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Autoantibody targets in vaccine-associated narcolepsy
KTH, Centra, Science for Life Laboratory, SciLifeLab.ORCID-id: 0000-0002-0056-1313
KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.ORCID-id: 0000-0003-1242-0873
KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.ORCID-id: 0000-0002-5248-8568
Visa övriga samt affilieringar
2016 (Engelska)Ingår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 49, nr 6, s. 421-433Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Narcolepsy is a chronic sleep disorder with a yet unknown cause, but the specific loss of hypocretin-producing neurons together with a strong human leukocyte antigen (HLA) association has led to the hypothesis that autoimmune mechanisms might be involved. Here, we describe an extensive effort to profile autoimmunity repertoires in serum with the aim to find disease-related autoantigens. Initially, 57 serum samples from vaccine-associated and sporadic narcolepsy patients and controls were screened for IgG reactivity towards 10 846 fragments of human proteins using planar microarrays. The discovered differential reactivities were verified on suspension bead arrays in the same sample collection followed by further investigation of 14 antigens in 176 independent samples, including 57 narcolepsy patients. Among these 14 antigens, methyltransferase-like 22 (METTL22) and 5'-nucleotidase cytosolic IA (NT5C1A) were recognized at a higher frequency in narcolepsy patients of both sample sets. Upon sequence analysis of the 14 proteins, polymerase family, member 3 (PARP3), acyl-CoA-binding domain containing 7 (ARID4B), glutaminase 2 (GLS2) and cyclin-dependent kinase-like 1 (CDKL1) were found to contain amino acid sequences with homology to proteins found in the H1N1 vaccine. These findings could become useful elements of further clinical assays that aim towards a better phenotypic understanding of narcolepsy and its triggers.

Ort, förlag, år, upplaga, sidor
Taylor & Francis, 2016. Vol. 49, nr 6, s. 421-433
Nyckelord [en]
Narcolepsy, autoantibody, vaccine-associated, protein microarray, serum
Nationell ämneskategori
Immunologi
Identifikatorer
URN: urn:nbn:se:kth:diva-198898DOI: 10.1080/08916934.2016.1183655ISI: 000388594400009PubMedID: 27206786Scopus ID: 2-s2.0-84969988196OAI: oai:DiVA.org:kth-198898DiVA, id: diva2:1063006
Forskningsfinansiär
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceVINNOVAKnut och Alice Wallenbergs Stiftelse
Anmärkning

QC 20170109

Tillgänglig från: 2017-01-09 Skapad: 2016-12-22 Senast uppdaterad: 2017-11-29Bibliografiskt 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

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Av författaren/redaktören
Häggmark-Månberg, AnnaZandian, ArashForsström, BjörnHellström, CeciliaUhlén, MathiasSchwenk, Jochen M.Nilsson, Peter
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Science for Life Laboratory, SciLifeLabProteomik och nanobioteknologi
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