{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T06:59:05Z","timestamp":1764053945333,"version":"build-2065373602"},"reference-count":127,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,26]],"date-time":"2025-01-26T00:00:00Z","timestamp":1737849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibodies"],"abstract":"<jats:p>Background: Autoantibodies such as rheumatoid factor (RF) and anticitrullinated protein autoantibodies (ACPAs) are useful tools for rheumatoid arthritis (RA). The presence of ACPAs against citrullinated proteins (CPs), especially citrullinated fibrinogen (cFBG), seems to be a useful serological marker for diagnosing RA. RA patients\u2019 sera were found to be enriched in exosomes that can transmit many proteins. Exosomes have been found to express citrullinated protein such as cFBG. Objective: We conducted this study in two stages. In the first phase, we aimed to evaluate the association between autoantibodies and risk factors. In the next step, ACPA-positive serum samples from the first phase were subjected to exosomal studies to explore the presence of cFBG, which is a frequent target for ACPAs. Methods: We investigated the autoantibodies in one hundred and sixteen Saudi RA patients and correlated with host-related risk factors. Exosomes were extracted from patients\u2019 sera and examined for the presence of cFBG using monoclonal antibodies. Results: The study reported a high female-to-male ratio of 8:1, and seropositive RA (SPRA) was more frequent among included RA patients. The frequency and the levels of ACPAs were similar in both genders. Autoantibodies incidences have a direct correlations with patient age, while the average titers decreased as the age increased. Further, the highest incidence and levels of autoantibodies were reported in patients with RA duration between 5 and 10 years. Smoking and family history have no impact on autoantibody, except for ACPAs titers among smokers\u2019 RA. Our analysis of serum exosomes revealed that about 50% of SPRA patients expressed cFBG. Conclusions: The female-to-male ratio is 8:1, which is higher than the global ratio. We can conclude that patients\u2019 age and disease duration contribute to the autoantibodies, particularly RF and anti-MCV, whereas smoking and family history had no effects on autoantibodies. We detected cFBG in all exosomes from SPRA patients; thus, we suggest that the precise mechanism of exosomes in RA pathogenesis can be investigated to develop effective treatment strategies.<\/jats:p>","DOI":"10.3390\/antib14010010","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T03:54:27Z","timestamp":1737950067000},"page":"10","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Exploring Anticitrullinated Antibodies (ACPAs) and Serum-Derived Exosomes Cargoes"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2606-4427","authenticated-orcid":false,"given":"Mohammed A.","family":"Alghamdi","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia"},{"name":"Laboratory Department, University Medical Services Center, King Abdulaziz University, P.O. Box 80200, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sami M.","family":"Bahlas","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, King Abdulaziz University, P.O. Box 80215, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4344-9436","authenticated-orcid":false,"given":"Sultan Abdulmughni","family":"Alamry","sequence":"additional","affiliation":[{"name":"Immunology Diagnostic Laboratory Department, King Abdulaziz University Hospital, P.O. Box 80215, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8396-4547","authenticated-orcid":false,"given":"Ehab H.","family":"Mattar","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8246-0075","authenticated-orcid":false,"given":"Elrashdy M.","family":"Redwan","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia"},{"name":"Centre of Excellence in Bionanoscience Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Therapeutic and Protective Proteins Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg EL-Arab, Alexandria 21934, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s00296-013-2865-2","article-title":"Comparison of the 1987 American College of Rheumatology and the 2010 American College of Rheumatology\/European League against Rheumatism criteria for classification of rheumatoid arthritis in the Nurses\u2019 Health Study cohorts","volume":"34","author":"Kasturi","year":"2014","journal-title":"Rheumatol. Int."},{"key":"ref_2","first-page":"591","article-title":"Global epidemiology of rheumatoid arthritis","volume":"18","author":"Finckh","year":"2022","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s00296-020-04731-0","article-title":"The global prevalence of rheumatoid arthritis: A meta-analysis based on a systematic review","volume":"41","author":"Almutairi","year":"2021","journal-title":"Rheumatol. