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N-Methyl-D-Aspartate Receptor Autoimmunity Affects Cognitive Performance in Herpes Simplex Encephalitis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Department of Infectious Diseases, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Umea Univ, Dept Clin Microbiol, Infect Dis, Umea, Sweden.
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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.

Place, publisher, year, edition, pages
2016. Vol. 22, no 11, 934-940 p.
Keyword [en]
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: urn:nbn:se:uu:diva-246376DOI: 10.1016/j.cmi.2016.07.028ISI: 000388119300009PubMedID: 27497810OAI: oai:DiVA.org:uu-246376DiVA: diva2:795201
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
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. 80 p.
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: 2015-07-07

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Westman, GabrielPersson, BarbroEriksson, Britt-MarieRönnelid, Johan

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