B-cell phenotypes and BCR clonality in the human gut-liver axis : a tissue-specific analysis

RWTH Publications (RWTH Aachen)

Abstract

The gastrointestinal tract is constantly exposed to enormous amounts of potentially harmful antigens through dietary intake and the microbiota. Therefore the immune response of the gut in precise coordination with the liver is critical to prevent pathogens from entering the systemic circulation. B-cells play an important role in this defense, and although the intestinal B-cell properties has been studied to some extent, only limited information is available on the human hepatic B-cell compartment. To obtain a complete picture, we performed an in-depth phenotypic and repertoire analysis of B-cells in the human gut-liver axis, both under normal conditions and in diseases known to involve interactions between these two organs. Our analysis revealed that the distribution of B-cell subsets and the expression of markers associated with cell migration, particularly CCR9 and integrin beta 1, differed in hepatic B-cells from their intestinal and blood counterparts. In addition, we found that plasma cells of the liver and intestine did not exhibit clonal sharing. By extending the analysis to non-alcoholic fatty liver disease (NAFLD), we observed no major differences in both the phenotype and repertoire of intestinal B-cells at different disease stages. Finally, we confirmed the impairment of the B-cell compartment with a reduction of memory B-cells in patients with liver cirrhosis. We extended these observations to the B-cells of the peritoneal cavity and demonstrated that these alterations were more pronounced in patients with poor clinical outcome. In addition, we found a decreased expression of the B-cell-activating factor receptor (BAFFR) in diseased patients. Our results thus provide new insights into B-cells in the human gut and liver. We suggest that hepatic plasma cells represent a small but tissue-specific population that potentially performs specific functions in the gut-liver axis. Although we showed that there is no significant phenotypic or repertoire difference in the different stages of NAFLD, our analysis cannot exclude the role of intestinal B-cells in the development and progression. Finally, we were able to confirm the alterations in the B-cell subsets in cirrhotic patients. Our observation of decreased expression of BAFFR could also help to determine the reason for the decreased memory B-cell population. In conclusion, our detailed characterization of B-cells in the human gut-liver axis contributes to a deeper understanding of the interaction of these two organs, both in a healthy immune response and under dysregulated conditions associated with chronic liver disease, and thus provides new approaches for further studies.

Authors 1

1. Monika Schütz corresponding Aachen

   RWTH Aachen University

   Affiliation as printed

   RWTH Aachen