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1002\/art.27425","article-title":"Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955\u20132007","volume":"62","author":"Myasoedova","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_5","first-page":"2096","article-title":"Prevalence of RA and SLE in Saudi Arabia","volume":"3","author":"Albishri","year":"2015","journal-title":"Sch. J. App. Med. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"396","DOI":"10.5144\/0256-4947.1998.396","article-title":"The prevalence of rheumatoid arthritis in the Qassim region of Saudi Arabia","volume":"18","author":"Al","year":"1998","journal-title":"Ann. Saudi Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"545","DOI":"10.23958\/ijirms\/vol02-i02\/07","article-title":"Rheumatoid Arthritis in Hail Region, Saudi Arabia","volume":"2","author":"Alamri","year":"2017","journal-title":"Int. J. Innov. Res. Med. Sci."},{"key":"ref_8","first-page":"1442","article-title":"Rheumatoid arthritis in Saudi Arabia","volume":"35","author":"Almoallim","year":"2014","journal-title":"Saudi Med. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.autrev.2015.01.013","article-title":"Citrullination and autoimmunity","volume":"14","author":"Valesini","year":"2015","journal-title":"Autoimmun. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"797","DOI":"10.7326\/0003-4819-146-11-200706050-00008","article-title":"Meta-analysis: Diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis","volume":"146","author":"Nishimura","year":"2007","journal-title":"Ann. Intern. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19","DOI":"10.21608\/ejrci.2014.9983","article-title":"The Diagnostic Utility of Anti-Mutated Citrullinated Vimentin Antibodies, Anti-Cyclic Citrullinated Peptide Antibodies and Rheumatoid Factor in Rheumatoid Arthritis","volume":"2","author":"Mobasher","year":"2014","journal-title":"Egypt. J. Rheumatol. Clin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.cca.2012.02.002","article-title":"Analytical and clinical comparison of anti-CCP assays with rheumatoid factor for the diagnosis of rheumatoid arthritis","volume":"413","author":"Block","year":"2012","journal-title":"Clin. Chim. Acta"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2478\/rir-2021-0003","article-title":"Rethink about the role of rheumatoid factor and anti-citrullinated protein antibody in rheumatoid arthritis","volume":"2","author":"Sung","year":"2021","journal-title":"Rheumatol. Immunol. Res."},{"key":"ref_14","first-page":"368","article-title":"One year in review 2017: Pathogenesis of rheumatoid arthritis","volume":"35","author":"Angelotti","year":"2017","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_15","first-page":"174","article-title":"Microbial Infection and Rheumatoid Arthritis","volume":"4","author":"Li","year":"2013","journal-title":"J. Clin. Cell Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3754","DOI":"10.5504\/BBEQ.2013.0027","article-title":"Microbiology of periodontal diseases. A review","volume":"27","author":"Popova","year":"2013","journal-title":"Biotechnol. Biotechnol. Equip."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1034\/j.1600-051X.2002.291107.x","article-title":"Porphyromonas gingivalis, Bacteroides forsythus and other putative periodontal pathogens in subjects with and without periodontal destruction","volume":"29","author":"Loos","year":"2002","journal-title":"J. Clin. Periodontol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.jbspin.2020.04.024","article-title":"Rheumatoid arthritis risk in periodontitis patients: A systematic review and meta-analysis","volume":"87","author":"Qiao","year":"2020","journal-title":"Jt. Bone Spine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4635","DOI":"10.1007\/s00018-019-03237-8","article-title":"An interplay of structure and intrinsic disorder in the functionality of peptidylarginine deiminases, a family of key autoimmunity-related enzymes","volume":"76","author":"Alghamdi","year":"2019","journal-title":"Cell Mol. Life Sci."},{"key":"ref_20","first-page":"141","article-title":"Guidelines for the diagnosis of rheumatoid arthritis","volume":"53","author":"Mota","year":"2013","journal-title":"Rev. Bras. Reum."