Journal
ONCOTARGET
Volume 7, Issue 19, Pages 26992-27006Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.8853
Keywords
B1a cell; autoimmune cholangitis; dysregulation; Breg; peritoneal cavity; Immunology and Microbiology Section; Immune response; Immunity
Categories
Funding
- National Basic Research Program of China (973 Program) [2013CB944900]
- National Natural Science Foundation of China [81130058, 81430034, 91542123, 81401336]
- Research Fund for the Doctoral Program of Higher Education of China [RFDP 20133402110015]
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Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease with progressive cholestasis and liver fibrosis. Similar to human patients with PBC, p40(-/-)IL-2Ra(-/-) 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-2Ra(-/-) 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-2Ra(-/-) mice compared to controls. In contrast, there was a dramatic increase of CD4(+) and CD8(+) T cells accompanied by elevated production of IFN-gamma. 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-2Ra(-/-) mice. From a functional perspective, B cells from p40(-/-)IL-2Ra(-/-) 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.
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