The plasma proteome reveals distinct signaling pathways associated with PR3-ANCA positive and MPO-ANCA positive vasculitis
ObjectiveDespite recent advances, the pathophysiological mechanisms underlying anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) remain incompletely understood, and comparative proteomic analyses of AAV subtypes are lacking. This study aimed to identify key molecular signalin...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1600754/full |
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| author | Erik Hellbacher Erik Hellbacher Vincent van Hoef Alina Johansson Ann Knight Ann Knight Iva Gunnarsson Iva Gunnarsson Annette Bruchfeld Annette Bruchfeld Per Eriksson Sophie Ohlsson Solbritt Rantapää-Dahlqvist Johanna Dahlqvist Johanna Dahlqvist |
| author_facet | Erik Hellbacher Erik Hellbacher Vincent van Hoef Alina Johansson Ann Knight Ann Knight Iva Gunnarsson Iva Gunnarsson Annette Bruchfeld Annette Bruchfeld Per Eriksson Sophie Ohlsson Solbritt Rantapää-Dahlqvist Johanna Dahlqvist Johanna Dahlqvist |
| author_sort | Erik Hellbacher |
| collection | DOAJ |
| description | ObjectiveDespite recent advances, the pathophysiological mechanisms underlying anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) remain incompletely understood, and comparative proteomic analyses of AAV subtypes are lacking. This study aimed to identify key molecular signaling pathways activated in AAV and to elucidate molecular distinctions between AAV with proteinase 3 ANCA (PR3-AAV) and AAV with myeloperoxidase ANCA (MPO-AAV).MethodsPlasma samples from 41 cases with active PR3-AAV, 24 with active MPO-AAV and 138 population controls were analyzed for 185 proteins using proximity extension assay and Luminex. Differential expression was assessed between PR3-AAV, MPO-AAV and controls using univariate and partial least squares discriminant analyses. Protein-protein interactions and pathway enrichment were explored using STRING and Cytoscape databases.ResultsCompared with controls, 31 proteins were significantly upregulated in PR3-AAV and 29 in MPO-AAV; 18 were shared, whereas 13 and 11 were specific to PR3-AAV and MPO-AAV, respectively. Shared proteins were enriched in general immune pathways, including IL-6 signaling. AAV subgroup-specific proteins were combined with proteins differentiating between PR3-AAV and MPO-AAV in a direct comparison. MMP-1, MMP-9, HGF, and OSM were uniquely upregulated in PR3-AAV, while TNF, TNF-R1/R2, TNFRSF14, and TNFRSF9 were prominent in MPO-AAV. Functional enrichment analyses underscored STAT3 signaling in PR3-AAV and TNF signaling in MPO-AAV.ConclusionsThis study identifies distinct and shared signaling pathways in PR3-AAV and MPO-AAV, highlighting STAT3 and TNF pathways as potential subtype-specific mechanisms. These findings offer insight into AAV pathogenesis and may guide the development of more targeted, less toxic treatments tailored to AAV subtypes. |
| format | Article |
| id | doaj-art-57c91901fee84a489b866c3e4c8226b9 |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-57c91901fee84a489b866c3e4c8226b92025-08-20T02:40:27ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.16007541600754The plasma proteome reveals distinct signaling pathways associated with PR3-ANCA positive and MPO-ANCA positive vasculitisErik Hellbacher0Erik Hellbacher1Vincent van Hoef2Alina Johansson3Ann Knight4Ann Knight5Iva Gunnarsson6Iva Gunnarsson7Annette Bruchfeld8Annette Bruchfeld9Per Eriksson10Sophie Ohlsson11Solbritt Rantapää-Dahlqvist12Johanna Dahlqvist13Johanna Dahlqvist14Department of Medical Sciences, Uppsala University, Uppsala, SwedenRheumatology, Uppsala University Hospital, Uppsala, SwedenNational Bioinformatics Support (NBIS), Science for Life Laboratory, Uppsala University, Uppsala, SwedenDepartment of Medical Sciences, Uppsala University, Uppsala, SwedenDepartment of Medical Sciences, Uppsala University, Uppsala, SwedenRheumatology, Uppsala University Hospital, Uppsala, SwedenDepartment of Medicine, Division of Rheumatology, Karolinska Institutet, Stockholm, SwedenUnit of Rheumatology, Karolinska