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.berh.2017.08.003","article-title":"Genetic and environmental risk factors for rheumatoid arthritis","volume":"31","author":"Deane","year":"2017","journal-title":"Best. Pract. Res. Clin. Rheumatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"663","DOI":"10.3899\/jrheum.211020","article-title":"Presence of Autoantibodies in Males and Females With Rheumatoid Arthritis: A Systematic Review and Metaanalysis","volume":"49","author":"Hadwen","year":"2022","journal-title":"J. Rheumatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1136\/annrheumdis-2017-211620","article-title":"Oral contraceptives, breastfeeding and the risk of developing rheumatoid arthritis: Results from the Swedish EIRA study","volume":"76","author":"Orellana","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1136\/ard.2009.111179","article-title":"Hormonal replacement therapy may reduce the risk for RA in women with early arthritis who carry HLA-DRB1 *01 and\/or *04 alleles by protecting against the production of anti-CCP: Results from the ESPOIR cohort","volume":"69","author":"Salliot","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"ref_25","first-page":"330","article-title":"Effects of Aging on Rheumatoid Factor and Anticyclic Citrullinated Peptide Antibody Positivity in Patients With Rheumatoid Arthritis","volume":"50","author":"Takanashi","year":"2023","journal-title":"J. Rheumatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"123","DOI":"10.2147\/OARRR.S306378","article-title":"Influence of Age and Sex on Disease Course and Treatment in Rheumatoid Arthritis","volume":"13","author":"Nilsson","year":"2021","journal-title":"Open Access Rheumatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1093\/rheumatology\/ket449","article-title":"Are there differences between young- and older-onset early inflammatory arthritis and do these impact outcomes? An analysis from the CATCH cohort","volume":"53","author":"Arnold","year":"2014","journal-title":"Rheumatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"R40","DOI":"10.1186\/ar1896","article-title":"Serial determination of cyclic citrullinated peptide autoantibodies predicted five-year radiological outcomes in a prospective cohort of patients with early rheumatoid arthritis","volume":"8","author":"Meyer","year":"2006","journal-title":"Arthritis Res. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"R8","DOI":"10.1186\/ar2907","article-title":"Levels of anti-citrullinated protein antibodies and IgM rheumatoid factor are not associated with outcome in early arthritis patients: A cohort study","volume":"12","author":"Ursum","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"R78","DOI":"10.1186\/ar4255","article-title":"New autoantibodies in early rheumatoid arthritis","volume":"15","author":"Charpin","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1136\/ard.62.9.835","article-title":"Quantification of the influence of cigarette smoking on rheumatoid arthritis: Results from a population based case-control study, using incident cases","volume":"62","author":"Stolt","year":"2003","journal-title":"Ann. Rheum. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1136\/ard.2008.096487","article-title":"Impact of smoking as a risk factor for developing rheumatoid arthritis: A meta-analysis of observational studies","volume":"69","author":"Sugiyama","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1111\/j.1699-0463.1998.tb00247.x","article-title":"Does smoking stimulate rheumatoid factor production in non-rheumatic individuals?","volume":"106","author":"Jonsson","year":"1998","journal-title":"APMIS"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1093\/rheumatology\/kei240","article-title":"The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis","volume":"45","author":"Manfredsdottir","year":"2006","journal-title":"Rheumatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1111\/1756-185X.12129","article-title":"Anti-citrullinated protein antibodies and their clinical utility in rheumatoid arthritis","volume":"16","author":"Farid","year":"2013","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1097\/BOR.0b013e32832a2e16","article-title":"Environmental influences on risk for rheumatoid arthritis","volume":"21","author":"Liao","year":"2009","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"538","DOI":"10.4049\/jimmunol.171.2.538","article-title":"Cutting edge: The conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule","volume":"171","author":"Hill","year":"2003","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jsps.2010.02.002","article-title":"Effect of tobacco smoking on tissue protein citrullination and disease progression in patients with rheumatoid arthritis","volume":"18","author":"Alsalahy","year":"2010","journal-title":"Saudi Pharm. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1002\/1529-0131(200001)43:1<30::AID-ANR5>3.0.CO;2-B","article-title":"Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins","volume":"43","author":"MacGregor","year":"2000","journal-title":"Arthritis Rheum."