Fc Proteoforms of ACPA IgG Discriminate Autoimmune Responses in Plasma and Synovial Fluid of Rheumatoid Arthritis Patients and Associate with Disease Activity
Abstract Autoantibodies and their post‐translational modifications (PTMs) are insightful markers of autoimmune diseases providing diagnostic and prognostic clues, thereby informing clinical decisions. However, current autoantibody analyses focus mostly on IgG1 glycosylation representing only a subpo...
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| Format: | Article |
| Language: | English |
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Wiley
2025-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202408769 |
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| author | Constantin Blöchl Eva Maria Stork Hans Ulrich Scherer Rene E. M. Toes Manfred Wuhrer Elena Domínguez‐Vega |
| author_facet | Constantin Blöchl Eva Maria Stork Hans Ulrich Scherer Rene E. M. Toes Manfred Wuhrer Elena Domínguez‐Vega |
| author_sort | Constantin Blöchl |
| collection | DOAJ |
| description | Abstract Autoantibodies and their post‐translational modifications (PTMs) are insightful markers of autoimmune diseases providing diagnostic and prognostic clues, thereby informing clinical decisions. However, current autoantibody analyses focus mostly on IgG1 glycosylation representing only a subpopulation of the actual IgG proteome. Here, by taking rheumatoid arthritis (RA) as prototypic autoimmune disease, we sought to circumvent these shortcomings and illuminate the importance of (auto)antibody proteoforms employing a novel comprehensive mass spectrometry (MS)‐based analytical workflow. Profiling of anti‐citrullinated protein antibodies (ACPA) IgG and total IgG in paired samples of plasma and synovial fluid revealed a clear distinction of autoantibodies from total IgG and between biofluids. This discrimination relied on comprehensive subclass‐specific PTM profiles including previously neglected features such as IgG3 CH3 domain glycosylation, allotype ratios, and non‐glycosylated IgG. Intriguingly, specific proteoforms were found to correlate with markers of inflammation and disease accentuating the need of such approaches in clinical investigations and calling for further mechanistic studies to comprehend the role of autoantibody proteoforms in defining autoimmune responses. |
| format | Article |
| id | doaj-art-c65eda0a83ce4c788617a2bb06c29732 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-c65eda0a83ce4c788617a2bb06c297322025-08-20T03:18:05ZengWileyAdvanced Science2198-38442025-04-011215n/an/a10.1002/advs.202408769Fc Proteoforms of ACPA IgG Discriminate Autoimmune Responses in Plasma and Synovial Fluid of Rheumatoid Arthritis Patients and Associate with Disease ActivityConstantin Blöchl0Eva Maria Stork1Hans Ulrich Scherer2Rene E. M. Toes3Manfred Wuhrer4Elena Domínguez‐Vega5Center for Proteomics and Metabolomics Leiden University Medical Center Albinusdreef 2 Leiden 2333 ZA The NetherlandsDepartment of Rheumatology Leiden University Medical Center Albinusdreef 2 Leiden 2333 ZA The NetherlandsDepartment of Rheumatology Leiden University Medical Center Albinusdreef 2 Leiden 2333 ZA The NetherlandsDepartment of Rheumatology Leiden University Medical Center Albinusdreef 2 Leiden 2333 ZA The NetherlandsCenter for Proteomics and Metabolomics Leiden University Medical Center Albinusdreef 2 Leiden 2333 ZA The NetherlandsCenter for Proteomics and Metabolomics Leiden University Medical Center Albinusdreef 2 Leiden 2333 ZA The NetherlandsAbstract Autoantibodies and their post‐translational modifications (PTMs) are insightful markers of autoimmune diseases providing diagnostic and prognostic clues, thereby informing clinical decisions. However, current autoantibody analyses focus mostly on IgG1 glycosylation representing only a subpopulation of the actual IgG proteome. Here, by taking rheumatoid arthritis (RA) as prototypic autoimmune disease, we sought to circumvent these shortcomings and illuminate the importance of (auto)antibody proteoforms employing a novel comprehensive mass spectrometry (MS)‐based analytical workflow. Profiling of anti‐citrullinated protein antibodies (ACPA) IgG and total IgG in paired samples of plasma and synovial fluid revealed a clear distinction of autoantibodies from total IgG and between biofluids. This discrimination relied on comprehensive subclass‐specific PTM profiles including previously neglected features such as IgG3 CH3 domain glycosylation, allotype ratios, and non‐glycosylated IgG. Intriguingly, specific proteoforms were found to correlate with markers of inflammation and disease accentuating the need of such approaches in clinical investigations and calling for further mechanistic studies to comprehend the role of autoantibody proteoforms in defining autoimmune responses.https://doi.org/10.1002/advs.202408769autoantibodiesautoimmunityHPLC‐MSIgG allotypes and subclassespolyclonal IgG |
| spellingShingle | Constantin Blöchl Eva Maria Stork Hans Ulrich Scherer Rene E. M. Toes Manfred Wuhrer Elena Domínguez‐Vega Fc Proteoforms of ACPA IgG Discriminate Autoimmune Responses in Plasma and Synovial Fluid of Rheumatoid Arthritis Patients and Associate with Disease Activity Advanced Science autoantibodies autoimmunity HPLC‐MS IgG allotypes and subclasses polyclonal IgG |
| title | Fc Proteoforms of ACPA IgG Discriminate Autoimmune Responses in Plasma and Synovial Fluid of Rheumatoid Arthritis Patients and Associate with Disease Activity |
| title_full | Fc Proteoforms of ACPA IgG Discriminate Autoimmune Responses in Plasma and Synovial Fluid of Rheumatoid Arthritis Patients and Associate with Disease Activity |
| title_fullStr | Fc Proteoforms of ACPA IgG Discriminate Autoimmune Responses in Plasma and Synovial Fluid of Rheumatoid Arthritis Patients and Associate with Disease Activity |
| title_full_unstemmed | Fc Proteoforms of ACPA IgG Discriminate Autoimmune Responses in Plasma and Synovial Fluid of Rheumatoid Arthritis Patients and Associate with Disease Activity |
| title_short | Fc Proteoforms of ACPA IgG Discriminate Autoimmune Responses in Plasma and Synovial Fluid of Rheumatoid Arthritis Patients and Associate with Disease Activity |
| title_sort | fc proteoforms of acpa igg discriminate autoimmune responses in plasma and synovial fluid of rheumatoid arthritis patients and associate with disease activity |
| topic | autoantibodies autoimmunity HPLC‐MS IgG allotypes and subclasses polyclonal IgG |
| url | https://doi.org/10.1002/advs.202408769 |
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