Hiroyoshi Doi1,2, Eiichi Hayashi1, Jun Arai1, Masayuki Tojo1, Kenichi Morikawa3, Junichi Eguchi4, Takayoshi Ito4, Tatsuya Kanto2, David E Kaplan5, Hitoshi Yoshida1. 1. Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Shinagawa, Tokyo, Japan. 2. National Center for Global Health and Medicine, The Research Center for Hepatitis and Immunology, Ichikawa, Japan. 3. Hokkaido University Graduate School of Medicine, Sapporo, Japan. 4. Showa University Koto Toyosu Hospital, Toyosu, Tokyo, Japan. 5. Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Abstract
BACKGROUND AND AIM: 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. METHODS: 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-cell-activating factor was measured by enzyme-linked immunosorbent assay. Expression of specific gene expression in magnetically separated B cells was also analyzed by real-time polymerase chain reaction. RESULTS: 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-like-receptor (TLR)9 expression in CD27+ B cell and serum B-cell-activating factor levels but decreased CD27+ memory B-cell frequency. The remaining CD27+ B cells in peripheral blood exhibited increased activation-induced 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 in vitro. CONCLUSIONS: Enhanced TLR9-induced differentiation into antibody secreting cell may explain peripheral reductions of circulating CD27+ memory B cells as well as increased serum Ig levels in cirrhosis.
BACKGROUND AND AIM: 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. METHODS: 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 diseasepatients. Peripheral blood mononuclear cell surface marker expressions were measured by flow cytometry and serum B-cell-activating factor was measured by enzyme-linked immunosorbent assay. Expression of specific gene expression in magnetically separated B cells was also analyzed by real-time polymerase chain reaction. RESULTS: 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-like-receptor (TLR)9 expression in CD27+ B cell and serum B-cell-activating factor levels but decreased CD27+ memory B-cell frequency. The remaining CD27+ B cells in peripheral blood exhibited increased activation-induced 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 in vitro. CONCLUSIONS: Enhanced TLR9-induced differentiation into antibody secreting cell may explain peripheral reductions of circulating CD27+ memory B cells as well as increased serum Ig levels in cirrhosis.
Authors: Marc Seifert; Martina Przekopowitz; Sarah Taudien; Anna Lollies; Viola Ronge; Britta Drees; Monika Lindemann; Uwe Hillen; Harald Engler; Bernhard B Singer; Ralf Küppers Journal: Proc Natl Acad Sci U S A Date: 2015-01-26 Impact factor: 11.205
Authors: Rubén Francés; Pedro Zapater; José M González-Navajas; Carlos Muñoz; Rocío Caño; Rocío Moreu; Sonia Pascual; Pablo Bellot; Miguel Pérez-Mateo; José Such Journal: Hepatology Date: 2008-03 Impact factor: 17.425