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1093\/rheumatology\/kew500","article-title":"Familial aggregation of rheumatoid arthritis and co-aggregation of autoimmune diseases in affected families: A nationwide population-based study","volume":"56","author":"Kuo","year":"2017","journal-title":"Rheumatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1136\/annrheumdis-2014-206133","article-title":"Familial aggregation of arthritis-related diseases in seropositive and seronegative rheumatoid arthritis: A register-based case-control study in Sweden","volume":"75","author":"Frisell","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1002\/art.24328","article-title":"Familial associations of rheumatoid arthritis with autoimmune diseases and related conditions","volume":"60","author":"Hemminki","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00281-022-00912-0","article-title":"Genetics of rheumatoid arthritis","volume":"44","author":"Padyukov","year":"2022","journal-title":"Semin. Immunopathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3236","DOI":"10.1074\/jbc.RA117.001013","article-title":"The interplay between citrullination and HLA-DRB1 polymorphism in shaping peptide binding hierarchies in rheumatoid arthritis","volume":"293","author":"Ting","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3433","DOI":"10.1002\/art.21385","article-title":"Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins","volume":"52","author":"Huizinga","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1136\/ard.29.4.357","article-title":"Heberden Oration, 1969. Rheumatoid arthritis--nature or nurture?","volume":"29","author":"Lawrence","year":"1970","journal-title":"Ann. Rheum. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1136\/ard.21.4.339","article-title":"Rheumatoid arthritis (R.A.) factor in near relatives of sero-positive and sero-negative patients with rheumatoid arthritis","volume":"21","author":"Boerma","year":"1962","journal-title":"Ann. Rheum. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"R156","DOI":"10.1186\/ar2833","article-title":"Increased levels of circulating microparticles in primary Sjogren\u2019s syndrome, systemic lupus erythematosus and rheumatoid arthritis and relation with disease activity","volume":"11","author":"Sellam","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"110560","DOI":"10.1016\/j.intimp.2023.110560","article-title":"Proteomics profiling of CD4 + T-cell-derived exosomes from patients with rheumatoid arthritis","volume":"122","author":"Huang","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1590\/1414-431X20132964","article-title":"Extracellular vesicles: Structure, function, and potential clinical uses in renal diseases","volume":"46","author":"Borges","year":"2013","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Doyle, L.M., and Wang, M.Z. (2019). Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells, 8.","DOI":"10.3390\/cells8070727"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Koniusz, S., Andrzejewska, A., Muraca, M., Srivastava, A.K., Janowski, M., and Lukomska, B. (2016). Extracellular Vesicles in Physiology, Pathology, and Therapy of the Immune and Central Nervous System, with Focus on Extracellular Vesicles Derived from Mesenchymal Stem Cells as Therapeutic Tools. Front. Cell Neurosci., 10.","DOI":"10.3389\/fncel.2016.00109"},{"key":"ref_53","first-page":"537","article-title":"Functions and application of exosomes","volume":"71","author":"Qin","year":"2014","journal-title":"Acta Pol. Pharm."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Lim, J., Choi, M., Lee, H., Kim, Y.H., Han, J.Y., Lee, E.S., and Cho, Y. (2019). Direct isolation and characterization of circulating exosomes from biological samples using magnetic nanowires. J. Nanobiotechnol., 17.","DOI":"10.1186\/s12951-018-0433-3"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.bcmd.2005.04.004","article-title":"Direct stimulation of naive T cells by antigen-presenting cell vesicles","volume":"35","author":"Sprent","year":"2005","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Cai, R., Wang, L., Zhang, W., Liu, B., Wu, Y., Pang, J., and Ma, C. (2023). The role of extracellular vesicles in periodontitis: Pathogenesis, diagnosis, and therapy. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1151322"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature01322","article-title":"Inflammation and cancer","volume":"420","author":"Coussens","year":"2002","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s12026-021-09202-7","article-title":"The p53 status in rheumatoid arthritis with focus on fibroblast-like synoviocytes","volume":"69","author":"Taghadosi","year":"2021","journal-title":"Immunol. