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On the profiling of autoantibodies in psychiatric disorders
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.ORCID iD: 0000-0001-6126-2256
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is a great need to increase our understanding of diseases affecting the brain and their underlying pathogenic mechanisms. To address this need, the work presented in this thesis applied affinity based proteomic techniques to profile proteins, and to investigate protein profiles and the autoantibody repertoire in brain related disorders. Studies included in this thesis cover traumatic brain injuries, first-episode psychosis, schizophrenia and obsessive-compulsive disorders. Paper I describes the profiling of rat serum samples of a traumatic brain injury model to increase the understanding of injury related protein markers and their potential role in patient outcome. Changes in protein profiles over time were characterized as well as potential injury markers related to oxygen intake. Paper II-IV describe the use of protein fragment-based arrays to investigate potential pathogenic autoantibodies associated to the disease. In Paper II possible predictive autoantibodies for the development of schizophrenia were identified, Paper III identified probable brain reactive autoantibodies in schizophrenia patients and Paper IV described the exploration of autoantibodies which might have an association to obsessive-compulsive disorder. Further characterization of these autoantibody repertoires in psychiatric disorders and future efforts could increase our understanding of their role in the associated diseases. Taken together, this work provides the basis for future research in the search for novel disease associated proteins and autoantibody profiles in brain related disorders. An increased understanding and additional diagnostic or prognostic markers of these disorders would be beneficial for both researchers and patients.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2019.
Series
TRITA-CBH-FOU ; 2019:3
Keywords [en]
affinity proteomics, microarrays, suspension bead array, autoantibodies, autoimmunity, psychiatric disorders, schizophrenia
National Category
Medical Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-241047ISBN: 978-91-7873-075-9 (print)OAI: oai:DiVA.org:kth-241047DiVA, id: diva2:1275845
Public defence
2019-02-08, Atrium, Nobelsväg 12B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20180108

Available from: 2019-01-08 Created: 2019-01-07 Last updated: 2019-01-08Bibliographically approved
List of papers
1. Protein profiling in serum after traumatic brain injury in rats reveals potential injury markers
Open this publication in new window or tab >>Protein profiling in serum after traumatic brain injury in rats reveals potential injury markers
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2018 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 340, p. 71-80Article in journal (Refereed) Published
Abstract [en]

Introduction: The serum proteome following traumatic brain injury (TBI) could provide information for outcome prediction and injury monitoring. The aim with this affinity proteomic study was to identify serum proteins over time and between normoxic and hypoxic conditions in focal TBI. Material and methods: Sprague Dawley rats (n = 73) received a 3 mm deep controlled cortical impact ("severe injury"). Following injury, the rats inhaled either a normoxic (22% O-2) or hypoxic (11% O-2) air mixture for 30 min before resuscitation. The rats were sacrificed at day 1, 3, 7, 14 and 28 after trauma. A total of 204 antibodies targeting 143 unique proteins of interest in TBI research, were selected. The sample proteome was analyzed in a suspension bead array set-up. Comparative statistics and factor analysis were used to detect differences as well as variance in the data. Results: We found that complement factor 9 (C9), complement factor B (CFB) and aldolase c (ALDOC) were detected at higher levels the first days after trauma. In contrast, hypoxia inducing factor (HIF)1 alpha, amyloid precursor protein (APP) and WBSCR17 increased over the subsequent weeks. S100A9 levels were higher in hypoxic-compared to normoxic rats, together with a majority of the analyzed proteins, albeit few reached statistical significance. The principal component analysis revealed a variance in the data, highlighting clusters of proteins. Conclusions: Protein profiling of serum following TBI using an antibody based microarray revealed temporal changes of several proteins over an extended period of up to four weeks. Further studies are warranted to confirm our findings.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Traumatic brain injury, Hypoxia, Serum proteins, Biomarkers, Protein-array
National Category
Neurology
Identifiers
urn:nbn:se:kth:diva-223246 (URN)10.1016/j.bbr.2016.08.058 (DOI)000424173400008 ()27591967 (PubMedID)2-s2.0-85011022724 (Scopus ID)
Funder
VINNOVAKnut and Alice Wallenberg FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20180219

Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2019-01-07Bibliographically approved
2. Untargeted screening for novel autoantibodies with prognostic value in first-episode psychosis
Open this publication in new window or tab >>Untargeted screening for novel autoantibodies with prognostic value in first-episode psychosis
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2017 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 7, article id e1177Article in journal (Refereed) Published
Abstract [en]

Immunological and inflammatory reactions have been suggested to have a role in the development of schizophrenia, a hypothesis that has recently been supported by genetic data. The aim of our study was to perform an unbiased search for autoantibodies in patients with a first psychotic episode, and to explore the association between any seroreactivity and the development of a Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) disorder characterized by chronic or relapsing psychotic symptoms. We collected plasma samples from 53 patients when they were treated for their first-episode psychosis, and 41 non-psychotic controls, after which the patients were followed for a mean duration of 7 years. Thirty patients were diagnosed with schizophrenia, delusional disorder, schizoaffective disorder, bipolar disorder or a long-term unspecified nonorganic psychosis during follow-up, whereas 23 patients achieved complete remission. At the end of follow-up, plasma samples were analyzed for IgG reactivity to 2304 fragments of human proteins using a multiplexed affinity proteomic technique. Eight patient samples showed autoreactivity to the N-terminal fragment of the PAGE (P antigen) protein family (PAGE2B/PAGE2/PAGE5), whereas no such autoreactivity was seen among the controls. PAGE autoreactivity was associated with a significantly increased risk of being diagnosed with schizophrenia during follow-up (odds ratio 6.7, relative risk 4.6). An immunohistochemistry analysis using antisera raised against the N-terminal fragment stained an unknown extracellular target in human cortical brain tissue. Our findings suggest that autoreactivity to the N-terminal portion of the PAGE protein family is associated with schizophrenia in a subset of patients with first-episode psychosis.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
National Category
Psychiatry
Identifiers
urn:nbn:se:kth:diva-212629 (URN)10.1038/tp.2017.160 (DOI)000406715200003 ()2-s2.0-85046053045 (Scopus ID)
Funder
Swedish Research Council, 521-2014-3857VINNOVAKnut and Alice Wallenberg FoundationEU, FP7, Seventh Framework Programme, FP7-PEOPLE-2013-ITN-607616Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20170824

Available from: 2017-08-24 Created: 2017-08-24 Last updated: 2019-01-07Bibliographically approved
3. Exploring autoantibody signatures in brain tissue lysates from patients with schizophrenia
Open this publication in new window or tab >>Exploring autoantibody signatures in brain tissue lysates from patients with schizophrenia
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-241046 (URN)
Note

QC 20190108

Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-08Bibliographically approved
4. Exploring the autoantibody repertoire in patients with obsessive compulsive disorder
Open this publication in new window or tab >>Exploring the autoantibody repertoire in patients with obsessive compulsive disorder
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-241045 (URN)
Note

QC 20190108

Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-08Bibliographically approved

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1011121314151613 of 17
CiteExportLink to record
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