Chemokine (C‐X‐C motif) ligand 13 promotes intrahepatic chemokine (C‐X‐C motif) receptor 5+ lymphocyte homing and aberrant B‐cell immune responses in primary biliary cirrhosis

Abstract

The serologic hallmark of primary biliary cirrhosis (PBC) is the presence of high titer, and specific anti-mitochondrial antibodies (AMA). Interestingly, although there is no global immune defect in patients with PBC, there is widespread dysregulated B cell function, including increased sera levels of IgM and enhanced B cell responses to CpG stimulation. The mechanisms involved in this B cell dysfunction have remained unknown. To address this issue, we focused on identifying the frequencies of B cell subsets in patients with PBC and the mechanisms that lead to B cell dysregulation, including the relationships with CXCR5+CD4+T cells. Herein we report that elevations of both serum and intrahepatic IL-21 were found in patients with PBC and, in particular, promoted B cell proliferation, STAT3 phosphorylation and AMA production in vitro. More importantly, upon stimulation with rPDC-E2, CXCR5+CD4+T cells in PBC produced higher levels of IL-21 than healthy controls. Additionally, sorted CXCR5+CD4+T cells increased production of AMA by autologous CD19+B cells. Indeed, elevated expression of intrahepatic CXCL13, a key chemokine of CXCR5+ cells, was uniquely found within the portal tracts in PBC, accompanied by infiltrates of CD4+, CXCR5+, CD19+, and CD38+ cells. In conclusion, CXCL13 promotes aggregation of CD19+B cells and CXCR5+CD4+T cells, which directs the aberrant AMA response via IL-21. These data have implications for potential immunotherapy and also reflect the unique lymphoid biology in the liver of PBC.

AAV-IL-22 modifies liver chemokine activity and ameliorates portal inflammation in murine autoimmune cholangitis

“…Treatment of patients with PBC is still not disease-specific and the standard of care involves therapy with the secondary bile acid ursodeoxycholic acid (UDCA) (34–36). We note, based upon the data herein, that the therapeutic improvements appear secondary to altering chemokine function and not due to several other T and B cell defects or autoantibody production which have been shown in patients with PBC (37–39). …”

Chronic expression of interferon‐gamma leads to murine autoimmune cholangitis with a female predominance

“…A s with most autoimmune diseases, primary biliary cholangitis (PBC) is female-predominant and has a long latency period between detection of autoantibodies and the clinical appearance of immunopathology. (1)(2)(3)(4) Although there are clearly major defects in adaptive immunity, including dysregulation of multiple T-cell and B-cell pathways, (5)(6)(7)(8)(9)(10)(11) there is significant evidence for the role of innate immunity in modulating and perhaps even initiating disease activity. (12)(13)(14)(15)(16)(17) Indeed, we have proposed that PBC is a multihit disease involving independent but overlapping immune path-ways that interact at different stages of disease activity, ultimately leading to the clinical entity of severe portal inflammation with potential cirrhosis.…”

Successful treatment of murine autoimmune cholangitis by parabiosis: Implications for hematopoietic therapy

“…There is extensive data on the putative effector pathways that lead to biliary destruction and the relationships between loss of tolerance and biliary pathology[3–7]. The destruction of bile ducts is associated with cholestasis, resulting in cirrhosis and liver failure.…”