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/s41467-018-03224-w","article-title":"Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246","volume":"9","author":"Cooks","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Li, Q., Wang, H., Peng, H., Huyan, T., and Cacalano, N.A. (2019). Exosomes: Versatile Nano Mediators of Immune Regulation. Cancers, 11.","DOI":"10.3390\/cancers11101557"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3252","DOI":"10.1074\/jbc.H118.001829","article-title":"How MHC molecules grab citrullinated peptides to foster rheumatoid arthritis","volume":"293","author":"Margulies","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1002\/eji.200737694","article-title":"B cell activation regulates exosomal HLA production","volume":"38","author":"Arita","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Tsuno, H., Arito, M., Suematsu, N., Sato, T., Hashimoto, A., Matsui, T., Omoteyama, K., Sato, M., Okamoto, K., and Tohma, S. (2018). A proteomic analysis of serum-derived exosomes in rheumatoid arthritis. BMC Rheumatol., 2.","DOI":"10.1186\/s41927-018-0041-8"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1136\/ard.2005.044743","article-title":"Citrullinated fibrinogen detected as a soluble citrullinated autoantigen in rheumatoid arthritis synovial fluids","volume":"65","author":"Takizawa","year":"2006","journal-title":"Ann. Rheum. Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"R94","DOI":"10.1186\/ar2478","article-title":"Circulating immune complexes contain citrullinated fibrinogen in rheumatoid arthritis","volume":"10","author":"Zhao","year":"2008","journal-title":"Arthritis Res. Ther."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"R114","DOI":"10.1186\/ar3840","article-title":"Elevated levels of fibrinogen-derived endogenous citrullinated peptides in synovial fluid of rheumatoid arthritis patients","volume":"14","author":"Raijmakers","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3809","DOI":"10.1002\/art.22276","article-title":"Association of citrullinated proteins with synovial exosomes","volume":"54","author":"Skriner","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1007\/BF02207929","article-title":"The expression of rheumatoid arthritis in Saudi Arabia","volume":"14","author":"Alballa","year":"1995","journal-title":"Clin. Rheumatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S0531-5565(98)00072-2","article-title":"Rheumatoid arthritis in the elderly","volume":"34","author":"Mavragani","year":"1999","journal-title":"Exp. Gerontol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.jbspin.2015.09.010","article-title":"Effect of age at rheumatoid arthritis onset on clinical, radiographic, and functional outcomes: The ESPOIR cohort","volume":"83","author":"Krams","year":"2016","journal-title":"Jt. Bone Spine"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2147\/OARRR.S260426","article-title":"Rheumatoid Arthritis Saudi Database (RASD): Disease Characteristics and Remission Rates in a Tertiary Care Center","volume":"12","author":"Almoallim","year":"2020","journal-title":"Open Access Rheumatol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0049-0172(95)80032-8","article-title":"Clinical expression of rheumatoid arthritis in Chilean patients","volume":"25","author":"Massardo","year":"1995","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_73","first-page":"1166","article-title":"Prevalence of rheumatoid arthritis in Tucuman, Argentina","volume":"29","author":"Spindler","year":"2002","journal-title":"J. Rheumatol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.genm.2012.10.005","article-title":"Gender differences in Latin-American patients with rheumatoid arthritis","volume":"9","author":"Mantilla","year":"2012","journal-title":"Gend. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2147\/OARRR.S397489","article-title":"Depression in Saudi Patients with Rheumatoid Arthritis","volume":"15","author":"Alharbi","year":"2023","journal-title":"Open Access Rheumatol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/j.jsps.2019.07.002","article-title":"Prevalence of complementary and alternative medicine use among rheumatoid arthritis patients in Saudi Arabia","volume":"27","author":"Almuhareb","year":"2019","journal-title":"Saudi Pharm. J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"8103812","DOI":"10.1155\/2019\/8103812","article-title":"Clinical Characteristics in Patients with Rheumatoid Arthritis: Differences between Genders","volume":"2019","author":"Intriago","year":"2019","journal-title":"Sci. World J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1136\/ard.2006.069252","article-title":"QUEST-RA: Quantitative clinical assessment of patients with rheumatoid arthritis seen in standard rheumatology care in 15 countries","volume":"66","author":"Sokka","year":"2007","journal-title":"Ann. Rheum. Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1080\/14737159.2021.1933946","article-title":"Advances in the diagnosis of autoimmune diseases based on citrullinated peptides\/proteins","volume":"21","author":"Alghamdi","year":"2021","journal-title":"Expert. Rev. Mol. Diagn."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Raine, C., and Giles, I. (2022). What is the impact of sex hormones on the pathogenesis of rheumatoid arthritis?. Front. Med., 9.","DOI":"10.3389\/fmed.2022.909879"},{"key":"ref_81","first-page":"1254","article-title":"The role of female hormonal factors in the development of rheumatoid arthritis","volume":"56","author":"Pluchino","year":"2017","journal-title":"Rheumatology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/acr.24071","article-title":"Association of Seropositivity and Mortality in Rheumatoid Arthritis and the Impact of Treatment With Disease-Modifying Antirheumatic Drugs: Results From a Real-World Study","volume":"72","author":"Alemao","year":"2020","journal-title":"Arthritis Care Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1515\/rir-2024-0007","article-title":"Clinical implications of seropositive and seronegative autoantibody status in rheumatoid arthritis patients: A comparative multicentre observational study","volume":"5","author":"Hammam","year":"2024","journal-title":"Rheumatol. Immunol. Res."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Carbonell-Bobadilla, N., Soto-Fajardo, C., Amezcua-Guerra, L.M., Batres-Marroquin, A.B., Vargas, T., Hernandez-Diazcouder, A., Jimenez-Rojas, V., Medina-Garcia, A.C., Pineda, C., and Silveira, L.H. (2022). Patients with seronegative rheumatoid arthritis have a different phenotype than seropositive patients: A clinical and ultrasound study. Front. Med., 9.","DOI":"10.3389\/fmed.2022.978351"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1136\/ard.2007.076679","article-title":"Duration of preclinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis","volume":"67","author":"Majka","year":"2008","journal-title":"Ann. Rheum. Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1136\/annrheumdis-2016-209991","article-title":"Presence of anticitrullinated protein antibodies in a large population-based cohort from the Netherlands","volume":"76","author":"Arends","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/s13075-017-1324-y","article-title":"The prevalence of ACPA is lower in rheumatoid arthritis patients with an older age of onset but the composition of the ACPA response appears identical","volume":"19","author":"Boeters","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1093\/mr\/road045","article-title":"Associations of disease duration and anti-citrullinated peptide antibody status with the effectiveness of abatacept in biologic-naive patients with rheumatoid arthritis: Post hoc analysis of a multicentre, real-world observational study in Japan (ORIGAMI)","volume":"34","author":"Misaki","year":"2024","journal-title":"Mod. Rheumatol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e7862","DOI":"10.1097\/MD.0000000000007862","article-title":"Disease duration of rheumatoid arthritis is a predictor of vascular stiffness: A cross-sectional study in patients without known cardiovascular comorbidities: A STROBE-compliant article","volume":"96","year":"2017","journal-title":"Medicine"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s12016-007-8016-3","article-title":"Antibodies to citrullinated vimentin are a specific and sensitive marker for the diagnosis of rheumatoid arthritis","volume":"34","author":"Poulsom","year":"2008","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"R61","DOI":"10.1186\/ar4498","article-title":"Cigarette smoking and risk of rheumatoid arthritis: A dose-response meta-analysis","volume":"16","author":"Discacciati","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"524","DOI":"10.3109\/s10165-011-0544-2","article-title":"Smoking is associated with an increased risk of developing ACPA-positive but not ACPA-negative rheumatoid arthritis in Asian populations: Evidence from the Malaysian MyEIRA case-control study","volume":"22","author":"Yahya","year":"2012","journal-title":"Mod. Rheumatol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1136\/ard.2009.120899","article-title":"Smoking is a major preventable risk factor for rheumatoid arthritis: Estimations of risks after various exposures to cigarette smoke","volume":"70","author":"Kallberg","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1093\/rheumatology\/kew285","article-title":"Increased inflammation and disease activity among current cigarette smokers with rheumatoid arthritis: A cross-sectional analysis of US veterans","volume":"55","author":"Sokolove","year":"2016","journal-title":"Rheumatology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1002\/art.24385","article-title":"Quantitative