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Herpesvirus Infection and Immunity in Neurocognitive Disorders
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
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. , 80 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1080
Keyword [en]
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: urn:nbn:se:uu:diva-247187ISBN: 978-91-554-9194-9 (print)OAI: oai:DiVA.org:uu-247187DiVA: diva2:795296
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: 2015-07-07
List of papers
1. Decreased Proportion of Cytomegalovirus Specific CD8 T-Cells but No Signs of General Immunosenescence in Alzheimer's Disease
Open this publication in new window or tab >>Decreased Proportion of Cytomegalovirus Specific CD8 T-Cells but No Signs of General Immunosenescence in Alzheimer's Disease
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, e77921- p.Article in journal (Refereed) Published
Abstract [en]

Cytomegalovirus (CMV) has been suggested as a contributing force behind the impaired immune responsiveness in the elderly, with decreased numbers of naive T-cells and an increased proportion of effector T-cells. Immunological impairment is also implicated as a part of the pathogenesis in Alzheimer's disease (AD). The aim of this study was to investigate whether AD patients present with a different CMV-specific CD8 immune profile compared to non-demented controls. Blood samples from 50 AD patients and 50 age-matched controls were analysed for HLA-type, CMV serostatus and systemic inflammatory biomarkers. Using multi-colour flow cytometry, lymphocytes from peripheral blood mononuclear cells were analysed for CMV-specific CD8 immunity with MHC-I tetramers A01, A02, A24, B07, B08 and B35 and further classified using CD27, CD28, CD45RA and CCR7 antibodies. Among CMV seropositive subjects, patients with AD had significantly lower proportions of CMV-specific CD8 T-cells compared to controls, 1.16 % vs. 4.13 % (p=0.0057). Regardless of dementia status, CMV seropositive subjects presented with a lower proportion of naive CD8 cells and a higher proportion of effector CD8 cells compared to seronegative subjects. Interestingly, patients with AD showed a decreased proportion of CMV-specific CD8 cells but no difference in general CD8 differentiation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-211457 (URN)10.1371/journal.pone.0077921 (DOI)000325887300111 ()
Available from: 2013-11-25 Created: 2013-11-25 Last updated: 2017-12-06Bibliographically approved
2. Increased Inflammatory Response in Cytomegalovirus Seropositive Patients with Alzheimer's Disease
Open this publication in new window or tab >>Increased Inflammatory Response in Cytomegalovirus Seropositive Patients with Alzheimer's Disease
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, e96779- p.Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) has been associated with increased local inflammation in the affected brain regions, and in some studies also with elevated levels of proinflammatory cytokines in peripheral blood. Cytomegalovirus (CMV) is known to promote a more effector-oriented phenotype in the T-cell compartment, increasing with age. The aim of this study was to investigate the inflammatory response of peripheral blood mononuclear cells (PBMCs) from AD patients and non-demented (ND) controls. Using a multiplex Luminex xMAP assay targeting GM-CSF, IFN-gamma, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10 and TNF-alpha, cytokine profiles from PBMCs were analysed after stimulation with anti-CD3/CD28 beads, CMV pp65 peptide mix or amyloid beta (A beta) protofibrils, respectively. CMV seropositive AD subjects presented with higher IFN-gamma levels after anti-CD3/ CD28 and CMV pp65 but not after Ab stimulation, compared to CMV seropositive ND controls. When analysing IFN-gamma response to anti-CD3/CD28 stimulation on a subgroup level, CMV seropositive AD subjects presented with higher levels compared to both CMV seronegative AD and CMV seropositive ND subjects. Taken together, our data from patients with clinically manifest AD suggest a possible role of CMV as an inflammatory promoter in AD immunology. Further studies of AD patients at earlier stages of disease, could provide better insight into the pathophysiology.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-227733 (URN)10.1371/journal.pone.0096779 (DOI)000335728900093 ()
Available from: 2014-06-30 Created: 2014-06-30 Last updated: 2017-12-05Bibliographically approved
3. Application of a Multiplex Herpesvirus Immunoassay in Alzheimer’s Disease
Open this publication in new window or tab >>Application of a Multiplex Herpesvirus Immunoassay in Alzheimer’s Disease
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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:nbn:se:uu:diva-246406 (URN)
Available from: 2015-03-15 Created: 2015-03-06 Last updated: 2015-07-07
4. N-Methyl-D-Aspartate Receptor Autoimmunity Affects Cognitive Performance in Herpes Simplex Encephalitis
Open this publication in new window or tab >>N-Methyl-D-Aspartate Receptor Autoimmunity Affects Cognitive Performance in Herpes Simplex Encephalitis
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2016 (English)In: Clinical Microbiology And Infection, ISSN 1198-743X, Vol. 22, no 11, 934-940 p.Article in journal (Other academic) Published
Abstract [en]

Objectives: To investigate the prevalence and temporal development of N-methyl-D-aspartate receptor (NMDAR) autoantibodies in relation to neurocognitive performance in patients with herpes simplex encephalitis (HSE). Methods: This prospective observational study enrolled a total of 49 HSE patients within a randomized controlled trial of valacyclovir. Cerebrospinal fluid and serum samples were drawn in the initial stage of disease, after 2 to 3 weeks and after 3 months. Anti-NMDAR IgG was detected with HEK293 cells transfected with plasmids encoding the NMDA NR1 type glutamate receptor. A batch of neurocognitive tests, including the Mattis Dementia Rating Scale (MDRS), Glasgow Coma Scale (GCS), Reaction Level Scale (RLS85), Mini-Mental State Examination (MMSE) and National Institutes of Health (NIH) stroke scale, was performed during 24 months' follow-up. Results: Anti-NMDAR IgG was detected in 12 of 49 participants. None were antibody positive in the initial stage of disease. In ten of 12 positive cases, specific antibodies were detectable only after 3 months. Notably, the development of NMDAR autoantibodies was associated with significantly impaired recovery of neurocognitive performance. After 24 months' follow-up, the median increase in MDRS total score was 1.5 vs. 10 points in antibody-positive and -negative participants (p = 0.018). Conclusions: Anti-NMDAR autoimmunity is a common complication to HSE that develops within 3 months after onset of disease. The association to impaired neurocognitive recovery could have therapeutical implications, as central nervous system autoimmunity is potentially responsive to immunotherapy.

Keyword
Autoantibodies, Autoimmunity, Herpes simplex encephalitis, IgG, Mattis Dementia Rating Scale, N-methyl-D-aspartate receptor, Neurocognitive impairment, NMDAR
National Category
Clinical Medicine
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-246376 (URN)10.1016/j.cmi.2016.07.028 (DOI)000388119300009 ()27497810 (PubMedID)
Note

C. Ahlm har tillkommit som författare sedan posten lades in som manuskript.

Available from: 2015-03-15 Created: 2015-03-05 Last updated: 2016-12-22Bibliographically approved

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