B cell depletion therapy exacerbates murine primary biliary cirrhosis.

Abstract

UNLABELLED:

Primary biliary cirrhosis (PBC) is considered a model autoimmune disease due to the clinical homogeneity of patients and the classic hallmark of antimitochondrial antibodies (AMAs). Indeed, the presence of AMAs represents the most highly directed and specific autoantibody in autoimmune diseases. However, the contribution of B cells to the pathogenesis of PBC is unclear. Therefore, although AMAs appear to interact with the biliary cell apotope and contribute to biliary pathology, there is no correlation of disease severity and titer of AMAs. The recent development of well-characterized monoclonal antibodies specific for the B cell populations, anti-CD20 and anti-CD79, and the development of a well-defined xenobiotic-induced model of autoimmune cholangitis prompted us to use these reagents and the model to address the contribution of B cells in the pathogenesis of murine PBC. Prior to the induction of autoimmune cholangitis, mice were treated with either anti-CD20, anti-CD79, or isotype-matched control monoclonal antibody and followed for B cell development, the appearance of AMAs, liver pathology, and cytokine production. Results of the studies reported herein show that the in vivo depletion of B cells using either anti-CD20 or anti-CD79 led to the development of a more severe form of cholangitis than observed in control mice, which is in contrast with results from several other autoimmune models that have documented an important therapeutic role of B cell-specific depletion. Anti-CD20/CD79-treated mice had increased liver T cell infiltrates and higher levels of proinflammatory cytokines.

CONCLUSION:

Our results reflect a novel disease-protective role of B cells in PBC and suggest that B cell depletion therapy in humans with PBC should be approached with caution.

• Authors: Amy Dhirapong, Ana Lleo, Guo-Xiang Yang, Koichi Tsuneyama, Robert Dunn, Marilyn Kehry, Thomas A Packard, John C Cambier, Fu-Tong Liu, Keith Lindor, Ross L Coppel, Aftab A Ansari, M Eric Gershwin
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 53 Issue 2 Pg. 527-35 (Feb 2011) ISSN: 1527-3350 [Electronic] United States
• PMID: 21274873 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2010 American Association for the Study of Liver Diseases.

Chemical References

• Antibodies, Monoclonal
• Antigens, CD20
• CD79 Antigens
• Cytokines
• Xenobiotics

Topics

• Animals
• Antibodies, Monoclonal (metabolism, pharmacology)
• Antigens, CD20 (drug effects, immunology)
• B-Lymphocytes (drug effects, physiology)
• CD4-Positive T-Lymphocytes (pathology)
• CD79 Antigens (drug effects, immunology)
• CD8-Positive T-Lymphocytes (pathology)
• Cytokines (metabolism)
• Disease Models, Animal
• Female
• Liver (drug effects, enzymology, pathology)
• Liver Cirrhosis, Biliary (chemically induced, pathology, physiopathology)
• Lymphocyte Depletion (adverse effects)
• Mice
• Mice, Inbred C57BL
• Mitochondria (immunology)
• Severity of Illness Index
• Xenobiotics (adverse effects)