Identification of autoantibodies targeting citrullinated CLEC12A in rheumatoid arthritis patients
Objective: Rheumatoid arthritis is an autoimmune disease characterized by anti-citrullinated protein antibodies (ACPA). The pathogenic and protective roles of ACPA of distinct specificities are emerging and remains poorly understood. Thus, it is crucial to define the range of ACPA specificities and...
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Elsevier
2025-06-01
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| Series: | Journal of Translational Autoimmunity |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S258990902500022X |
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| author | Lillian Barra Sheri Saunders Mathias Mangion Guillaume Paré Halim Maaroufi Alain Garnier Ewa Cairns Maria J. Fernandes |
| author_facet | Lillian Barra Sheri Saunders Mathias Mangion Guillaume Paré Halim Maaroufi Alain Garnier Ewa Cairns Maria J. Fernandes |
| author_sort | Lillian Barra |
| collection | DOAJ |
| description | Objective: Rheumatoid arthritis is an autoimmune disease characterized by anti-citrullinated protein antibodies (ACPA). The pathogenic and protective roles of ACPA of distinct specificities are emerging and remains poorly understood. Thus, it is crucial to define the range of ACPA specificities and determine their contribution to disease and their potential clinical relevance. Since extracellular citrullination occurs in RA, we investigated whether autoantibodies in RA patients bind a citrullinated form of the cell-surface receptor CLEC12A that is expressed on neutrophils, the most abundant leukocyte in inflamed joints. Methods: We generated a FLAG-tagged, recombinant form of the extracellular portion of human CLEC12A. After purification, the tag was removed prior to citrullination by PAD2 that was confirmed by mass spectrometry. We developed an ELISA for citrullinated CLEC12A to screen for seropositivity in sera of 68 RA patients and 36 healthy controls. Potential associations between these autoantibodies and clinical variables were determined. Results: In our cohort, 40 % of RA patients were positive for anti-citrullinated CLEC12A autoantibodies. Those seropositive patients were younger than RA patients that tested negative for these autoantibodies (p = 0.0058). Most patients had antibodies to multiple citrullinated and homocitrullinated antigens; 17 % of patients negative for other ACPA were positive for anti-citrullinated CLEC12A autoantibodies. Conclusion: This is the first report of seropositivity towards citrullinated CLEC12A in RA patients. A validation cohort will confirm our findings and identify additional correlations between these autoantibodies and clinical parameters. Citrullination may be a mechanism through which CLEC12A's inhibitory function is altered to exacerbate inflammation in RA. Identifying citrullinated neoantigens advances our understanding of the diverse molecular mechanisms that contribute to RA pathogenesis. |
| format | Article |
| id | doaj-art-855a39ecd8bb4463a98d85350310d8ec |
| institution | OA Journals |
| issn | 2589-9090 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Translational Autoimmunity |
| spelling | doaj-art-855a39ecd8bb4463a98d85350310d8ec2025-08-20T02:30:55ZengElsevierJournal of Translational Autoimmunity2589-90902025-06-011010028710.1016/j.jtauto.2025.100287Identification of autoantibodies targeting citrullinated CLEC12A in rheumatoid arthritis patientsLillian Barra0Sheri Saunders1Mathias Mangion2Guillaume Paré3Halim Maaroufi4Alain Garnier5Ewa Cairns6Maria J. Fernandes7Department of Microbiology and Immunology, Western University, London, Ontario, Canada; Department of Medicine, Division of Rheumatology, Western University, London, Ontario, CanadaDepartment of Microbiology and Immunology, Western University, London, Ontario, Canada; Department of Medicine, Division of Rheumatology, Western University, London, Ontario, CanadaDepartment of Chemical Engineering, Faculty of Science and Engineering, Laval University, Québec, QC, CanadaInfectious and Immune Diseases Division, CHU de Québec-Laval University Research Center, Québec, QC, Canada; Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Laval University, Québec, QC, CanadaInstitute of Integrative Biology and Systems, Laval University, Québec, QC, CanadaDepartment of Chemical Engineering, Faculty of Science and Engineering, Laval University, Québec, QC, CanadaDepartment of Microbiology and Immunology, Western University, London, Ontario, Canada; Department of Medicine, Division of Rheumatology, Western University, London, Ontario, CanadaInfectious and Immune Diseases Division, CHU de Québec-Laval University Research Center, Québec, QC, Canada; Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Laval University, Québec, QC, Canada; Corresponding author. Infectious and Immune Diseases Division, CHU de Québec-Laval University Research Center, Room T1-49, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada.Objective: Rheumatoid arthritis is an autoimmune disease characterized by anti-citrullinated protein antibodies (ACPA). The pathogenic and protective roles of ACPA of distinct specificities are emerging and remains poorly understood. Thus, it is crucial to define the range of ACPA specificities and determine their contribution to disease and their potential clinical relevance. Since extracellular citrullination occurs in RA, we investigated whether autoantibodies in RA patients bind a citrullinated form of the cell-surface receptor CLEC12A that is expressed on neutrophils, the most abundant leukocyte in inflamed joints. Methods: We generated a FLAG-tagged, recombinant form of the extracellular portion of human CLEC12A. After purification, the tag was removed prior to citrullination by PAD2 that was confirmed by mass spectrometry. We developed an ELISA for citrullinated CLEC12A to screen for seropositivity in sera of 68 RA patients and 36 healthy controls. Potential associations between these autoantibodies and clinical variables were determined. Results: In our cohort, 40 % of RA patients were positive for anti-citrullinated CLEC12A autoantibodies. Those seropositive patients were younger than RA patients that tested negative for these autoantibodies (p = 0.0058). Most patients had antibodies to multiple citrullinated and homocitrullinated antigens; 17 % of patients negative for other ACPA were positive for anti-citrullinated CLEC12A autoantibodies. Conclusion: This is the first report of seropositivity towards citrullinated CLEC12A in RA patients. A validation cohort will confirm our findings and identify additional correlations between these autoantibodies and clinical parameters. Citrullination may be a mechanism through which CLEC12A's inhibitory function is altered to exacerbate inflammation in RA. Identifying citrullinated neoantigens advances our understanding of the diverse molecular mechanisms that contribute to RA pathogenesis.http://www.sciencedirect.com/science/article/pii/S258990902500022XAutoantibodyCitrullinationRheumatoid arthritisInhibitory receptorCLEC12A |
| spellingShingle | Lillian Barra Sheri Saunders Mathias Mangion Guillaume Paré Halim Maaroufi Alain Garnier Ewa Cairns Maria J. Fernandes Identification of autoantibodies targeting citrullinated CLEC12A in rheumatoid arthritis patients Journal of Translational Autoimmunity Autoantibody Citrullination Rheumatoid arthritis Inhibitory receptor CLEC12A |
| title | Identification of autoantibodies targeting citrullinated CLEC12A in rheumatoid arthritis patients |
| title_full | Identification of autoantibodies targeting citrullinated CLEC12A in rheumatoid arthritis patients |
| title_fullStr | Identification of autoantibodies targeting citrullinated CLEC12A in rheumatoid arthritis patients |
| title_full_unstemmed | Identification of autoantibodies targeting citrullinated CLEC12A in rheumatoid arthritis patients |
| title_short | Identification of autoantibodies targeting citrullinated CLEC12A in rheumatoid arthritis patients |
| title_sort | identification of autoantibodies targeting citrullinated clec12a in rheumatoid arthritis patients |
| topic | Autoantibody Citrullination Rheumatoid arthritis Inhibitory receptor CLEC12A |
| url | http://www.sciencedirect.com/science/article/pii/S258990902500022X |
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