The Role Of B Cells For Bile Duct Damage In Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a progressive, organ-specific autoimmune disease that predominantly affects woman and is characterized by lymphocytic infiltration in portal tracts, immune-mediated destruction of small intrahepatic small bile ducts, and the presence of high titers of serum anti-mitochondrial Abs (AMAs). The destruction of biliary epithelial cells (BEC) in primary biliary cirrhosis (PBC) is primarily attributed to autoreactive T cells. In contrast, the contribution of B cells to PBC immunopathology remains to be clarified, despite the nearly universal presence of serum autoantibodies to the pyruvate dehydrogenase E subunit (PDC-E2, anti-mitochondrial antibodies [AMA]) which is the major auto-antigen found in human PBC. Autoantibodies to the E2 subunit of the PDC enzymes inhibit catalytic activity,which is thought to facilitate IgA-AMA transcytosis through BEC in the form of dimeric IgA-AMA complexes, leading to the induction of apoptosis of these cells. Moreover, autoantibodies to PDC-E2 markedly enhanced cross presentation as well as generation of PDC-E2-specific cytotoxic T cell responses in the presence of PDC-E2-pulsed antigen presenting cells. Thus, although there is evidence for a profound loss of both B- and T- cell tolerance to the autoantigenic epitope(s) of PDC-E2, the degree to which B cells or autoantibodies are involved as effector elements in the pathogenesis of BEC damage in PBC remains unclear.In a mouse model of PBC with TGF-βreceptor II dominant negative (dnTGF-βRII) mice, there is a readily detectable inflammatory lymphocytic infiltrate in the liver that closely simulates that seen in chronic non-suppurative destructive cholangitis (CNSDC) of human PBC. In this model, therapeutic B cell depletion from around 4 weeks of age for 16 weeks using anti-CD20 monoclonal antibody (mAb) markedly attenuated the PBC-like liver disease but exacerbated the colitis in dnTGF-βRII mice. In contrast, the same treatment in 20 week-old mice induced less effective changes on either cholangitis and/or colitis. Thus, anti-CD20 therapy may be potentially efficacious, and extrapolation of murine research data to human PBC implies that the effectiveness of therapeutic B cell depletion is restricted to patients with early stage PBC.In this study, we evaluated B cell distribution and the degree of their infiltration in portal areas in livers with PBC and chronic viral hepatitis type C (CHC). In inflamed portal areas, follicle-like periductal aggregation of CD20+ cells were more frequently observed in CHC, whereas ductal invasion was quite common in PBC livers and accompanied by more severe CD20+ cell infiltration. In addition, we examined CD5 expression on CD20+ cells. Double positive cells for CD20 and CD5 were occasionally observed in follicle-like aggregations in livers of both PBC and CHC. However, they were absent during the ductal invasion of PBC livers. Levels of ductal invasion of single positive cells either for CD20 or CD5 were comparable at the initial to intermediate stages of bile duct damage. However, after a transient increase in CD20+ and CD5+ cells, the latter became reduced in number but was nevertheless more commonly observed than the former cells at the ductopenic stage. Furthermore, IgG-producing cells were predominantly observed than IgA or IgM producers in inflamed portal areas of PBC livers.These data suggest that B cells in ductal invasion are inducers/early contributors, whereas T cells contribute substantially to bile duct damage in PBC.