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,

Recently, we identified a child born with a genetic deficiency of IL-2 receptor ␣ (IL-2R␣, CD25) expression who had several clinical manifestations of primary biliary cirrhosis (PBC). In addition, there has been suggestive evidence in both patients with PBC and their first-degree relatives that a deficiency of regulatory T cells (Tregs) is an integral component for susceptibility to PBC. Based on these observations, we generated IL-2R␣/CD25 deficient (IL-2R␣ ؊/؊ ) mice and wildtype littermate controls and followed them longitudinally for the natural history of liver immunopathology and appearance of antimitochondrial antibodies (AMAs). The analyses included immunohistochemical staining of liver and portal tract infiltrates as well as FACS profiles of lymphoid subpopulations in liver and spleen. In addition, serum cytokine profiles were quantitated. Importantly, IL-2R␣ ؊/؊ , but not littermate controls, develop portal inflammation and biliary ductular damage similar to human patients with PBC. CD4 ؉ and CD8 ؉ T cells predominate among portal cell infiltrates and sera reflect a Th1 cytokine bias with increased levels of IFN-␥, TNF-␣, IL-2 and IL-12p40. Of importance is the finding that the IL-2R␣ ؊/؊ mice not only develop significantly increased serum levels of IgG and IgA, but they also develop AMAs with specificity for PDC-E2, which maps to the inner lipoyl domain of the autoantigen, all characteristics which are hallmarks of human PBC. In conclusion, the IL-2R␣ ؊/؊ mice should facilitate studies of the early events in PBC and especially the tantalizing connection between Treg deficiency and autoimmunity specifically directed to mitochondrially located PDC-E2 and subsequent biliary ductular cell damage. (HEPATOLOGY 2006;44:1240-1249.) P rimary biliary cirrhosis (PBC) is a chronic autoimmune liver disease primarily affecting smaller intrahepatic bile ducts and characterized by autoantibodies to the mitochondrially located E2 subunits of pyruvate dehydrogenase and related enzymes (PDC-E2), traditionally known as antimitochondrial antibodies (AMA). 1 A better understanding of the initial pathologic events will lead to better understanding for this eventually morbid and often fatal human disease. In particular, the early immunologic events in PBC have remained obscure, partly because of the long asymptomatic period. Clearly animal models of human PBC would greatly facilitate studies of the etiology of this disease and specially facilitate the identification of the early events that lead to this disease. Two murine models have recently been described that provide data which suggest that indeed this goal may be achieved. The first is the presence of AMA and severe biliary disease in a congenic strain of NOD mice, coined NOD.c3c4. 2,3 The second model is the appearance of autoimmune cholangitis and AMAs in TGF-␤ receptor II dominant-negative mice. 4 We have also seen a PBC-like disease in a child with homozygous IL-2R␣ (CD25) deficiency. 5 This latter finding is of interest since our laboratory has previously documente...

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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.

MicroRNAs (miRNAs) are small RNA molecules that negatively regulate protein coding gene expression and are thought to play a critical role in many biological processes. Aberrant levels of miRNAs have been associated with numerous diseases and cancers, and as such, miRNAs have gain much interests as diagnostic biomarkers, and as therapeutic targets. However, their role in autoimmunity is largely unknown. The aims of this study are to: (1) identify differentially expressed miRNAs in human primary biliary cirrhosis (PBC); (2) validate these independently; and (3) indentify potential targets of differentially expressed miRNAs. We compared the expression of 377 miRNAs in explanted livers form subjects with PBC versus controls with normal liver histology. A total of 35 independent miRNAs were found to be differentially expressed in PBC (p< 0.001). Quantitative PCR was employed to validate down-regulation of microRNA-122a (miR-122a) and miR-26a and the increased expression of miR-328 and miR-299-5p. The predicted targets of these miRNAs are known to affect cell proliferation, apoptosis, inflammation, oxidative stress, and metabolism. Our data are the first to demonstrate that PBC is characterized by altered expression of hepatic miRNA; however additional studies are required to demonstrate a causal link between those miRNA and the development of PBC.