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  • 1.
    Ayoglu, Burcu
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Mitsios, Nicholas
    Kockum, Ingrid
    Khademi, Mohsen
    Zandian, Arash
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sjoberg, Ronald
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Forsstrom, Bjorn
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bredenberg, Johan
    Bomfim, Izaura Lima
    Holmgren, Erik
    Gronlund, Hans
    Guerreiro-Cacais, Andre Ortlieb
    Abdelmagid, Nada
    Uhlen, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Waterboer, Tim
    Alfredsson, Lars
    Mulder, Jan
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Olsson, Tomas
    Nilsson, Peter
    Anoctamin 2 identified as an autoimmune target in multiple sclerosis2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 8, p. 2188-2193Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.

  • 2. Checa, A.
    et al.
    Idborg, H.
    Zandian, Arash
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sar, D. Garcia
    Surowiec, I.
    Trygg, J.
    Svenungsson, E.
    Jakobsson, P-J
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Gunnarsson, I.
    Wheelock, C. E.
    Dysregulations in circulating sphingolipids associate with disease activity indices in female patients with systemic lupus erythematosus: a cross-sectional study2017In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 26, no 10, p. 1023-1033Article in journal (Refereed)
    Abstract [en]

    Objective The objective of this study was to investigate the association of clinical and renal disease activity with circulating sphingolipids in patients with systemic lupus erythematosus. Methods We used liquid chromatography tandem mass spectrometry to measure the levels of 27 sphingolipids in plasma from 107 female systemic lupus erythematosus patients and 23 controls selected using a design of experiment approach. We investigated the associations between sphingolipids and two disease activity indices, the Systemic Lupus Activity Measurement and the Systemic Lupus Erythematosus Disease Activity Index. Damage was scored according to the Systemic Lupus International Collaborating Clinics damage index. Renal activity was evaluated with the British Island Lupus Activity Group index. The effects of immunosuppressive treatment on sphingolipid levels were evaluated before and after treatment in 22 female systemic lupus erythematosus patients with active disease. Results Circulating sphingolipids from the ceramide and hexosylceramide families were increased, and sphingoid bases were decreased, in systemic lupus erythematosus patients compared to controls. The ratio of C-16:0-ceramide to sphingosine-1-phosphate was the best discriminator between patients and controls, with an area under the receiver-operating curve of 0.77. The C-16:0-ceramide to sphingosine-1-phosphate ratio was associated with ongoing disease activity according to the Systemic Lupus Activity Measurement and the Systemic Lupus Erythematosus Disease Activity Index, but not with accumulated damage according to the Systemic Lupus International Collaborating Clinics Damage Index. Levels of C-16:0- and C-24:1-hexosylceramides were able to discriminate patients with current versus inactive/no renal involvement. All dysregulated sphingolipids were normalized after immunosuppressive treatment. Conclusion We provide evidence that sphingolipids are dysregulated in systemic lupus erythematosus and associated with disease activity. This study demonstrates the utility of simultaneously targeting multiple components of a pathway to establish disease associations.

  • 3. Ch'ng, Jun-Hong
    et al.
    Sirel, Madle
    Zandian, Arash
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Quintana, Maria del Pilar
    Chan, Sherwin Chun Leung
    Moll, Kirsten
    Tellgren-Roth, Asa
    Nilsson, IngMarie
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Qundos, Ulrika
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Wahlgren, Mats
    Epitopes of anti-RIFIN antibodies and characterization of rif-expressing Plasmodium falciparum parasites by RNA sequencing2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 43190Article in journal (Refereed)
    Abstract [en]

    Variable surface antigens of Plasmodium falciparum have been a major research focus since they facilitate parasite sequestration and give rise to deadly malaria complications. Coupled with its potential use as a vaccine candidate, the recent suggestion that the repetitive interspersed families of polypeptides (RIFINs) mediate blood group A rosetting and influence blood group distribution has raised the research profile of these adhesins. Nevertheless, detailed investigations into the functions of this highly diverse multigene family remain hampered by the limited number of validated reagents. In this study, we assess the specificities of three promising polyclonal anti-RIFIN antibodies that were IgG-purified from sera of immunized animals. Their epitope regions were mapped using a 175,000-peptide microarray holding overlapping peptides of the P. falciparum variable surface antigens. Through immunoblotting and immunofluorescence imaging, we show that different antibodies give varying results in different applications/assays. Finally, we authenticate the antibody-based detection of RIFINs in two previously uncharacterized non-rosetting parasite lines by identifying the dominant rif transcripts using RNA sequencing.

