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AMA production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG and suppressed by potassium channel blockers

, : AMA production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG and suppressed by potassium channel blockers. Hepatology 45(2): 314-322

We previously reported that peripheral blood mononuclear cells (PBMCs) from patients with primary biliary cirrhosis (PBC) produce significantly higher levels of polyclonal IgM than controls after exposure to CpG. Furthermore, the prevalence and unusually high levels of antimito-chondrial antibodies (AMAs) in patients with PBC suggest a profound loss of B cell tolerance. We have addressed the issue of whether CpG will promote the production of AMAs and whether new experimental agents that inhibit the lymphocyte potassium channels Kv1.3 and KCa3.1 can suppress CpG-mediated B cell activation and AMA production. PBMCs were stimulated with and without CpG and were subsequently analyzed for phenotype, including expression of TLR9, CD86, and KCa3.1 concurrent with measurements of AMA and responses to a control antigen, tetanus toxoid, in supernatants. Additionally, K+ channel expression on B cells from PBC patients and controls was studied using whole-cell patch-damp technology. In patients with PBC, CpG induces secretion of AMAs in PBMCs and also up-regulates B cell expression of TLR9, CD86, and KCa3.1. Additionally, K+ channel blockers suppress secretion of AMA without a reduction of CpG-B-enhanced IgM production. Furthermore, there is diminished upregulation of TLR9 and CD86 without affecting proliferation of B cells, B cell apoptosis, or viability. Conclusion: These data suggest that the hyperresponsiveness of B cells in PBC accelerates B cell-mediated autoimmunity.


PMID: 17256753

DOI: 10.1002/hep.21522

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