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Enhanced B‐cell differentiation driven by advanced cirrhosis resulting in hyperglobulinemia
Author(s) -
Doi Hiroyoshi,
Hayashi Eiichi,
Arai Jun,
Tojo Masayuki,
Morikawa Kenichi,
Eguchi Junichi,
Ito Takayoshi,
Kanto Tatsuya,
Kaplan David E,
Yoshida Hitoshi
Publication year - 2018
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.14123
Subject(s) - cirrhosis , medicine , peripheral blood mononuclear cell , immunology , antibody , b cell , biology , in vitro , biochemistry
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.