  • 4.
    Häggmark, Anna
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Zandian, Arash
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Forsström, Björn
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Autoantibody targets in vaccine-associated narcolepsyManuscript (preprint) (Other academic)
  • 5.
    Häggmark-Månberg, Anna
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Zandian, Arash
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Forsström, Björn
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Khademi, Mohsen
    Bomfim, Izaura Lima
    Hellström, Cecilia
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Arnheim-Dahlström, Lisen
    Hallböök, Tove
    Darin, Niklas
    Lundberg, Ingrid E.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Partinen, Markku
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Olsson, Tomas
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Autoantibody targets in vaccine-associated narcolepsy2016In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 49, no 6, p. 421-433Article in journal (Refereed)
    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.

  • 6.
    Idborg, H.
    et al.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Zandian, Arash
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Gustafsson, J. T.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Gunnarsson, I.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Svenungsson, E.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Jakobsson, P. J.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    CHARACTERISATION OF SYSTEMIC LUPUS ERYTHEMATOSUS SUBGROUPS WITH FEATURES OF ANTIPHOSPHOLIPID OR SJOGRENS'S SYNDROME UTILISING AFFINITY PROTEOMICS2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. A53-A53Article in journal (Other academic)
  • 7.
    Idborg, H.
    et al.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Zandian, Arash
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Gustafsson, J. T.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Gunnarsson, I.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Svenungsson, E.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Jakobsson, P. -J
    CHARACTERIZATION OF SYSTEMIC LUPUS ERYTHEMATOSUS SUBGROUPS WITH FEATURES OF ANTIPHOSPHOLIPID OR SJOGRENS'S SYNDROME UTILIZING AFFINITY PROTEOMICS2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. 116-116Article in journal (Other academic)
  • 8. Idborg, H.
    et al.
    Zandian, Arash
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Gustafsson, J. T.
    Gunnarsson, I.
    Svenungsson, E.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Jakobsson, P-J
    Characterization of systemic lupus erythematosus subgroups with features of antiphospholipid syndrome or Sjogren's syndrome using affinity proteomics2016In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 45, p. 4-4Article in journal (Other academic)
  • 9.
    Idborg, H.
    et al.
    Karolinska Inst, Dept Med, Solna, Sweden..
    Zandian, Arash
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sandberg, A.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Truedsson, L.
    Lund Univ, Dept Lab Med, Lund, Sweden..
    Nilsson, B.
    Uppsala Univ, Dept Immunol, Uppsala, Sweden..
    Elvin, K.
    Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden..
    Mo, J.
    AstraZeneca, R&D, Molndal, Sweden..
    Gustafsson, J.
    Karolinska Inst, Dept Med, Solna, Sweden..
    Gunnarsson, I.
    Karolinska Inst, Dept Med, Solna, Sweden..
    Lehtio, J.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Nilsson, P.
    Royal Inst Technol, Sch Biotechnol, Stockholm, Sweden..
    Svenungsson, E.
    Karolinska Inst, Dept Med, Solna, Sweden..
    Jakobsson, P.
    Karolinska Inst, Dept Med, Solna, Sweden..
    Systemic lupus erythematosus subgroups, with features of antiphospholipid or Sjogren's syndrome, differ in molecular signatures and treatment perspectives2018In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, p. 2-2Article in journal (Other academic)
  • 10. Idborg, Helena
    et al.
    Zandian, Arash
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hellstrom, Cecilia
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mattsson, Cecilia
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fredolini, Claudia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Schwenk, Jochen M.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Ayoglu, Burcu
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Neiman, Maja
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Jakobsson, Per-Johan
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    PROTEIN PROFILING IN PLASMA REVEALS MOLECULAR SUBGROUPS IN SYSTEMIC LUPUS ERYTHEMATOSUS2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, p. A52-A52Article in journal (Refereed)
  • 11.
    Idborg, Helena
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Zandian, Arash
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Ossipova, Elena
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Wigren, Edvard
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Preger, Charlotta
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Mobarrez, Fariborz
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden.;Uppsala Univ, Akad Hosp, Dept Med Sci, Uppsala, Sweden..
    Checa, Antonio
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden..
    Sohrabian, Azita
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Pucholt, Pascal
    Uppsala Univ, Dept Med Sci, Rheumatol, Uppsala, Sweden..
    Sandling, Johanna K.
    Uppsala Univ, Dept Med Sci, Rheumatol, Uppsala, Sweden..
    Fernandes-Cerqueira, Catia
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Ronnelid, Johan
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Oke, Vilija
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Grosso, Giorgia
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Kvarnstrom, Marika
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Larsson, Anders
    Uppsala Univ, Dept Med Sci, Clin Chem, Uppsala, Sweden..
    Wheelock, Craig E.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden..
    Syvanen, Ann-Christine
    Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden..
    Ronnblom, Lars
    Uppsala Univ, Dept Med Sci, Rheumatol, Uppsala, Sweden..
    Kultima, Kim
    Uppsala Univ, Dept Med Sci, Clin Chem, Uppsala, Sweden..
    Persson, Helena
    KTH Royal Inst Technol, Sci Life Lab, Drug Discovery & Dev, Stockholm, Sweden.;KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Stockholm, Sweden..
    Graslund, Susanne
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Jakobsson, Per-Johan
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1029Article in journal (Refereed)
    Abstract [en]

    Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease, which currently lacks specific diagnostic biomarkers. The diversity within the patients obstructs clinical trials but may also reflect differences in underlying pathogenesis. Our objective was to obtain protein profiles to identify potential general biomarkers of SLE and to determine molecular subgroups within SLE for patient stratification. Plasma samples from a cross-sectional study of well-characterized SLE patients (n = 379) and matched population controls (n = 316) were analyzed by antibody suspension bead array targeting 281 proteins. To investigate the differences between SLE and controls, Mann-Whitney U-test with Bonferroni correction, generalized linear modeling and receiver operating characteristics (ROC) analysis were performed. K-means clustering was used to identify molecular SLE subgroups. We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively). The lowest p-values comparing SLE patients and controls were obtained for S100A12, Matrix metalloproteinase-1 (MMP1) and SLC22A2 (p(adjusted) = 3 x 10(-9), 3 x 10(-6), and 5 x 10(-6) respectively). In a set of 15 potential biomarkers differentiating SLE patients and controls, two of the proteins were transcription factors, i.e., IRF5 and SAM pointed domain containing ETS transcription factor (SPDEF). IRF5 was up-regulated while SPDEF was found to be down-regulated in SLE patients. Unsupervised clustering of all investigated proteins identified three molecular subgroups among SLE patients, characterized by (1) high levels of rheumatoid factor-IgM, (2) low IRF5, and (3) high IRF5. IRF5 expressing microparticles were analyzed by flow cytometry in a subset of patients to confirm the presence of IRF5 in plasma and detection of extracellular IRF5 was further confirmed by immunoprecipitation-mass spectrometry (IP-MS). Interestingly IRF5, a known genetic risk factor for SLE, was detected extracellularly and suggested by unsupervised clustering analysis to differentiate between SLE subgroups. Our results imply a set of circulating molecules as markers of possible pathogenic importance in SLE. We believe that these findings could be of relevance for understanding the pathogenesis and diversity of SLE, as well as for selection of patients in clinical trials.

