The PILRA G78R Variant Correlates with Higher HSV-1-Specific IgG Titers in Alzheimer’s Disease

  • Simone AgostiniEmail author
  • Andrea Saul Costa
  • Roberta Mancuso
  • Franca Rosa Guerini
  • Raffaello Nemni
  • Mario Clerici
Brief Communication


Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a progressive decline in cognitive performance; Mild Cognitive Impairment (MCI) is instead an objective decline in cognitive performance that does not reach pathology. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is a cell surface inhibitory receptor that was recently suggested to be involved in AD pathogenesis. In particular, the arginine-to-glycine substitution in position 78 (R78, rs1859788) was shown to be protective against AD. Herpes simplex virus type 1 (HSV-1) infection is suspected as well to be involved in AD. Interestingly, HSV-1 uses PILRA to infect cells, and HSV-1 infects more efficiently PIRLA G78 compared to R78 macrophages. We analyzed PILRA rs1859788 polymorphism and HSV-1 humoral immune responses in AD (n = 61) and MCI patients (n = 48), and in sex and age matched healthy controls (HC; n = 57). The rs1859788 PILRA genotype distribution was similar among AD, MCI and HC; HSV-1 antibody (Ab) titers were increased in AD and MCI compared to HC (p < 0.05 for both comparisons). Notably, HSV-1-specific IgG1 were significantly increased in AD patients carrying PILRA R78 rs1859788 AA than in those carrying G78 AG or GG (p = 0.01 for both comparisons), and the lowest titers of HSV-1-specific IgG1 were observed in rs1859788 GG AD. HSV-1 IgG are increased in AD patients with the protective R78 PILRA genotype. Because in AD patients brain atrophy is inversely correlated with HSV-1-specific IgG titers, results herein suggest a possible link between two important genetic and infective factors suspected to be involved in AD pathogenesis.


HSV-1 Alzheimer’s disease Mild Cognitive Impairment IgG1 Paired immunoglobulin-like type 2 receptor alpha (PILRA) 



This work was supported by 2018–2019 Ricerca Corrente (Italian Ministry of Health).

Author Contributions

MC, SA, and ASC designed the experiment; RN recruited subjects and collected biological samples; ASC, RM, and SA performed experiments and data collection; ASC, FG, and SA analyzed the data; and MC, ASC, and SA interpreted the data and drafted the manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of Fondazione Don Carlo Gnocchi—ONLUS committee (reference number: 12_21/06/2018) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants, or their legal guardians, included in the study.

Research Involving Animals

This article does not contain any studies with animals performed by any of the authors.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.IRCCS Fondazione Don Carlo GnocchiMilanItaly
  2. 2.Department of Pathophysiology and TransplantationUniversity of MilanMilanItaly

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