Plasma cells and the chronic nonsuppurative destructive cholangitis of primary biliary cirrhosis

Abstract

There has been increased interest in the role of B cells in the pathogenesis of primary biliary cirrhosis. Although the vast majority of patients with primary biliary cirrhosis have antimitochondrial antibodies, there is no correlation of antimitochondrial antibody titer and/or presence with disease severity. Further, in murine models of primary biliary cirrhosis, it has been suggested that depletion of B cells may exacerbate biliary pathology. To address this issue, we have focused on detailed phenotypic characterization of mononuclear cell infiltrates surrounding the intrahepatic bile ducts of patients with PBC, PSC, AIH, CH-C and GVHD, including CD3, CD4, CD8, CD20, CD38 and immunoglobulin classes, as well as double immunohistochemical staining for CD38 and IgM. Interestingly, CD20 B lymphocytes, which are a precursor of plasma cells, were found in scattered locations or occasionally forming follicle-like aggregations but were not noted at the proximal location of chronic nonsuppurative destructive cholangitis. In contrast, there was a unique and distinct coronal arrangement of CD38 cells around the intrahepatic ducts in primary biliary cirrhosis but not controls; the majority of such cells were considered plasma cells based on their expression of intracellular immunoglobulins, including IgM and IgG, but not IgA. Patients with primary biliary cirrhosis who manifest this unique coronal arrangement were those with significantly higher titers of antimitochondrial antibodies. These data collectively suggest a role of plasma cells in the specific destruction of intrahepatic bile ducts in primary biliary cirrhosis and highlight the increasing interest in plasma cells and autoimmunity.

Interleukin-33 Promotes Disease Progression in Patients with Primary Biliary Cirrhosis

“…Firstly, there is a multi-lineage loss of tolerance to pyruvate-dehydrogenasecomplex E2, including the presence of autoreactive CD4 and CD8 cells and a highly directed B cell response (Shimoda et al 1995;Kita et al 2002). There is also evidence that the pathogenesis of the disease may involve different cytokines at different stages of disease activity (Takahashi et al 2012). Despite these accumulating data, the effects of IL-33 in patients with PBC remain unknown.…”

“…A widely accepted notion is that PBC arises as a consequence of combinations of genetic predisposition and environmental mutagens. Collective evidence nevertheless has shown that immune cells, such as autoreactive pyruvate-dehydrogenase-complex-E2-specific CD4 or CD8 T cells, are clearly associated with its pathology or etiology (Shimoda et al 1995;Kita et al 2002;Takahashi et al 2012). Currently, ursodeoxycholic acid is the only drug that has been specifically approved for the treatment of PBC.…”

Primary Biliary Cholangitis: Its Pathological Characteristics and Immunopathological Mechanisms

“…Takahashi et al reported that CD38-positive plasma cells accumulated around the bile duct in PBC patients (32). These periductal plasma cells produced IgM and IgG, but not IgA ; therefore, they may be candidates for the source of serum IgM.…”

“…A direct correlation between TLOs and injured bile ducts has not yet been demonstrated. Takahashi et al reported that, rather than the folliclelike aggregation of CD20 -positive Bcells, the periductal infiltration of CD38-positive plasma cells was strongly associated with bile duct injury (32). TLOs may indirectly correlate with bile duct injury via the maturation of effector cells.…”

Primary biliary cirrhosis: From bench to bedside

“…The combination of anti-nuclear envelope antibody (ANEA) and anti-gp210 identified a subgroup of patients with increased fibrosis and inflammation and was associated with poor prognosis in our group of PBC patients [77] . There is recent evidence to support deregulated B-cell immune responses in patients with PBC [78] .…”