Dysregulation of peritoneal cavity B1a cells and murine primary biliary cholangitis.

Yan-Qing Yang,Yin-Hu Wang,Zhe-Xiong Lian,Liang Li,Wei Yang,Hong-Di Ma,M Eric Gershwin,Qingfa Wu,Yuan Yao

doi:10.18632/oncotarget.8853

Abstract

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease with progressive cholestasis and liver fibrosis. Similar to human patients with PBC, p40−/−IL-2Rα−/− mice spontaneously develop severe autoimmune cholangitis. Although there has been considerable work on immune regulation and autoimmunity, there is a relative paucity of work directed at the functional implications of the key peritoneal cavity (PC) B cell subset, coined B1a cells in PBC. We used flow cytometry and high-resolution microarrays to study the qualitative and quantitative characteristics of B cells, particularly B1a cells, in the PC of p40−/−IL-2Rα−/− mice compared to controls. Importantly, B1a cell proliferation was markedly lower as the expression of Ki67 decreased. Meanwhile, the apoptosis level was much higher. These lead to a reduction of B1a cells in the PC of p40−/−IL-2Rα−/− mice compared to controls. In contrast, there was a dramatic increase of CD4+ and CD8+ T cells accompanied by elevated production of IFN-γ. In addition, we found a negative correlation between the frequency of B1a cells and the presence of autoreactive CD8+ T cells in both liver and PC of p40−/−IL-2Rα−/− mice. From a functional perspective, B cells from p40−/−IL-2Rα−/− mice downregulated IL-10 production and CTLA-4 expression, leading to loss of B cell regulatory function. We suggest that the dysfunction of B1a cells in the PC in this murine model of autoimmune cholangitis results in defective regulatory function. This highlights a new potential therapeutic target in PBC.

Highlights

It is interesting that the liver, whose immunological function is to facilitate immune tolerance, itself becomes a victim of autoimmunity, including primary biliary cholangitis (PBC), a disease characterized by lymphocytic infiltrates in portal tracts and the presence of antimitochondrial Abs (AMAs) secreted by autoreactive B
The numbers of T cells (P = 0.0015), CD4+ T cells (P = 0.0008) and CD8+ T cells (P = 0.0024) were much higher in peritoneal cavity (PC) of p40-/IL-2Rα-/- compared to p40-/-IL-2Rα+/- mice, while B cell number (P < 0.0001) was dramatically lower
We thought that the change of PC cell subsets in p40-/IL-2Rα-/- mice might be resulted from the inflammatory environment of PC

Summary

Introduction

It is interesting that the liver, whose immunological function is to facilitate immune tolerance, itself becomes a victim of autoimmunity, including primary biliary cholangitis (PBC), a disease characterized by lymphocytic infiltrates in portal tracts and the presence of antimitochondrial Abs (AMAs) secreted by autoreactive B cells [1,2,3,4,5,6,7]. A major difficulty in understanding PBC is that the latency time between the onset of autoantibodies and the appearance of clinical disease may lag by years. The use of murine models has become important in defining the earliest events that lead to portal inflammation [8,9,10,11,12]. An interesting feature of both humans and mice with autoimmune cholangitis is that there are www.impactjournals.com/oncotarget.

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