titers and subclasses, neutralizing antibody (NAb) titers, and complement C3 concentration-critical component of antibody-mediated effector activity-were measured in sera by ELISA; IgG neutralizing activity was performed on HSV-1 infected Vero cells. Results showed that, whereas HSV-1-specific IgG₁, IgG₂, and IgG₄ titers as well as complement C3 serum concentration were comparable in all groups of individuals, IgG₃ were more frequently detected in MCI (89%) compared to AD (75%; p < 0.05) and HC (68%; p = 0.003), whereas the titer is similar among the three groups (AD: 0.66 ± 0.21 OD; MCI: 0.68 ± 0.24 OD; HC: 0.72 ± 0.28 OD). Notably, HSV-1 specific neutralizing ability of AD sera was reduced even in the presence of high quantity of IgG₃. As IgG₃ plays a key role in counteracting the ability of HSV-1 to evade immune responses, these data reinforce the hypothesis of a pathogenetic role of HSV-1 in AD.