heritability of anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis","volume":"60","author":"Toes","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2773","DOI":"10.1002\/art.38097","article-title":"Familial risks and heritability of rheumatoid arthritis: Role of rheumatoid factor\/anti-citrullinated protein antibody status, number and type of affected relatives, sex, and age","volume":"65","author":"Frisell","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"45","DOI":"10.3904\/kjim.2013.28.1.45","article-title":"Greater prevalence of seropositivity for anti-cyclic citrullinated peptide antibody in unaffected first-degree relatives in multicase rheumatoid arthritis-affected families","volume":"28","author":"Kim","year":"2013","journal-title":"Korean J. Intern. Med."},{"key":"ref_98","first-page":"56482","article-title":"Sample Preparation and Imaging of Exosomes by Transmission Electron Microscopy","volume":"131","author":"Jung","year":"2018","journal-title":"J. Vis. Exp."},{"key":"ref_99","first-page":"6135","article-title":"Identification and analysis of exosomes secreted from macrophages extracted by different methods","volume":"8","author":"Wang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_100","first-page":"2574","article-title":"Single particle electron microscopy reconstruction of the exosome complex using the random conical tilt method","volume":"49","author":"Liu","year":"2011","journal-title":"J. Vis. Exp."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1002\/pmic.201300282","article-title":"Comparative proteomics evaluation of plasma exosome isolation techniques and assessment of the stability of exosomes in normal human blood plasma","volume":"13","author":"Kalra","year":"2013","journal-title":"Proteomics"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Akers, J.C., Ramakrishnan, V., Nolan, J.P., Duggan, E., Fu, C.C., Hochberg, F.H., Chen, C.C., and Carter, B.S. (2016). Comparative Analysis of Technologies for Quantifying Extracellular Vesicles (EVs) in Clinical Cerebrospinal Fluids (CSF). PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0149866"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Dash, M., Palaniyandi, K., Ramalingam, S., Sahabudeen, S., and Raja, N.S. (2021). Exosomes isolated from two different cell lines using three different isolation techniques show variation in physical and molecular characteristics. Biochim. Biophys. Acta Biomembr., 1863.","DOI":"10.1016\/j.bbamem.2020.183490"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"eaau6977","DOI":"10.1126\/science.aau6977","article-title":"The biology, function, and biomedical applications of exosomes","volume":"367","author":"Kalluri","year":"2020","journal-title":"Science"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"6917","DOI":"10.2147\/IJN.S264498","article-title":"Exosome: A Review of Its Classification, Isolation Techniques, Storage, Diagnostic and Targeted Therapy Applications","volume":"15","author":"Zhang","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Jankovicova, J., Secova, P., Michalkova, K., and Antalikova, J. (2020). Tetraspanins, More than Markers of Extracellular Vesicles in Reproduction. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207568"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"4389","DOI":"10.1038\/s41467-021-24384-2","article-title":"Specificities of exosome versus small ectosome secretion revealed by live intracellular tracking of CD63 and CD9","volume":"12","author":"Mathieu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"834","DOI":"10.3892\/ijmm.2017.3080","article-title":"Comparison of isolation methods of exosomes and exosomal RNA from cell culture medium and serum","volume":"40","author":"Tang","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Moelants, E.A., Van Damme, J., and Proost, P. (2011). Detection and quantification of citrullinated chemokines. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028976"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1021\/acs.jproteome.0c00474","article-title":"Elucidating Citrullination by Mass Spectrometry and Its Role in Disease Pathogenesis","volume":"20","author":"Vitorino","year":"2021","journal-title":"J. Proteome Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.clinbiochem.2022.04.002","article-title":"A new pattern of citrullinated peptides improves the sensitivity for diagnosing rheumatoid arthritis","volume":"105\u2013106","author":"Ru","year":"2022","journal-title":"Clin. Biochem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1136\/ard.2004.031211","article-title":"Are there autoantibodies reacting against citrullinated peptides derived from type I and type II collagens in patients with rheumatoid arthritis?","volume":"64","author":"Koivula","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"585","DOI":"10.4049\/jimmunol.162.1.585","article-title":"The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues","volume":"162","author":"Durieux","year":"1999","journal-title":"J. Immunol."