{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:53:24Z","timestamp":1787014404746,"version":"build-2736575974"},"reference-count":45,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,11,18]],"date-time":"2019-11-18T00:00:00Z","timestamp":1574035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunol Cell Biol"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Acute rheumatic fever (\n                    <jats:styled-content style=\"fixed-case\">ARF<\/jats:styled-content>\n                    ) and chronic rheumatic heart disease (\n                    <jats:styled-content style=\"fixed-case\">RHD<\/jats:styled-content>\n                    ) are autoimmune sequelae of a Group A streptococcal infection with significant global mortality and poorly understood pathogenesis. Immunoglobulin and complement deposition were observed in\n                    <jats:styled-content style=\"fixed-case\">ARF<\/jats:styled-content>\n                    \/\n                    <jats:styled-content style=\"fixed-case\">RHD<\/jats:styled-content>\n                    valve tissue over 50\u00a0years ago, yet contemporary investigations have been lacking. This study applied systems immunology to investigate the relationships between the complement system and immunoglobulin in\n                    <jats:styled-content style=\"fixed-case\">ARF<\/jats:styled-content>\n                    . Patients were stratified by C\u2010reactive protein (\n                    <jats:styled-content style=\"fixed-case\">CRP<\/jats:styled-content>\n                    ) concentration into high (\u226510\u00a0\u03bcg\u00a0\n                    <jats:styled-content style=\"fixed-case\">mL<\/jats:styled-content>\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) and low (&lt;10\u00a0\u03bcg\u00a0\n                    <jats:styled-content style=\"fixed-case\">mL<\/jats:styled-content>\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) groups to distinguish those with clinically significant inflammatory processes from those with abating inflammation. The circulating concentrations of 17 complement factors and six immunoglobulin isotypes and subclasses were measured in\n                    <jats:styled-content style=\"fixed-case\">ARF<\/jats:styled-content>\n                    patients and highly matched healthy controls using multiplex bead\u2010based immunoassays. An integrative statistical approach combining feature selection and principal component analysis revealed a linked IgG3\u2013C4 response in\n                    <jats:styled-content style=\"fixed-case\">ARF<\/jats:styled-content>\n                    patients with high\n                    <jats:styled-content style=\"fixed-case\">CRP<\/jats:styled-content>\n                    that was absent in controls. Strikingly, both IgG3 and C4 were elevated above clinical reference ranges, suggesting these features are a marker of\n                    <jats:styled-content style=\"fixed-case\">ARF<\/jats:styled-content>\n                    \u2010associated inflammation. Humoral immunity in response to M protein, an antigen implicated in\n                    <jats:styled-content style=\"fixed-case\">ARF<\/jats:styled-content>\n                    pathogenesis, was completely polarized to IgG3 in the patient group. Furthermore, the anti\u2010M\u2010protein IgG3 response was correlated with circulating IgG3 concentration, highlighting a potential role for this potent immunoglobulin subclass in disease. In conclusion, a linked IgG3\u2013C4 response appears important in the initial, inflammatory stage of\n                    <jats:styled-content style=\"fixed-case\">ARF<\/jats:styled-content>\n                    and may have immediate utility as a clinical biomarker given the lack of specific diagnostic tests currently available.\n                  <\/jats:p>","DOI":"10.1111\/imcb.12298","type":"journal-article","created":{"date-parts":[[2019,11,18]],"date-time":"2019-11-18T14:01:58Z","timestamp":1574085718000},"page":"12-21","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Systems immunology reveals a linked IgG3\u2013C4 response in patients with acute rheumatic fever"],"prefix":"10.1111","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0020-9704","authenticated-orcid":false,"given":"Amy W","family":"Chung","sequence":"first","affiliation":[{"name":"Peter Doherty Institute for Infection and 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