  • 12.
    Idborg, Helena
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, S-17176 Stockholm, Sweden..
    Zandian, Arash
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sandberg, Ann-Sofi
    Sci Life Lab, Dept Oncol Pathol, Clin Prote Mass Spectrometry, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Nilsson, Bo
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Elvin, Kerstin
    Karolinska Inst, Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Unit Clin Immunol, Stockholm, Sweden..
    Truedsson, Lennart
    Lund Univ, Dept Lab Med, Sect Microbiol Immunol & Glycobiol, Lund, Sweden..
    Sohrabian, Azita
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Ronnelid, Johan
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Mo, John
    AstraZeneca R&D, Patient Safety Resp Inflammat Autoimmun Infect &, Gothenburg, Sweden..
    Grosso, Giorgia
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, S-17176 Stockholm, Sweden..
    Kvarnström, Marika
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, S-17176 Stockholm, Sweden..
    Gunnarsson, Iva
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, S-17176 Stockholm, Sweden..
    Lehtio, Janne
    Sci Life Lab, Dept Oncol Pathol, Clin Prote Mass Spectrometry, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Nilsson, Peter
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Svenungsson, Elisabet
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, S-17176 Stockholm, Sweden..
    Jakobsson, Per-Johan
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, S-17176 Stockholm, Sweden..
    Two subgroups in systemic lupus erythematosus with features of antiphospholipid or Sjogren's syndrome differ in molecular signatures and treatment perspectives2019In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 21, article id 62Article in journal (Refereed)
    Abstract [en]

    BackgroundPrevious studies and own clinical observations of patients with systemic lupus erythematosus (SLE) suggest that SLE harbors distinct immunophenotypes. This heterogeneity might result in differences in response to treatment in different subgroups and obstruct clinical trials. Our aim was to understand how SLE subgroups may differ regarding underlying pathophysiology and characteristic biomarkers.MethodsIn a cross-sectional study, including 378 well-characterized SLE patients and 316 individually matched population controls, we defined subgroups based on the patients' autoantibody profile at inclusion. We selected a core of an antiphospholipid syndrome-like SLE (aPL+ group; positive in the lupus anticoagulant (LA) test and negative for all three of SSA (Ro52 and Ro60) and SSB antibodies) and a Sjogren's syndrome-like SLE (SSA/SSB+ group; positive for all three of SSA (Ro52 and Ro60) and SSB antibodies but negative in the LA test). We applied affinity-based proteomics, targeting 281 proteins, together with well-established clinical biomarkers and complementary immunoassays to explore the difference between the two predefined SLE subgroups.ResultsThe aPL+ group comprised 66 and the SSA/SSB+ group 63 patients. The protein with the highest prediction power (receiver operating characteristic (ROC) area under the curve=0.89) for separating the aPL+ and SSA/SSB+ SLE subgroups was integrin beta-1 (ITGB1), with higher levels present in the SSA/SSB+ subgroup. Proteins with the lowest p values comparing the two SLE subgroups were ITGB1, SLC13A3, and CERS5. These three proteins, rheumatoid factor, and immunoglobulin G (IgG) were all increased in the SSA/SSB+ subgroup. This subgroup was also characterized by a possible activation of the interferon system as measured by high KRT7, TYK2, and ETV7 in plasma. In the aPL+ subgroup, complement activation was more pronounced together with several biomarkers associated with systemic inflammation (fibrinogen, -1 antitrypsin, neutrophils, and triglycerides).ConclusionsOur observations indicate underlying pathogenic differences between the SSA/SSB+ and the aPL+ SLE subgroups, suggesting that the SSA/SSB+ subgroup may benefit from IFN-blocking therapies while the aPL+ subgroup is more likely to have an effect from drugs targeting the complement system. Stratifying SLE patients based on an autoantibody profile could be a way forward to understand underlying pathophysiology and to improve selection of patients for clinical trials of targeted treatments.