},{"key":"ref_114","first-page":"455","article-title":"Diagnostic Value of Anti-Fibrinogen Citrullinated Peptide in Rheumatoid Arthritis","volume":"16","author":"Rodriguez","year":"2020","journal-title":"Reum. Clin."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Kim, J.S., Choi, M., Choi, J.Y., Kim, J.Y., Kim, J.Y., Song, J.S., Ivashkiv, L.B., and Lee, E.Y. (2020). Implication of the Association of Fibrinogen Citrullination and Osteoclastogenesis in Bone Destruction in Rheumatoid Arthritis. Cells, 9.","DOI":"10.3390\/cells9122720"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Heydari, R., Koohi, F., Rasouli, M., Rezaei, K., Abbasgholinejad, E., Bekeschus, S., and Doroudian, M. (2023). Exosomes as Rheumatoid Arthritis Diagnostic Biomarkers and Therapeutic Agents. Vaccines, 11.","DOI":"10.3390\/vaccines11030687"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s00018-021-04020-4","article-title":"Circulating extracellular vesicles and rheumatoid arthritis: A proteomic analysis","volume":"79","author":"Alghamdi","year":"2021","journal-title":"Cell Mol. Life Sci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"9421720","DOI":"10.1155\/2021\/9421720","article-title":"Systemic Proteomic Analysis Reveals Distinct Exosomal Protein Profiles in Rheumatoid Arthritis","volume":"2021","author":"Qin","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/ar648","article-title":"Autoantibodies to deiminated fibrinogen are the most efficient serological criterion for early rheumatoid arthritis diagnosis","volume":"5","author":"Nogueira","year":"2003","journal-title":"Arthritis Res. Ther."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1136\/annrheumdis-2012-202868","article-title":"The fibrin-derived citrullinated peptide beta60-74Cit(6)(0),(7)(2),(7)(4) bears the major ACPA epitope recognised by the rheumatoid arthritis-specific anticitrullinated fibrinogen autoantibodies and anti-CCP2 antibodies","volume":"73","author":"Cornillet","year":"2014","journal-title":"Ann. Rheum. Dis."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.clim.2014.02.011","article-title":"In Black Africans with rheumatoid arthritis, ACPA recognize citrullinated fibrinogen and the derived peptides alpha36-50Cit38,42 and beta60-74Cit60,72,74, like in Caucasians","volume":"152","author":"Nogueira","year":"2014","journal-title":"Clin. Immunol."},{"key":"ref_122","first-page":"2115","article-title":"Serum autoantibodies that bind citrullinated fibrinogen are frequently found in patients with rheumatoid arthritis","volume":"33","author":"Hill","year":"2006","journal-title":"J. Rheumatol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"103484","DOI":"10.1016\/j.jprot.2019.103484","article-title":"Expanding the citrullinome of synovial fibrinogen from rheumatoid arthritis patients","volume":"208","author":"Sharma","year":"2019","journal-title":"J. Proteom."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"4177","DOI":"10.4049\/jimmunol.166.6.4177","article-title":"The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin","volume":"166","author":"Sebbag","year":"2001","journal-title":"J. Immunol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/nrrheum.2011.76","article-title":"Anti-CCP antibodies: The past, the present and the future","volume":"7","author":"Pruijn","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/j.0105-2896.2009.00850.x","article-title":"Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis","volume":"233","author":"Wegner","year":"2010","journal-title":"Immunol. Rev."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"2662","DOI":"10.1002\/art.27552","article-title":"Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and alpha-enolase: Implications for autoimmunity in rheumatoid arthritis","volume":"62","author":"Wegner","year":"2010","journal-title":"Arthritis Rheum."}],"container-title":["Antibodies"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4468\/14\/1\/10\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:36:43Z","timestamp":1759919803000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4468\/14\/1\/10"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,26]]},"references-count":127,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["antib14010010"],"URL":"https:\/\/doi.org\/10.3390\/antib14010010","relation":{},"ISSN":["2073-4468"],"issn-type":[{"type":"electronic","value":"2073-4468"}],"subject":[],"published":{"date-parts":[[2025,1,26]]}}}