{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:37:52Z","timestamp":1774917472581,"version":"3.50.1"},"reference-count":28,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2015,11,25]],"date-time":"2015-11-25T00:00:00Z","timestamp":1448409600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate the presence and patterns of specific IgG subclass recognition by IgM rheumatoid factor (IgM\u2010RF) and IgA\u2010RF with a newly developed enzyme\u2010linked immunosorbent assay (ELISA), which can discriminate between polyspecific and restricted RF responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Polyspecific and restricted RF responses were determined with our ELISA, which uses individually coated recombinant IgG subclasses instead of polyclonal IgG as target antibodies. Fine specificity was determined using target antibodies with single amino acid mutations in the Fc region.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In a screening panel of 93 sera that were previously found to be IgM\u2010RF positive in a conventional RF assay, we were able to discriminate between sera with polyspecific IgM\u2010RF responses (i.e., RF responses directed against all 4 IgG subclasses) and those with restricted IgM\u2010RF responses, with low or absent relative reactivity against IgG2, IgG3, or IgG4. We found the largest variation for anti\u2010IgG3 reactivity. Samples without detectable anti\u2010IgG4 reactivity formed an independent group from the other restricted RF responses and the polyspecific RF responses. The specificity of these anti\u2010IgG4\u2013negative sera could be pinpointed to single amino acid differences between IgG1 and IgG4. Polyspecific RF responses more often showed signs of RF response maturation, with more isotype switching to IgA\u2010RF, as compared to restricted RF responses. In a cohort of IgM\u2010RF+ and\/or anti\u2013citrullinated protein antibody (ACPA)\u2013positive arthralgia patients, we found restricted RF responses in 35% (49 of 140) of RF+\/ACPA\u2013 patients, while RF+\/ACPA+ patients, who have a much higher risk of developing rheumatoid arthritis, virtually always (123 of 128 [96%]) showed a polyspecific RF response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>IgG subclass\u2013specific RF distinguishes between immature restricted RF responses and potentially more pathogenic, ACPA\u2010associated polyspecific responses.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39299","type":"journal-article","created":{"date-parts":[[2015,8,5]],"date-time":"2015-08-05T20:35:29Z","timestamp":1438806929000},"page":"3124-3134","source":"Crossref","is-referenced-by-count":34,"title":["IgG Subclass Specificity Discriminates Restricted IgM Rheumatoid Factor Responses From More Mature Anti\u2013Citrullinated Protein Antibody\u2013Associated or Isotype\u2010Switched IgA Responses"],"prefix":"10.1002","volume":"67","author":[{"given":"Willem J. J.","family":"Falkenburg","sequence":"first","affiliation":[{"name":"Amsterdam Rheumatology and immunology Center, Reade, and Sanquin Research  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirkjan","family":"van Schaardenburg","sequence":"additional","affiliation":[{"name":"Amsterdam Rheumatology and immunology Center, Reade, and Academic Medical Center  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pleuni","family":"Ooijevaar\u2010de Heer","sequence":"additional","affiliation":[{"name":"Sanquin Research, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gertjan","family":"Wolbink","sequence":"additional","affiliation":[{"name":"Amsterdam Rheumatology and immunology Center, and Reade Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theo","family":"Rispens","sequence":"additional","affiliation":[{"name":"Sanquin Research, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,11,25]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.105759"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.10167"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204154"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-201117"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.56.5.285"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204543"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22279"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2005.041376"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.11223"},{"key":"e_1_2_7_11_1","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.4049\/jimmunol.160.5.2496","article-title":"Mapping IgG epitopes bound by rheumatoid factors from immunized controls identifies disease\u2010specific rheumatoid factors produced by patients with rheumatoid arthritis","volume":"160","author":"Bonagura VR","year":"1998","journal-title":"J Immunol"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.151.7.3840"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2013.07.022"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(93)81108-C"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(97)79049-9"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2012.06.012"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1144603"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.46.9.674"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780090603"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.3109\/08916938909029148"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.02.085"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0804338"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001637"},{"key":"e_1_2_7_24_1","doi-asserted-by":"crossref","first-page":"5057","DOI":"10.4049\/jimmunol.155.10.5057","article-title":"Localization of an Fc\u2010binding reactivity to the constant region of human IgG4: implications for the pathogenesis of rheumatoid arthritis","volume":"155","author":"Zack DJ","year":"1995","journal-title":"J Immunol"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2011.02626.x"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00541519"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402334"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38307"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2012.10.029"}],"container-title":["Arthritis &amp; 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