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Application of a Multiplex Herpesvirus Immunoassay in Alzheimer’s Disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. (Sektionen för Infektionssjukdomar)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Human herpesviruses have previously been implicated in the pathogenesis of Alzheimer's disease (AD) but whether they are causal, facilitating or confounding factors is yet to be established. Here, we present an application of a suspension matrix immunoassay (SMIA) allowing multiplex detection of IgG levels related to five human herpesviruses. Furthermore, we analysed peripheral blood mononuclear cells with a subtype specific HHV-6 PCR. The level of HHV-6 antibodies was lower in AD subjects (n=51) than in non-demented controls (ND, n=52), whereas there were no differences in HSV, VZV, CMV or EBV antibody levels between groups. AD and ND subjects presented with comparable DNA levels in PBMC and all positive samples were of subtype B. The SMIA protocol, applied to herpesvirus antigens, could provide an useful addition to the scientific arsenal. Whether HHV-6 is a factor in AD remains a hypothesis for future studies.

National Category
Microbiology in the medical area
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-246406OAI: oai:DiVA.org:uu-246406DiVA, id: diva2:795202
Available from: 2015-03-15 Created: 2015-03-06 Last updated: 2018-01-11
In thesis
1. Herpesvirus Infection and Immunity in Neurocognitive Disorders
Open this publication in new window or tab >>Herpesvirus Infection and Immunity in Neurocognitive Disorders
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Herpesviruses have co-speciated with several vertebrate and invertebrate animals throughout the history of evolution. In the immunocompetent human host, primary infection is usually benign, whereafter the virus is brought into life-long latency. Viral reactivation can however cause severe disease in immunocompromised, and rarely also in immunocompetent, patients. The overall aim of this thesis was to study the immunologic effects of cytomegalovirus (CMV) and herpes simplex type 1 (HSV-1) infection in neurocognitive disorders.

CMV is known to promote T-cell differentiation towards a more effector-oriented phenotype, similar to what is seen in the elderly. We have addressed the frequency of CMV-specific CD8+ T-cells in Alzheimer's disease (AD). Furthermore, we have investigated whether AD patients present with a different CMV-specific immune profile, overall CD8 phenotype or inflammatory cytokine response to anti-CD3/CD28 beads, CMV pp65 and amyloid beta. Subjects with AD presented with a lower proportion of CMV-specific CD8+ T-cells compared to non-demented (ND) controls, but no differences in overall CD8 differentiation were seen. Overall, AD subjects presented with a more pro-inflammatory peripheral blood mononuclear cell (PBMC) phenotype. When PBMCs were challenged with CD3/CD28-stimulation, CMV seropositive AD subjects presented with more IFN-γ release than both CMV seronegative AD subjects and CMV seropositive ND controls.

For effective screening of humoral herpesvirus immunity, both in research and in clinical practice, efficient immunoassays are needed. We have addressed the methodology of multiplex herpesvirus immunoassays and related bioinformatics and investigated antibody levels in AD patients and ND controls. Subjects with AD presented with lower levels of human herpesvirus 6 (HHV-6) IgG. However, there was no difference in HHV-6 DNA levels in PBMCs between the groups.

Herpes simplex encephalitis (HSE) is a devastating disease, where antiviral treatment has greatly decreased mortality but not eliminated the associated long-term neurocognitive morbidity. We have investigated the correlation between N-Methyl-D-Aspartate Receptor (NMDAR) autoimmunity and recovery of neurocognitive functions after HSE. Approximately one quarter of all HSE cases developed NMDAR autoantibodies within 3 months after onset of disease. Antibody development was associated with an impaired neurocognitive recovery during the two year follow-up and could become an important therapy guiding factor in the future.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. p. 80
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1080
Keyword
Alzheimer's disease, Herpes simplex encephalitis, Herpesvirus, Cytomegalovirus, CMV, HSV-1, HHV-6, CD8 T-cells, Cellular immunity, Immunosenescence, Autoimmunity, NMDA receptor
National Category
Infectious Medicine Immunology in the medical area
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-247187 (URN)978-91-554-9194-9 (ISBN)
Public defence
2015-05-09, Auditorium minus, Gustavianum, Akademigatan 3, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2015-04-17 Created: 2015-03-15 Last updated: 2018-01-11

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Westman, Gabriel

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