{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T19:51:33Z","timestamp":1769975493742,"version":"3.49.0"},"reference-count":86,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T00:00:00Z","timestamp":1693440000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K99HL150595, U54HL141981 , HD072245"],"award-info":[{"award-number":["K99HL150595, U54HL141981 , HD072245"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011918","name":"Hemophilia of Georgia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011918","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005881","name":"Hemostasis and Thrombosis Research Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005881","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Soluble antigens complexed with immunoglobulin G (IgG) antibodies can induce robust adaptive immune responses <jats:italic>in vitro<\/jats:italic> and in animal models of disease. Factor VIII immune complexes (FVIII-ICs) have been detected in individuals with hemophilia A and severe von Willebrand disease following FVIII infusions. Yet, it is unclear if and how FVIII-ICs affect antibody development over time.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we analyzed internalization of FVIII complexed with epitope-mapped FVIII-specific IgG monoclonal antibodies (MAbs) by murine bone marrow-derived dendritic cells (BMDCs) <jats:italic>in vitro<\/jats:italic> and antibody development in hemophilia A (FVIII<jats:sup>-\/-<\/jats:sup>) mice injected with FVIII-IC over time.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>FVIII complexed with 2-116 (A1 domain MAb), 2-113 (A3 domain MAb), and I55 (C2 domain MAb) significantly increased FVIII uptake by BMDC but only FVIII\/2-116 enhanced antibody titers in FVIII<jats:sup>-\/-<\/jats:sup> mice compared to FVIII alone. FVIII\/4A4 (A2 domain MAb) showed similar FVIII uptake by BMDC to that of isolated FVIII yet significantly increased antibody titers when injected in FVIII<jats:sup>-\/-<\/jats:sup> mice. Enhanced antibody responses observed with FVIII\/2-116 and FVIII\/4A4 complexes <jats:italic>in vivo<\/jats:italic> were abrogated in the absence of the FVIII carrier protein von Willebrand factor.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings suggest that a subset of FVIII-IC modulates the humoral response to FVIII in an epitope-dependent manner, which may provide insight into the antibody response observed in some patients with hemophilia A.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1233356","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T13:37:56Z","timestamp":1693489076000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Factor VIII antibody immune complexes modulate the humoral response to factor VIII in an epitope-dependent manner"],"prefix":"10.3389","volume":"14","author":[{"given":"Glaivy","family":"Batsuli","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasmine","family":"Ito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth S.","family":"York","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Courtney","family":"Cox","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wallace","family":"Baldwin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surinder","family":"Gill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pete","family":"Lollar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shannon L.","family":"Meeks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2516.2002.00626.x","article-title":"Inhibitors: resolving diagnostic and therapeutic dilemmas","volume":"8","author":"Dimichele","year":"2002","journal-title":"Haemophilia."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/hae.12621","article-title":"Factor VIII alloantibody inhibitors: cost analysis of immune tolerance induction vs. prophylaxis and on-demand with bypass treatment","volume":"21","author":"Earnshaw","year":"2015","journal-title":"Haemophilia."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.23957","article-title":"Impact of inhibitors on hemophilia A mortality in the United States","volume":"90","author":"Walsh","year":"2015","journal-title":"Am J hematology"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.2830420408","article-title":"Loss of high-responder inhibitors in patients with severe hemophilia A and human immunodeficiency virus type 1 infection: a report from the Multi-Center Hemophilia Cohort Study","volume":"42","author":"Bray","year":"1993","journal-title":"Am J hematology."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1615873","article-title":"CD4+ T cell response to factor VIII in hemophilia A, acquired hemophilia, and healthy subjects","volume":"82","author":"Reding","year":"1999","journal-title":"Thromb Haemost."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1612915","article-title":"Mechanism of the immune response to human factor VIII in murine hemophilia A","volume":"85","author":"Wu","year":"2001","journal-title":"Thromb Haemost."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-05-782912","article-title":"Marginal zone B cells are critical to factor VIII inhibitor formation in mice with hemophilia A","volume":"130","author":"Zerra","year":"2017","journal-title":"Blood."},{"key":"B8","article-title":"The inhibitor antibody response is more complex in hemophilia A patients than in most nonhemophiliacs with factor VIII autoantibodies","volume":"89","author":"Prescott","year":"1997","journal-title":"Recombinate Kogenate Study Groups. 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