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Treatment of primary biliary cirrhosis ( PBC) has lagged behind that of other autoimmune diseases. In this study we have addressed the potential utility of immunotherapy using regulatory T cells ( Treg) to treat murine autoimmune cholangitis. In particular, we have taken advantage of our ability to produce portal inflammation and bile duct cell loss by transfer of CD8+ T cells from the dominant negative form of transforming growth factor beta receptor type II ( dnTGF-β RII) mice to recombination-activating gene ( Rag)1-/- recipients. We then used this robust established adoptive transfer system and co-transferred CD8+ T cells from dnTGF-β RII mice with either C57 BL/6 or dnTGF-β RII forkhead box protein 3 ( FoxP3+) T cells. Recipient mice were monitored for histology, including portal inflammation and intralobular biliary cell damage, and also included a study of the phenotypical changes in recipient lymphoid populations and local and systemic cytokine production. Importantly, we report herein that adoptive transfer of Treg from C57 BL/6 but not dnTGF-β RII mice significantly reduced the pathology of autoimmune cholangitis, including decreased portal inflammation and bile duct damage as well as down-regulation of the secondary inflammatory response. Further, to define the mechanism of action that explains the differential ability of C57 BL/6 Treg versus dnTGF-β RII Treg on the ability to down-regulate autoimmune cholangitis, we noted significant differential expression of glycoprotein A repetitions predominant (GA RP), CD73, CD101 and CD103 and a functionally significant increase in interleukin ( IL)-10 in Treg from C57 BL/6 compared to dnTGF-β RII mice. Our data reflect the therapeutic potential of wild-type CD4+ FoxP3+ Treg in reducing the excessive T cell responses of autoimmune cholangitis, which has significance for the potential immunotherapy of PBC. [ABSTRACT FROM AUTHOR]

Several epidemiological studies have demonstrated that patients with primary biliary cirrhosis ( PBC) have a higher incidence of urinary tract infections ( UTI) and there is significant homology of the immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex ( PDC- E2), between mammals and bacteria. Previous work has demonstrated that non-obese diabetic ( NOD). B6 Idd10/ Idd18 infected with Novosphingobium aromaticivorans developed liver lesions similar to human PBC. It was postulated that the biliary disease was dependent upon the presence of the unique N. aro glycosphingolipids in activating natural killer T ( NK T) cells. To address this issue, we infected NOD. B6 Idd10/ Idd18 mice with either Escherichia coli, N. aro or use of a phosphate-buffered saline ( PBS) vehicle control and serially followed animals for the appearance of liver pathology and anti-mitochondrial autoantibodies ( AMA). Of striking importance, the biliary disease of E. coli-infected mice was more severe than N. Aro-infected mice and the titre of AMA was higher in E. coli-infected mice. Furthermore, the immunopathology did not correlate with the ability of bacterial extracts to produce antigen-dependent activation of NK T cells. Our data suggest that the unique glycosphingolipids of N. aro are not required for the development of autoimmune cholangitis. Importantly, the data highlight the clinical significance of E. coli infection in a genetically susceptible host, and we suggest that the appearance of autoimmune cholangitis is dependent upon molecular mimicry. These data highlight that breach of tolerance to PDC-E2 is probably the first event in the natural history of PBC in genetically susceptible hosts. [ABSTRACT FROM AUTHOR]

Recent accumulating evidence suggests that innate immunity is associated with obesity-induced chronic inflammation and metabolic disorders. Here, we show that a Toll-like receptor (TLR) protein, radioprotective 105 (RP105)/myeloid differentiation protein (MD)-1 complex, contributes to high-fat diet (HFD)-induced obesity, adipose tissue inflammation, and insulin resistance. An HFD dramatically increased RP105 mRNA and protein expression in stromal vascular fraction of epididymal white adipose tissue (eWAT) in wild-type (WT) mice. RP105 mRNA expression also was significantly increased in the visceral adipose tissue of obese human subjects relative to nonobese subjects. The RP105/MD-1 complex was expressed by most adipose tissue macrophages (ATMs). An HFD increased RP105/MD-1 expression on the M1 subset of ATMs that accumulate in eWAT. Macrophages also acquired this characteristic in coculture with 3T3-L1 adipocytes. RP105 knockout (KO) and MD-1 KO mice had less HFD-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance compared with wild-type (WT) and TLR4 KO mice. Finally, the saturated fatty acids, palmitic and stearic acids, are endogenous ligands for TLR4, but they did not activate RP105/MD-1. Thus, the RP105/MD-1 complex is a major mediator of adipose tissue inflammation independent of TLR4 signaling and may represent a novel therapeutic target for obesity-associated metabolic disorders. [ABSTRACT FROM AUTHOR]

Summary [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is characterized by destructive inflammation and fibrosis affecting the bile ducts. The etiology of PSC is still unknown, although lymphocytic infiltration in the portal areas suggests an immune-mediated destruction of the bile ducts. Patients with one autoimmune disease often suffer from one or more other autoimmune diseases. It is well known that there is a close relationship between PSC and inflammatory bowel disease, particularly ulcerative colitis(UC). However, the pathological findings in UC and other overlap diseases do not resemble those of PSC. In the present study, we report a patient with chronic sclerosing sialadenitis (Kuttner's tumor) and PSC. It is compared the sclerosing changes in both salivary glands and bile ducts histologically. In addition, the expression pattern of mast cell tryptase, b-FGF, and HLA-DR were examined in both tissues immunohistochemically. Histological features of sclerosing change in both salivary and bile ducts were quite similar. Marked mast cell infiltration and b-FGF expression were seen in the sclerosing areas in both tissues. In active inflammatory areas of the salivary glands, HLA-DR expression was also seen. We hypothesized that similar immune reactions occur in both the salivary gland and bile ducts and are responsible for the fibrosis that follows. [ABSTRACT FROM AUTHOR]

There is evidence that mast cells are involved in a number of pathophysiological processes. The significance of mast cells in hepatic fibrosis was examined in 28 patients with histologically normal livers, 34 with acute liver diseases, 51 with chronic liver diseases, and 59 with cholestatic biliary diseases, using immunostaining of the mast cell-specific proteinase, tryptase. Mast cells that were positive for tryptase and for chymase were significantly increased in frequency in fibrotic portal tracts and fibrous septa, particularly in cholestatic/biliary diseases. Mast cells were also increased in frequency around the fibrotic septal and intrahepatic large bile ducts and peribiliary glands of biliary diseases. However, they were less common or even rare in the sclerotic bile ducts and in scarred portal or septal fibrosis. More than half of these more numerous mast cells were positive for histamine, and some were also positive for basic fibroblast growth factor. These two substances were detectable by immunoelectron microscopic in the cytoplasmic granules of mast cells. In contrast, mast cell numbers were not significantly increased in acute viral or drug-induced hepatitis, or in zones 2 and 3 of the hepatic acinus with respect to pericellular and perivenular fibrosis in chronic liver diseases. These findings suggest that mast cells increase in number in cholestatic/biliary diseases, and to a lesser degree in chronic liver diseases, and are involved in the active fibrous enlargement of portal tract and fibrous septa formation and also in the fibrosis of the intrahepatic bile ducts as they display fibrosis-promoting factors such as tryptase, fibroblast growth factor and histamine. [ABSTRACT FROM AUTHOR]