Depletion of B cells induces remission of autoimmune hepatitis in mice through reduced antigen presentation and help to T cells

Abstract

Autoimmune hepatitis (AIH) is known as a T cell–mediated disease. However, AIH patients refractory to conventional treatment have been successfully treated with anti‐CD20‐mediated B‐cell depletion. The aim of this project was to understand the immunological changes underlying the AIH remission caused by B‐cell depletion in an experimental model of AIH. C57BL/6 AIH mice, xenoimmunized with DNA coding for human liver antigens, were treated with a single dose of depleting mouse anti‐CD20 antibody at the peak of liver inflammation. Liver inflammation, alanine aminotransferase levels, chemokine (C‐X‐C) ligand 10 expression, and circulating B‐cell, autoantibody, and total immunoglobulin G levels were monitored following depletion. T‐cell and B‐cell phenotype and function were characterized. Administration of a single dose of anti‐CD20 resulted in a drastic reduction of liver inflammation accompanied by a significant reduction of alanine aminotransferase levels and of proinflammatory chemokine (C‐X‐C) ligand 10 expression. The treatment did not result in significant changes in total immunoglobulin G levels or autoantibodies. There were significantly more naive and less antigen‐experienced CD4+ and CD8+ T cells, and T‐cell proliferation was significantly reduced following anti‐CD20 treatment. B cells served as antigen‐presenting cells to CD4+ T cells. Anti‐CD20 treatment also led to a profound reduction of T follicular helper cells. Conclusion: B cells play an active role in the pathogenesis of AIH in antigen presentation processes and the modulation of T‐cell functions and influence the T follicular helper–cell population; this active role of B cells could explain the success of B‐cell depletion for remission of AIH despite its classification as a T cell–mediated autoimmune liver disease. (Hepatology 2015;62:1511–1523)

B cells in autoimmune hepatitis: Friend or foe?

“…Similar to CD4 1 T cells, which can be either T-helper or regulatory T cells, B-cell subpopulations can be either pathologic (e.g., presenting autoantigens) or protective (e.g., interleukin-10 secreting B cells). In our recent article, we showed that B-cell depletion in a mouse model leads to remission of AIH, (1) a result also observed in patients. (2,3) These results may seem to conflict with the data of Liu et al, (4) in which a subset of regulatory B cells (interleukin-10-dependent CD11b 1 B cells) inhibited pathogenic CD4 T cells in a different model of AIH.…”

“…In a recent issue of HEPATOLOGY, Beland et al (1) reported that depletion of B cells could effectively ameliorate autoimmune hepatitis in mice through reduced antigen presentation and help to T cells. They also demonstrated that administration of a single dose of anti-CD20 could significantly reduce liver inflammation in mice.…”

B2-Lymphocyte responses to oxidative stress-derived antigens contribute to the evolution of nonalcoholic fatty liver disease (NAFLD)

“…However, this work did not investigate the actual role B-cells represent about 50% of intrahepatic lymphocytes. However, so far conflicting results have been obtained in studies investigating their role in liver diseases [32][33][34]. In mice, the pool of liver B-lymphocytes mainly consists of bone marrow-derived mature B220 + /IgM + /CD23 + /CD43 -B2-cells resembling spleen follicular B-cells [32].…”

Autoimmune hepatitis: Current and future therapeutic options

“…Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen of B cells and has been used in various autoimmune diseases. Although AIH has largely been considered a T cell‐mediated autoimmune disease, anti‐CD20 administered in an animal model of AIH demonstrated that B cells also play an important role in its pathogenesis . The study showed significant improvement in transaminases, hepatic inflammation and CXCL10 levels with a single dose of anti‐CD20 antibody.…”