Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients
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 ide...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.01029/full |
| _version_ | 1819227287919263744 |
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| author | Helena Idborg Arash Zandian Elena Ossipova Edvard Wigren Charlotta Preger Fariborz Mobarrez Fariborz Mobarrez Antonio Checa Azita Sohrabian Pascal Pucholt Johanna K. Sandling Cátia Fernandes-Cerqueira Johan Rönnelid Vilija Oke Giorgia Grosso Marika Kvarnström Anders Larsson Craig E. Wheelock Ann-Christine Syvänen Lars Rönnblom Kim Kultima Helena Persson Susanne Gräslund Iva Gunnarsson Peter Nilsson Elisabet Svenungsson Per-Johan Jakobsson |
| author_facet | Helena Idborg Arash Zandian Elena Ossipova Edvard Wigren Charlotta Preger Fariborz Mobarrez Fariborz Mobarrez Antonio Checa Azita Sohrabian Pascal Pucholt Johanna K. Sandling Cátia Fernandes-Cerqueira Johan Rönnelid Vilija Oke Giorgia Grosso Marika Kvarnström Anders Larsson Craig E. Wheelock Ann-Christine Syvänen Lars Rönnblom Kim Kultima Helena Persson Susanne Gräslund Iva Gunnarsson Peter Nilsson Elisabet Svenungsson Per-Johan Jakobsson |
| author_sort | Helena Idborg |
| collection | DOAJ |
| description | 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 (padjusted = 3 × 10−9, 3 × 10−6, and 5 × 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. |
| first_indexed | 2024-12-23T10:39:00Z |
| format | Article |
| id | doaj.art-6f325af014d94b0386831770ead16b27 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-23T10:39:00Z |
| publishDate | 2019-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-6f325af014d94b0386831770ead16b272022-12-21T17:50:13ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-05-011010.3389/fimmu.2019.01029442928Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus PatientsHelena Idborg0Arash Zandian1Elena Ossipova2Edvard Wigren3Charlotta Preger4Fariborz Mobarrez5Fariborz Mobarrez6Antonio Checa7Azita Sohrabian8Pascal Pucholt9Johanna K. Sandling10Cátia Fernandes-Cerqueira11Johan Rönnelid12Vilija Oke13Giorgia Grosso14Marika Kvarnström15Anders Larsson16Craig E. Wheelock17Ann-Christine Syvänen18Lars Rönnblom19Kim Kultima20Helena Persson21Susanne Gräslund22Iva Gunnarsson23Peter Nilsson24Elisabet Svenungsson25Per-Johan Jakobsson26Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenSciLifeLab, Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, SwedenDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDepartment of Medical Sciences, Akademiska Hospital, Uppsala University, Uppsala, SwedenDivision of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenDepartment of Medical Sciences, Rheumatology, Uppsala University, Uppsala, SwedenDepartment of Medical Sciences, Rheumatology, Uppsala University, Uppsala, SwedenDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDepartment of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, SwedenDivision of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenDepartment of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, SwedenDepartment of Medical Sciences, Rheumatology, Uppsala University, Uppsala, SwedenDepartment of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Drug Discovery and Development & School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, SwedenDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenSciLifeLab, Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, SwedenDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenSystemic 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 (padjusted = 3 × 10−9, 3 × 10−6, and 5 × 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.https://www.frontiersin.org/article/10.3389/fimmu.2019.01029/fullInterferon regulating factor 5 (IRF5)antibody suspension bead arrayssubgroupsbiomarker discoveryplasma proteomicsunsupervised clustering |
| spellingShingle | Helena Idborg Arash Zandian Elena Ossipova Edvard Wigren Charlotta Preger Fariborz Mobarrez Fariborz Mobarrez Antonio Checa Azita Sohrabian Pascal Pucholt Johanna K. Sandling Cátia Fernandes-Cerqueira Johan Rönnelid Vilija Oke Giorgia Grosso Marika Kvarnström Anders Larsson Craig E. Wheelock Ann-Christine Syvänen Lars Rönnblom Kim Kultima Helena Persson Susanne Gräslund Iva Gunnarsson Peter Nilsson Elisabet Svenungsson Per-Johan Jakobsson Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients Frontiers in Immunology Interferon regulating factor 5 (IRF5) antibody suspension bead arrays subgroups biomarker discovery plasma proteomics unsupervised clustering |
| title | Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients |
| title_full | Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients |
| title_fullStr | Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients |
| title_full_unstemmed | Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients |
| title_short | Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients |
| title_sort | circulating levels of interferon regulatory factor 5 associates with subgroups of systemic lupus erythematosus patients |
| topic | Interferon regulating factor 5 (IRF5) antibody suspension bead arrays subgroups biomarker discovery plasma proteomics unsupervised clustering |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.01029/full |
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