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-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 highresolution 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-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-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.
Original language | English (US) |
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Pages (from-to) | 26992-27006 |
Number of pages | 15 |
Journal | Oncotarget |
Volume | 7 |
Issue number | 19 |
DOIs | |
State | Published - May 10 2016 |
Keywords
- Autoimmune cholangitis
- B1a cell
- Breg
- Dysregulation
- Immune response
- Immunity
- Immunology and microbiology section
- Peritoneal cavity
ASJC Scopus subject areas
- Oncology