{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T10:29:52Z","timestamp":1778236192377,"version":"3.51.4"},"reference-count":15,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T00:00:00Z","timestamp":1608249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>We report the observation of a 75-year-old patient referred for cervical lymphadenopathies. A pre-lymphadenectomy blood work revealed an asymptomatic elevation of aPTT with low factor VIII (FVIII) levels and high anti-FVIII antibodies titers, consistent with acquired hemophilia A (AHA). Histological work-up of a cervical lymphadenopathy revealed benign follicular hyperplasia with IgG4<jats:sup>+<\/jats:sup> lymphoplasmacytic infiltration; and serum IgG4 levels were markedly elevated, compatible with IgG4-related disease (IgG4-RD). He was successfully treated with a 9-month course of prednisone, secondarily associated with rituximab when an AHA relapse occurred. As this patient presented with an unusual association of rare diseases, we wondered whether there was a link between the two conditions. Our first hypothesis was that the anti-FVIII autoantibodies could be directly produced by the proliferating IgG4<jats:sup>+<\/jats:sup> plasma cells as a result of broken tolerance to autologous FVIII. To test this assumption, we determined the anti-FVIII IgG subclasses in our patient and in a control group of 11 AHA patients without IgG4-RD. The FVIII inhibitor was mostly IgG4, with an anti-FVIII IgG4\/IgG1 ratio of 42 at diagnosis and 268 at relapse in our patient; similar values were observed in non-IgG4-RD AHA patients. As a second hypothesis, we considered whether the anti-FVIII activity could be the result of a non-specific autoantibody production due to polyclonal IgG4<jats:sup>+<\/jats:sup> plasma cell proliferation. To test this hypothesis, we measured the anti-FVIII IgG4\/total IgG4 ratio in our patient, as well as in several control groups: 11 AHA patients without IgG4-RD, 8 IgG4-RD patients without AHA, and 11 healthy controls. We found that the median [min-max] ratio was higher in AHA-only controls (2.4 10<jats:sup>-2<\/jats:sup> [5.7 10<jats:sup>-4<\/jats:sup>-1.79 10<jats:sup>-1<\/jats:sup>]), an oligoclonal setting in which only anti-FVIII plasma cells proliferate, than in IgG4-RD-only controls (3.0 10<jats:sup>-5<\/jats:sup> [2.0 10<jats:sup>-5<\/jats:sup>-6.0 10<jats:sup>-5<\/jats:sup>]), a polyclonal setting in which all IgG4<jats:sup>+<\/jats:sup> plasma cells proliferate equally. Our patient had intermediate ratio values (2.7 10<jats:sup>-3<\/jats:sup> at diagnosis and 1.0 10<jats:sup>-3<\/jats:sup> at relapse), which could plead for a combination of both mechanisms. Although no definitive conclusion can be drawn, we hypothesized that the anti-FVIII autoantibody production in our IgG4-RD AHA patient could be the result of both broken tolerance to FVIII and bystander polyclonal IgG4<jats:sup>+<\/jats:sup> plasma cell proliferation.<\/jats:p>","DOI":"10.3389\/fimmu.2020.558811","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T13:46:51Z","timestamp":1608299211000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Acquired Hemophilia A in IgG4-Related Disease: Case Report, Immunopathogenic Study, and Review of the Literature"],"prefix":"10.3389","volume":"11","author":[{"given":"S\u00e9bastien","family":"Sanges","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuelle","family":"Jeanpierre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Lopez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jules","family":"Russick","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandrine","family":"Delignat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Carpentier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romain","family":"Dubois","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvain","family":"Dubucquoi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Guerrier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c9ric","family":"Hachulla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre-Yves","family":"Hatron","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camille","family":"Paris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Susen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Launay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00e9bastien","family":"Lacroix-Desmazes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louis","family":"Terriou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012513-104708","article-title":"IgG4-Related Disease","volume":"9","author":"Mahajan","year":"2014","journal-title":"Annu Rev Pathology: Mech Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-310336","article-title":"Pathogenicity of IgG in patients with IgG4-related disease","volume":"65","author":"Shiokawa","year":"2016","journal-title":"Gut"},{"key":"B3","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1111\/ejh.12689","article-title":"Acquired haemophilia: an overview for clinical practice","author":"Kessler","year":"2015","journal-title":"Eur J Haematol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-018-2441-3","article-title":"Acquired hemophilia A associated with autoimmune pancreatitis with serum IgG4 elevation","volume":"108","author":"Narazaki","year":"2018","journal-title":"Int J Hematol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2016.3898","article-title":"Immunoglobulin G4-related acquired hemophilia: A case report","volume":"12","author":"Li","year":"2016","journal-title":"Exp Ther Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.51.8133","article-title":"Acquired hemophilia A associated with IgG4-related lung disease in a patient with autoimmune pancreatitis","volume":"51","author":"Sugino","year":"2012","journal-title":"Intern Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1136\/annrheumdis-2019-216561","article-title":"The 2019 American College of Rheumatology\/European League Against Rheumatism classification criteria for IgG4-related disease","volume":"79","author":"Wallace","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1615080","article-title":"A detailed comparison of the performance of the standard versus the Nijmegen modification of the Bethesda assay in detecting factor VIII:C inhibitors in the haemophilia A population of Canada. Association of Hemophilia Centre Directors of Canada. Factor VIII\/IX Subcommittee of Scientific and Standardization Committee of International Society on Thrombosis and Haemostasis","volume":"79","author":"Giles","year":"1998","journal-title":"Thromb Haemost"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1613214","article-title":"Giles A. 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