IL-2 receptor α−/− mice and the development of primary biliary cirrhosis

Abstract

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...

Experimental evidence on the immunopathogenesis of primary biliary cirrhosis

“…93 A mouse deficient for IL-2 receptor-a, which is highly expressed on Tregs, developed 100% AMA positivity against PDC-E2, 80% ANA positivity, and lymphocyte infiltration around the portal tracts associated with cholangiocyte injury. 94 Animal models support our hypothesis that xenobiotics can induce loss of tolerance. First, our group demonstrated loss of tolerance in rabbits immunized with 6-bromohexonate, a xenobiotically modified hapten mimicking lipoic acid, coupled with bovine serum albumin.…”

Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis

“…38 Future studies should address this issue by studying the administration of drugs that induce ALF in the recently described murine models of human PBC. [39][40][41] …”

Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation

“…17 Considering these observations, we speculated that some bacterial components originating from asymptomatic or less apparent chronic bacterial infection might have function(s) in the initiation and/or development of the autoimmune status in patients with PBC, eventually leading to chronic epithelial inflammation in the liver and multiple epithelial inflammation. Recently, a strain with a dominant-negative form of TGFb receptor II, 18 IL-2 receptor a À/À mice, 19 and Ae2 a,b -deficient mice 20 have been reported as spontaneous PBC animal models. However, as these mice are genetically engineered, they might not completely reflect the onset of human PBC.…”