  • 13.
    Persson, Mats
    et al.
    Karolinska Inst, Solna, Sweden..
    Zandian, Arasch
    KTH.
    Wingard, Louise
    Karolinska Inst, Solna, Sweden..
    Nilsson, Hanna
    Karolinska Inst, Solna, Sweden..
    Sjostedt, Evelina
    Uppsala Univ, Uppsala, Sweden..
    Johansson, Daniel
    Karolinska Inst, Solna, Sweden..
    Just, David
    KTH.
    Hellström, Cecilia
    KTH.
    Uhlén, Mathias
    Schwenk, Jochen M.
    Häggmark-Månberg, Anna
    KTH.
    Norbeck, Oscar
    Karolinska Inst, Solna, Sweden..
    Owe-Larsson, Bjorn
    Karolinska Inst, Solna, Sweden..
    Nilsson, Peter
    KTH.
    Searching for Novel Autoantibodies with Clinical Relevance in Psychiatric Disorders2018In: Schizophrenia Bulletin, ISSN 0586-7614, E-ISSN 1745-1701, Vol. 44, p. S120-S121Article in journal (Other academic)
  • 14.
    Quintana, Maria del Pilar
    et al.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden..
    Ch'ng, Jun-Hong
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.;Natl Univ Singapore, Dept Microbiol & Immunol, Singapore, Singapore..
    Moll, Kirsten
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden..
    Zandian, Arash
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Idris, Zulkarnain Md
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.;Univ Kebangsaan, Malaysia Med Ctr, Fac Med, Dept Parasitol & Med Entomol, Kuala Lumpur, Malaysia..
    Saiwaew, Somporn
    Mahidol Univ, Fac Trop Med, Dept Clin Trop Med, Bangkok, Thailand..
    Qundos, Ulrika
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Wahlgren, Mats
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden..
    Antibodies in children with malaria to PfEMP1, RIFIN and SURFIN expressed at the Plasmodium falciparum parasitized red blood cell surface2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 3262Article in journal (Refereed)
    Abstract [en]

    Naturally acquired antibodies to proteins expressed on the Plasmodium falciparum parasitized red blood cell (pRBC) surface steer the course of a malaria infection by reducing sequestration and stimulating phagocytosis of pRBC. Here we have studied a selection of proteins representing three different parasite gene families employing a well-characterized parasite with a severe malaria phenotype (FCR3S1.2). The presence of naturally acquired antibodies, impact on rosetting rate, surface reactivity and opsonization for phagocytosis in relation to different blood groups of the ABO system were assessed in a set of sera from children with mild or complicated malaria from an endemic area. We show that the naturally acquired immune responses, developed during malaria natural infection, have limited access to the pRBCs inside a blood group A rosette. The data also indicate that SURFIN4.2 may have a function at the pRBC surface, particularly during rosette formation, this role however needs to be further validated. Our results also indicate epitopes differentially recognized by rosette-disrupting antibodies on a peptide array. Antibodies towards parasite-derived proteins such as PfEMP1, RIFIN and SURFIN in combination with host factors, essentially the ABO blood group of a malaria patient, are suggested to determine the outcome of a malaria infection.

  • 15.
    Quintana, Maria del Pilar
    et al.
    Karolinska Inst, Biomedicum, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden..
    Ch'ng, Jun-Hong
    Karolinska Inst, Biomedicum, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.;Natl Univ Singapore, Dept Microbiol & Immunol, Singapore, Singapore..
    Zandian, Arash
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Imam, Maryam
    Karolinska Inst, Biomedicum, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden..
    Hultenby, Kjell
    Karolinska Inst, Dept Lab Med, Div Clin Res Ctr, Huddinge, Sweden..
    Theisen, Michael
    Statens Serum Inst, Dept Congenital Disorders, Copenhagen, Denmark.;Univ Copenhagen, Dept Int Hlth Immunol & Microbiol, Ctr Med Parasitol, Copenhagen, Denmark..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Qundos, Ulrika
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Moll, Kirsten
    Karolinska Inst, Biomedicum, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden..
    Chan, Sherwin
    Karolinska Inst, Biomedicum, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden..
    Wahlgren, Mats
    Karolinska Inst, Biomedicum, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden..
    SURGE complex of Plasmodium falciparum in the rhoptry-neck (SURFIN4.2-RON4-GLURP) contributes to merozoite invasion2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 8, article id e0201669Article in journal (Refereed)
    Abstract [en]

