NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis

Abstract

Primary biliary cirrhosis (PBC) is an autoimmune disease with a strong genetic component characterized by biliary ductular inflammation with eventual liver cirrhosis. The serologic hallmark of PBC is antimitochondrial antibodies that react with the pyruvate dehydrogenase complex, targeting the inner lipoyl domain of the E2 subunit (anti–PDC-E2). Herein we demonstrate that NOD.c3c4 mice congenically derived from the nonobese diabetic strain develop an autoimmune biliary disease (ABD) that models human PBC. NOD.c3c4 (at 9–10 wk, before significant biliary pathology) develop antibodies to PDC-E2 that are specific for the inner lipoyl domain. Affected areas of biliary epithelium are infiltrated with CD3+, CD4+, and CD8+ T cells, and treatment of NOD.c3c4 mice with monoclonal antibody to CD3 protects from ABD. Furthermore, NOD.c3c4-scid mice develop disease after adoptive transfer of splenocytes or CD4+ T cells, demonstrating a central role for T cells in pathogenesis. Histological analysis reveals destructive cholangitis, granuloma formation, and eosinophilic infiltration as seen in PBC, although, unlike PBC, the extrahepatic biliary ducts are also affected. Using a congenic mapping approach, we define the first ABD (Abd) locus, Abd1. These results identify the NOD.c3c4 mouse as the first spontaneous mouse model of PBC.

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] …”

Experimental evidence on the immunopathogenesis of primary biliary cirrhosis

“…Histologically, NOD.c3c4 presents lymphocyte infiltration around portal tracts with Experimental evidence on immunopathogenesis of PBC C Selmi et al 6 chronic non-suppurative destructive cholangitis and epithelioid granuloma formations; nevertheless, the morphological features of bile ducts differ somewhat from those in human PBC. 98 …”

Genetics and Genomics of Primary Biliary Cirrhosis

“…Subsequent congenic mapping of these mice identified the first autoimmune biliary disease locus in the mouse, Abd1, which is thought to contain alleles resulting in the switch between autoimmune targeting of the pancreatic islet and the biliary tract (84). However, coexistence of the autoimmune permissive NOD genetic background appears to be essential to development of the liver directed phenotype (83).…”

“…The observation that lack of TGF-β signaling in these mice leads to loss of tolerance to antigenic liver proteins suggests that genetic aberrations affecting the function of this pathway could contribute to human PBC. More clues to the possible location of genetic variants involved with PBC come from another mouse model known as NOD.c3c4 (83,84). These are congenic mice with insulin dependant diabetes (Idd) loci from diabetes-resistant strains introgressed onto the highly autoimmune prone non-obese diabetes (NOD) background (83).…”

“…These are congenic mice with insulin dependant diabetes (Idd) loci from diabetes-resistant strains introgressed onto the highly autoimmune prone non-obese diabetes (NOD) background (83). Interestingly, these mice are completely protected from diabetes, but instead develop a form of autoimmune cholangitis with similarities to human PBC, including the development of PDC-E2 reactive AMAs (84).…”