University Hospital, Stockholm, SwedenDepartment of Nephrology and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, SwedenDepartment of Renal Medicine, Karolinska University Hospital and CLINTEC Karolinska Institutet, Stockholm, SwedenDepartment of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linköping University, Linköping, SwedenDepartment of Clinical Sciences, Division of Nephrology, Lund University and Skåne University Hospital, Lund, Sweden0Department of Public Health and Clinical Medicine, Umeå University, Umeå, SwedenDepartment of Medical Sciences, Uppsala University, Uppsala, SwedenRheumatology, Uppsala University Hospital, Uppsala, SwedenObjectiveDespite recent advances, the pathophysiological mechanisms underlying anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) remain incompletely understood, and comparative proteomic analyses of AAV subtypes are lacking. This study aimed to identify key molecular signaling pathways activated in AAV and to elucidate molecular distinctions between AAV with proteinase 3 ANCA (PR3-AAV) and AAV with myeloperoxidase ANCA (MPO-AAV).MethodsPlasma samples from 41 cases with active PR3-AAV, 24 with active MPO-AAV and 138 population controls were analyzed for 185 proteins using proximity extension assay and Luminex. Differential expression was assessed between PR3-AAV, MPO-AAV and controls using univariate and partial least squares discriminant analyses. Protein-protein interactions and pathway enrichment were explored using STRING and Cytoscape databases.ResultsCompared with controls, 31 proteins were significantly upregulated in PR3-AAV and 29 in MPO-AAV; 18 were shared, whereas 13 and 11 were specific to PR3-AAV and MPO-AAV, respectively. Shared proteins were enriched in general immune pathways, including IL-6 signaling. AAV subgroup-specific proteins were combined with proteins differentiating between PR3-AAV and MPO-AAV in a direct comparison. MMP-1, MMP-9, HGF, and OSM were uniquely upregulated in PR3-AAV, while TNF, TNF-R1/R2, TNFRSF14, and TNFRSF9 were prominent in MPO-AAV. Functional enrichment analyses underscored STAT3 signaling in PR3-AAV and TNF signaling in MPO-AAV.ConclusionsThis study identifies distinct and shared signaling pathways in PR3-AAV and MPO-AAV, highlighting STAT3 and TNF pathways as potential subtype-specific mechanisms. These findings offer insight into AAV pathogenesis and may guide the development of more targeted, less toxic treatments tailored to AAV subtypes.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1600754/fullANCAvasculitisproteinase 3myeloperoxidaseproteome |
| spellingShingle | Erik Hellbacher Erik Hellbacher Vincent van Hoef Alina Johansson Ann Knight Ann Knight Iva Gunnarsson Iva Gunnarsson Annette Bruchfeld Annette Bruchfeld Per Eriksson Sophie Ohlsson Solbritt Rantapää-Dahlqvist Johanna Dahlqvist Johanna Dahlqvist The plasma proteome reveals distinct signaling pathways associated with PR3-ANCA positive and MPO-ANCA positive vasculitis Frontiers in Immunology ANCA vasculitis proteinase 3 myeloperoxidase proteome |
| title | The plasma proteome reveals distinct signaling pathways associated with PR3-ANCA positive and MPO-ANCA positive vasculitis |
| title_full | The plasma proteome reveals distinct signaling pathways associated with PR3-ANCA positive and MPO-ANCA positive vasculitis |
| title_fullStr | The plasma proteome reveals distinct signaling pathways associated with PR3-ANCA positive and MPO-ANCA positive vasculitis |
| title_full_unstemmed | The plasma proteome reveals distinct signaling pathways associated with PR3-ANCA positive and MPO-ANCA positive vasculitis |
| title_short | The plasma proteome reveals distinct signaling pathways associated with PR3-ANCA positive and MPO-ANCA positive vasculitis |
| title_sort | plasma proteome reveals distinct signaling pathways associated with pr3 anca positive and mpo anca positive vasculitis |
| topic | ANCA vasculitis proteinase 3 myeloperoxidase proteome |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1600754/full |
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