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Untargeted screening for novel autoantibodies with prognostic value in first-episode psychosis
KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
Visa övriga samt affilieringar
2017 (Engelska)Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 7, artikel-id e1177Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group, 2017. Vol. 7, artikel-id e1177
Nationell ämneskategori
Psykiatri
Identifikatorer
URN: urn:nbn:se:kth:diva-212629DOI: 10.1038/tp.2017.160ISI: 000406715200003Scopus ID: 2-s2.0-85046053045OAI: oai:DiVA.org:kth-212629DiVA, id: diva2:1135742
Forskningsfinansiär
Vetenskapsrådet, 521-2014-3857VINNOVAKnut och Alice Wallenbergs StiftelseEU, FP7, Sjunde ramprogrammet, FP7-PEOPLE-2013-ITN-607616Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Anmärkning

QC 20170824

Tillgänglig från: 2017-08-24 Skapad: 2017-08-24 Senast uppdaterad: 2019-01-07Bibliografiskt granskad
Ingår i avhandling
1. Array-based Autoantibody Profiling and Epitope Mapping
Öppna denna publikation i ny flik eller fönster >>Array-based Autoantibody Profiling and Epitope Mapping
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Antibodies are a class of proteins that are made by the immune system to recognize harmful organisms and molecules. Their exceptional capability of specifically recognizing molecules has been investigated for over a century and information thereof has been utilized for a variety of applications including vaccine and generation of therapeutic antibodies. Occasionally, instead of protecting the host against pathogens, antibodies can recognize constituents of the host and thereby cause an autoimmune reaction that eventually can lead to a disease. Therefore, it is of great interest to understand what the antibodies bind to and their specificities.

 

The last decades of technical development and availability of protein and peptide microarrays have enabled large-scale profiling of antibodies and precise determination of their specificities through epitope mapping. In this thesis the aim was to use affinity proteomics tools to profile antibodies, determine their specificities, and discover potential associations of autoantigens to disease by analyzing blood-derived samples with microarray-based methods.

 

In Paper I, 57 serum samples from patients with the suggested autoimmune disease narcolepsy, were analyzed on planar antigen microarrays with 10,846 human protein fragments. Verification on an independent sample collection consisting of serum samples from 176 individuals, revealed METTL22 and NT5C1A as two potential autoantigens. In Paper II, antibodies from 53 plasma samples from patients with first-episode psychosis, a condition suggested to have a partial autoimmune component, were analyzed on planar antigen microarrays with 2,304 human protein fragments. After a follow-up study of the patients, antibodies toward an antigen representing the three proteins, PAGE2, PAGE2B, PAGE5, was found associated to an increased risk of developing schizophrenia. In Paper III, serum and plasma samples from patients with the autoimmune diseases multiple sclerosis and narcolepsy, were epitope mapped on high-density peptide microarrays with approximately 2.2 million peptides. Technical and biological verification, by using other microarray technology and analyzing  samples from 448 patients, revealed one peptide for multiple sclerosis and narcolepsy, representing the proteins MAP3K7 and NRXN1, with higher antibody reactivity towards in each group, respectively. In Paper IV, purified polyclonal antibodies raised against a surface antigen found on malaria-infected erythrocytes, were profiled on the peptide microarrays representing all proteins found on malaria-infected erythrocytes derived from Plasmodium falciparum. Then, different Plasmodium falciparum strains were analyzed by immunofluorescence microscopy and western blots, using the epitope mapped antibodies. The performance of the immunoassays were compared to the identified epitopes, and validated by RNA sequencing.

 

In conclusion, these investigations describe multiplex methods to identify and characterize antibodies, their disease association and epitopes. Follow-up studies are needed to determine their potential use and clinical value.

Ort, förlag, år, upplaga, sidor
Stockholm: KTH Royal Institute of Technology, 2017. s. 89
Serie
TRITA-BIO-Report, ISSN 1654-2312 ; 2017:19
Nyckelord
antibody, antigens, peptide, epitope mapping, autoimmunity, autoantibodies, microarrays
Nationell ämneskategori
Medicinsk bioteknik
Forskningsämne
Bioteknologi
Identifikatorer
urn:nbn:se:kth:diva-213689 (URN)978-91-7729-499-3 (ISBN)
Disputation
2017-10-06, Air & Fire, Tomtebodavägen 23A, Solna, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

QC 20170905

Tillgänglig från: 2017-09-05 Skapad: 2017-09-04 Senast uppdaterad: 2017-09-05Bibliografiskt granskad
2. On the profiling of autoantibodies in psychiatric disorders
Öppna denna publikation i ny flik eller fönster >>On the profiling of autoantibodies in psychiatric disorders
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Stockholm: KTH Royal Institute of Technology, 2019
Serie
TRITA-CBH-FOU ; 2019:3
Nyckelord
affinity proteomics, microarrays, suspension bead array, autoantibodies, autoimmunity, psychiatric disorders, schizophrenia
Nationell ämneskategori
Medicinsk bioteknologi
Identifikatorer
urn:nbn:se:kth:diva-241047 (URN)978-91-7873-075-9 (ISBN)
Disputation
2019-02-08, Atrium, Nobelsväg 12B, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

QC 20180108

Tillgänglig från: 2019-01-08 Skapad: 2019-01-07 Senast uppdaterad: 2019-01-08Bibliografiskt granskad

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Zandian, ArashJust, DavidHellström, CeciliaUhlén, MathiasSchwenk, Jochen M.Häggmark-Månberg, AnnaNilsson, Peter
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Proteomik och nanobioteknologiScience for Life Laboratory, SciLifeLab
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Translational Psychiatry
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