{"doi":"10.1002/art.38046","title":"Incomplete B Cell Tolerance to Cartilage Oligomeric Matrix Protein in Mice","abstract":"<jats:sec><jats:title>Objective</jats:title><jats:p>Cartilage oligomeric matrix protein (COMP) is a major noncollagenous component of cartilage and is used as a biomarker in rheumatoid arthritis and experimental arthritis. Injection of COMP leads to severe inflammatory joint disease, and antibodies play a critical role in mediating arthritis. The arthritogenicity of COMP might be due to the lack of self tolerance. This study was undertaken to determine the status of COMP‐specific B cell tolerance using COMP‐deficient mice.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Arthritis development and antibody responses were compared between COMP‐sufficient and COMP‐deficient littermates after immunization with rat COMP. Serum anti‐COMP antibody levels were measured using a panel of recombinant mouse COMP proteins, and antibody‐secreting cells were enumerated by enzyme‐linked immunospot assays. A novel sandwich enzyme‐linked immunosorbent assay was developed to assess COMP molecules in serum.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>COMP‐sufficient mice, but not COMP‐deficient mice, developed severe arthritis following immunization with rat COMP. However, anti‐COMP antibody titers to native COMP and recombinant protein domains covering the entire mouse COMP sequence, except the less immunodominant type 3 repeat domains, were decreased in COMP‐sufficient mice compared to COMP‐deficient mice. In addition, COMP‐sufficient mice had fewer B cells secreting COMP‐reactive antibodies. Detectable levels of full‐length COMP in arthritic COMP‐sufficient B10.Q NCF‐1<jats:sup>*/*</jats:sup> and healthy mice suggested systemic availability of COMP to the immune system.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The lack of arthritis, together with high levels of COMP‐specific antibodies, in COMP‐deficient mice indicates that susceptibility to arthritis is COMP specific and that endogenous expression of COMP in wild‐type mice tolerizes B cells in vivo.</jats:p></jats:sec>","journal":"Arthritis &amp; Rheumatism","year":2013,"id":629438,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1042578,"name":"Kutty Selva Nandakumar","orcid":"0000-0001-7790-8197","position":1,"is_corresponding":false},{"id":536576,"name":"Li Xiong","orcid":"0000-0003-3851-937X","position":2,"is_corresponding":false},{"id":1630138,"name":"Rui Jie","orcid":null,"position":3,"is_corresponding":false},{"id":939460,"name":"Jiahui Dong","orcid":"0000-0001-9211-3149","position":4,"is_corresponding":false},{"id":378095,"name":"Rikard Holmdahl","orcid":"0000-0002-4969-2576","position":5,"is_corresponding":false},{"id":5728,"name":"Hui Geng","orcid":"0000-0002-7290-4055","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Incomplete B Cell Tolerance to Cartilage Oligomeric Matrix Protein in Mice","abstract":"<jats:sec><jats:title>Objective</jats:title><jats:p>Cartilage oligomeric matrix protein (COMP) is a major noncollagenous component of cartilage and is used as a biomarker in rheumatoid arthritis and experimental arthritis. Injection of COMP leads to severe inflammatory joint disease, and antibodies play a critical role in mediating arthritis. The arthritogenicity of COMP might be due to the lack of self tolerance. This study was undertaken to determine the status of COMP‐specific B cell tolerance using COMP‐deficient mice.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Arthritis development and antibody responses were compared between COMP‐sufficient and COMP‐deficient littermates after immunization with rat COMP. Serum anti‐COMP antibody levels were measured using a panel of recombinant mouse COMP proteins, and antibody‐secreting cells were enumerated by enzyme‐linked immunospot assays. A novel sandwich enzyme‐linked immunosorbent assay was developed to assess COMP molecules in serum.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>COMP‐sufficient mice, but not COMP‐deficient mice, developed severe arthritis following immunization with rat COMP. However, anti‐COMP antibody titers to native COMP and recombinant protein domains covering the entire mouse COMP sequence, except the less immunodominant type 3 repeat domains, were decreased in COMP‐sufficient mice compared to COMP‐deficient mice. In addition, COMP‐sufficient mice had fewer B cells secreting COMP‐reactive antibodies. Detectable levels of full‐length COMP in arthritic COMP‐sufficient B10.Q NCF‐1<jats:sup>*/*</jats:sup> and healthy mice suggested systemic availability of COMP to the immune system.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The lack of arthritis, together with high levels of COMP‐specific antibodies, in COMP‐deficient mice indicates that susceptibility to arthritis is COMP specific and that endogenous expression of COMP in wild‐type mice tolerizes B cells in vivo.</jats:p></jats:sec>","is_dataset_classified":null,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"23754310","pmcid":null,"openalex_id":"https://openalex.org/W1513586510","authors":[],"funders":[{"funder_name":"Natural Science Foundation of China","grant_id":"30972693","title":null},{"funder_name":"Fundamental Research Funds for the Central Universities (Central China Normal University grant)","grant_id":"CCNU11A02011","title":null},{"funder_name":"European Union (project Masterswitch)","grant_id":"EALTH-F2-2008-223404","title":null},{"funder_name":"European Commission","grant_id":"223404","title":"Mechanisms to Attack Steering Effectors of Rheumatoid Syndromes with Innovated Therapy Choices"},{"funder_name":"Swedish Research Council","grant_id":"unidentified","title":"unidentified"},{"funder_name":"Ministry of Education of China (Scientific Research Foundation for the Returned Overseas Chinese Scholars funding)","grant_id":"","title":null},{"funder_name":"Swedish Foundation for Strategic Research","grant_id":"","title":null},{"funder_name":"Innovative Medicines Initiative (BeTheCure project)","grant_id":"","title":null},{"funder_name":"Swedish Research Council","grant_id":"","title":null}],"total_grants":9,"fwci":0.6899,"citation_percentile":0.68877929,"influential_citations":0,"citation_trend":[{"year":2014,"count":2},{"year":2015,"count":1},{"year":2020,"count":1}],"oa_status":"green","license":"other-oa","oa_locations":[{"url":"https://zenodo.org/record/3409157","host_type":"repository"},{"url":"https://zenodo.org/record/3409157","host_type":"repository"},{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fart.38046","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.38046","host_type":"publisher"},{"url":"https://doi.org/10.1002/art.38046","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/23754310","host_type":"repository"},{"url":"http://dx.doi.org/10.1002/art.38046","host_type":""},{"url":"https://dx.doi.org/10.1002/art.38046","host_type":""}],"fields_of_study":["Osteoarthritis Treatment and Mechanisms","Rheumatoid Arthritis Research and Therapies","Asthma and respiratory diseases","0301 basic medicine","0303 health sciences","03 medical and health sciences","0302 clinical medicine"],"mesh_terms":["Animals","Arthritis, Experimental","Autoantibodies","B-Lymphocytes","Cartilage","Immune Tolerance","Mice, Knockout","Genetic Predisposition to Disease","Mice","Cartilage Oligomeric Matrix Protein"],"keywords":["Cartilage oligomeric matrix protein","Antibody","Arthritis","Immunology","Medicine","Rheumatoid arthritis","Pathology","Osteoarthritis","Mice, Knockout","B-Lymphocytes","Arthritis, Experimental","Mice","Cartilage","Immune Tolerance","Animals","Genetic Predisposition to Disease","Autoantibodies"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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