    Plasmodium falciparum invasion into red blood cells (RBCs) is a complex process engaging proteins on the merozoite surface and those contained and sequentially released from the apical organelles (micronemes and rhoptries). Fundamental to invasion is the formation of a moving junction (MJ), a region of close apposition of the merozoite and the RBC plasma membranes, through which the merozoite draws itself before settling into a newly formed parasitophorous vacuole (PV). SURFIN4.2 was identified at the surface of the parasitized RBCs (pRBCs) but was also found apically associated with the merozoite. Using antibodies against the N-terminus of the protein we show the presence of SURFIN4.2 in the neck of the rhoptries, its secretion into the PV and shedding into the culture supernatant upon schizont rupture. Using immunoprecipitation followed by mass spectrometry we describe here a novel protein complex we have named SURGE where SURFIN4.2 forms interacts with the rhoptry neck protein 4 (RON4) and the Glutamate Rich Protein (GLURP). The N-terminal cysteine-rich domain (CRD) of SURFIN4.2 mediates binding to the RBC membrane and its interaction with RON4 suggests its involvement in the contact between the merozoite apex and the RBC at the MJ. Supporting this suggestion, we also found that polyclonal antibodies to the extracellular domain (including the CRD) of SURFIN4.2 partially inhibit merozoite invasion. We propose that the formation of the SURGE complex participates in the establishment of parasite infection within the PV and the RBCs.

  • 16.
    Zandian, Arash
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Array-based Autoantibody Profiling and Epitope Mapping2017Doctoral thesis, comprehensive summary (Other academic)
    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.

  • 17.
    Zandian, Arash
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Forsström, Björn
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Häggmark-Månberg, Anna
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, School of Biotechnology (BIO), Nano Biotechnology (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ayoglu, Burcu
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Whole-Proteome Peptide Microarrays for Profiling Autoantibody Repertoires within Multiple Sclerosis and Narcolepsy2017In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 16, no 3, p. 1300-1314Article in journal (Refereed)
    Abstract [en]

    The underlying molecular mechanisms of autoimmune diseases are poorly understood. To unravel the autoimmune processes across diseases, comprehensive and unbiased analyses of proteins targets recognized by the adaptive immune system are needed. Here we present an approach starting from high-density peptide arrays to characterize autoantibody repertoires and to identify new autoantigens. A set of ten plasma and serum samples from subjects with multiple sclerosis, narcolepsy, and without any disease diagnosis were profiled on a peptide array representing the whole proteome, hosting 2.2 million 12-mer peptides with a six amino acid lateral shift. On the basis of the IgG reactivities found on these whole-proteome peptide micro arrays, a set of 23 samples was then studied on a targeted array with 174 000 12-mer peptides of single amino acid lateral shift. Finally, verification of IgG reactivities was conducted with a larger sample set (n = 448) using the bead-based peptide microarrays. The presented workflow employed three different peptide microarray formats to discover and resolve the epitopes of human autoantibodies and revealed two potentially new autoantigens: MAP3K7 in multiple sclerosis and NRXN1 in narcolepsy. The presented strategy provides insights into antibody repertoire reactivity at a peptide level and may accelerate the discovery and validation of autoantigens in human diseases.

  • 18.
    Zandian, Arash
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Wingård, L.
    Nilsson, H.
    Sjöstedt, E.
    Johansson, D. X.
    Just, David
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hellström, Cecilia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Häggmark-Månberg, Anna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Norbeck, O.
    Owe-Larsson, B.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Persson, M. A. A.
    Untargeted screening for novel autoantibodies with prognostic value in first-episode psychosis2017In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 7, article id e1177Article in journal (Refereed)
    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.

1 - 18 of 18
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