The presence of AMAs and autoreactive T and B cells, in conjunction with the co-occurrence of other autoimmune diseases, characterizes PBC as a typical autoimmune disease. 3 Although the etiology of PBC remains obscure,
Our understanding of primary biliary cirrhosis (PBC) has been significantly enhanced by the rigorous dissection of the multilineage T and B cell response against the immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2). PDC-E2 is a ubiquitous protein present in mitochondria of nucleated cells. However, the damage of PBC is confined to small biliary epithelial cells (BECs). We have previously demonstrated that BECs translocate immunologically intact PDC-E2 to apoptotic bodies and create an apotope. To define the significance of this observation, we have studied the ability of biliary or control epithelial apotopes to induce cytokine secretion from mature monocyte-derived macrophages (MDMUs) from either patients with PBC or controls in the presence or absence of anti-mitochondrial antibodies (AMAs). We demonstrate that there is intense inflammatory cytokine production in the presence of the unique triad of BEC apotopes, macrophages from patients with PBC, and AMAs. The cytokine secretion is inhibited by anti-CD16 and is not due to differences in apotope uptake. Moreover, MDMUs from PBC patients cultured with BEC apoptotic bodies in the presence of AMAs markedly increase tumor necrosis factor-related apoptosis-inducing ligand expression. Conclusion: These results provide a mechanism for the biliary specificity of PBC, the recurrence of disease after liver transplantation, and the success of ursodiol in treatment. They further emphasize the critical role of the innate immune system in the perpetuation of this autoimmune disease. (HEPATOLOGY 2010;52:987-998) Abbreviations: ABMU, number of phagocytosed bodies per macrophage; AMA, anti-mitochondrial antibody; APC, antigen-presenting cell; BEC, biliary epithelial cell; CCR2, chemokine (C-C motif ) receptor 2; CFSE, carboxyfluorescein diacetate succinimidyl ester; CI, confidence interval; CX3CR1, chemokine (C-X3-C motif) receptor 1; Cy7, cyanine 7; DAPI, 4 0 ,6-diamidino-2-phenylindole; FasL, Fas ligand; FccR, fragment crystallizable receptor for immunoglobulin G; FcR, fragment crystallizable receptor; FITC, fluorescein isothiocyanate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GM-CSF, granulocyte-macrophage colony-stimulating factor; HC, healthy control; HIBEC, human intrahepatic biliary epithelial cell; HLA, human leukocyte antigen; IFN-c, interferon gamma; IgA, immunoglobulin A; IgG, immunoglobulin G; IL, interleukin; M-CSF, macrophage colony-stimulating factor; MDMU, monocyte-derived macrophage; MFI, median fluorescence intensity; MIP, macrophage inflammatory protein; mRNA, messenger RNA; NA, not available; NS, not significant; PBC, primary biliary cirrhosis; PBMC, peripheral blood mononuclear cell; PDC-E2, E2 component of the pyruvate dehydrogenase complex; PE, R-phycoerythrin; PSC, primary sclerosing cholangitis; RPMI, Roswell Park Memorial Institute; SLE, systemic lupus erythematosus; TNF-a, tumor necrosis factor alpha; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand.From the
The emergence of new regulatory and pro-inflammatory immune cell subsets and cytokines dictates the need to re-examine the role of these subsets in various diseases involving the immune system. IL-17 has been recently identified as a key cytokine involved in numerous autoimmune processes. However, its role in liver autoimmune diseases remains unclear. Primary biliary cirrhosis (PBC) is characterized histologically by autoreactive CD4 and CD8 T cells surrounding damaged bile ducts. CD4+ T cells are a major source of IL-17, which compose a distinct T helper subset (Th17). Thus we set out determine the role of IL-17 in both human and a murine model of PBC in a liver-targeted manner. Our data demonstrate an increase in the frequency of IL-17+ lymphocytic infiltration in liver tissues from PBC patients and those with other liver dysfunctions as compared to healthy livers. IL-2 receptor α knockout mice, a recently identified murine model of human PBC, also demonstrate marked aggregations of IL-17 positive cells within portal tracts and increased frequencies of Th17 cells in the liver compared to the periphery. Interestingly, CD4+ T cells from livers of normal C57BL/6J mice also secreted higher levels of IL-17 relative to those from spleens, indicating a preferential induction of Th17 cells in liver tissues. Importantly, C57BL/6J cocultures of splenic CD4+ T cells and liver non-parenchymal cells increased IL-17 production approximately 10 fold compared to T cells alone, suggesting a role of the liver microenvironment in Th17 induction in cases of liver autoimmunity and other liver inflammatory diseases.
In most autoimmune diseases the serologic hallmarks of disease precede clinical pathology by years. Therefore the use of animal models in defining early disease events becomes critical. Herein we have taken advantage of a “designer” mouse with dysregulation of interferon gamma (IFNγ) characterized by prolonged and chronic expression of IFNγ through deletion of the IFNγ 3′ UTR AU-rich element. These mice develop primary biliary cholangitis (PBC) with a female predominance that mimics human disease and is characterized by upregulation of total bile acids, spontaneous production of AMA, and portal duct inflammation. Transfer of CD4 T cells from ARE-Del−/− to B6/Rag1−/− mice induced moderate portal inflammation, and parenchymal inflammation, RNA-sequencing of liver gene expression revealed that upregulated genes potentially define early stages of cholangitis. Interestingly, upregulated genes specifically overlap with the gene expression signature of biliary epithelial cells in PBC, implying that IFNγ may play a pathogenic role in biliary epithelial cells (BEC) in the initiation stage of PBC. Moreover, differentially expressed genes in female mice have stronger Type I and II interferon signaling and lymphocyte-mediated immune responses and thus may drive the female bias of the disease. In conclusion, changes in IFNγ expression are critical for the pathogenesis of PBC.
Primary biliary cirrhosis (PBC) is an organ-specific autoimmune liver disease characterized by the presence of antimitochondrial antibodies and the destruction of small intrahepatic bile ducts with portal inflammation. In previous studies, we reported that both CD1d expression and the frequency of CD1d-restricted natural killer T (NKT) cells were increased in the livers of patients with PBC. To define a specific role of CD1d-restricted NKT cells in the pathogenesis of PBC, particularly early events, we investigated the function of hepatic CD1d-restricted NKT cells in our transforming growth factor  (TGF-) receptor II dominant-negative (dnTGFRII) mouse model of PBC. We generated CD1d ؊/؊ and CD1d ؉/؊ dnTGFRII mice and performed a comparative study of liver immunopathology. We report herein that these dnTGFRII mice demonstrate a massive increase of hyperactive CD1d-restricted NKT cells within the hepatic tissues. CD1d ؊/؊ dnTGFRII mice, which lack CD1d-restricted CD1d-restricted NKT cells, exhibit significantly decreased hepatic lymphoid cell infiltrates and milder cholangitis compared with CD1d ؉/؊ dnTGFRII mice. Interestingly, there was a significant increase in the production of interferon-␥ in hepatic CD1d-restricted NKT cells activated by ␣-galactosylceramide in young but not older dnTGFRII mice, suggesting an age-dependent role of CD1d-restricted NKT cells. Conclusion: These data demonstrate that CD1d-restricted NKT cells in dnTGFRII mice are a critical factor in liver injury. (HEPATOLOGY 2008;47:571-580.)
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