{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:56:48Z","timestamp":1791323808931,"version":"4.3.1"},"reference-count":42,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2018,3,13]],"date-time":"2018-03-13T00:00:00Z","timestamp":1520899200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Grant-in-Aid for Young Scientists B","award":["25860563"],"award-info":[{"award-number":["25860563"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Gastro and Hepatol"],"published-print":{"date-parts":[[2018,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Aim<\/jats:title><jats:p>The mechanism underlying hyperglobulinemia in cirrhosis, a long appreciated phenomenon, has never been clearly understood. The aim of this study is to investigate the basis for changes in humoral immunity observed in cirrhosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We retrospectively reviewed our medical record to analyze serum immunoglobulin (Ig) levels in patients with liver disease. We also prospectively analyzed peripheral blood mononuclear cells and sera from liver disease patients. Peripheral blood mononuclear cell surface marker expressions were measured by flow cytometry and serum B\u2010cell\u2010activating factor was measured by enzyme\u2010linked immunosorbent assay. Expression of specific gene expression in magnetically separated B cells was also analyzed by real\u2010time polymerase chain reaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In retrospective analysis, we found that advancing cirrhosis, irrespective of underlying etiology or hepatocellular carcinoma, resulted in progressively increasing levels of serum IgG and IgA. In prospective analysis using clinical samples, we demonstrated that advancing cirrhosis stage was associated with increased toll\u2010like\u2010receptor (TLR)9 expression in CD27<jats:sup>+<\/jats:sup> B cell and serum B\u2010cell\u2010activating factor levels but decreased CD27<jats:sup>+<\/jats:sup> memory B\u2010cell frequency. The remaining CD27<jats:sup>+<\/jats:sup> B cells in peripheral blood exhibited increased activation\u2010induced cytidine deaminase mRNA expression. Finally, we also demonstrated isolated B cells from advanced cirrhosis were more reactive to TLR9 stimulation that drove antibody secreting cells differentiation leading to hyperimmunoglobulinemia <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Enhanced TLR9\u2010induced differentiation into antibody secreting cell may explain peripheral reductions of circulating CD27<jats:sup>+<\/jats:sup> memory B cells as well as increased serum Ig levels in cirrhosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jgh.14123","type":"journal-article","created":{"date-parts":[[2018,2,10]],"date-time":"2018-02-10T09:42:33Z","timestamp":1518255753000},"page":"1667-1676","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Enhanced B\u2010cell differentiation driven by advanced cirrhosis resulting in hyperglobulinemia"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3860-1496","authenticated-orcid":false,"given":"Hiroyoshi","family":"Doi","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine Showa University School of Medicine  Shinagawa Tokyo Japan"},{"name":"National Center for Global Health and Medicine The Research Center for Hepatitis and Immunology  Ichikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiichi","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine Showa University School of Medicine  Shinagawa Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Arai","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine Showa University School of Medicine  Shinagawa Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Tojo","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine Showa University School of Medicine  Shinagawa Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3891-5113","authenticated-orcid":false,"given":"Kenichi","family":"Morikawa","sequence":"additional","affiliation":[{"name":"Hokkaido University Graduate School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Eguchi","sequence":"additional","affiliation":[{"name":"Showa University Koto Toyosu Hospital  Toyosu Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayoshi","family":"Ito","sequence":"additional","affiliation":[{"name":"Showa University Koto Toyosu Hospital  Toyosu Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Kanto","sequence":"additional","affiliation":[{"name":"National Center for Global Health and Medicine The Research Center for Hepatitis and Immunology  Ichikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine Showa University School of Medicine  Shinagawa Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,3,13]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.08.010"},{"key":"e_1_2_6_3_1","first-page":"1","article-title":"Immune dysfunction and infections in patients with cirrhosis","author":"Bonnel AR","year":"2011","journal-title":"Clin. 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