Epitope‐specific anti‐nuclear antibodies are expressed in a mouse model of primary biliary cirrhosis and are cytokine‐dependent

Summary Although the hallmark of primary biliary cirrhosis (PBC) is the presence of anti‐mitochondrial antibodies (AMA), a significant number of patients have anti‐nuclear antibodies (ANA) directed primarily against two nuclear proteins, gp210 and sp100. In PBC, there are considerable data on the specificity of these anti‐nuclear antibodies as well as suggestive evidence that antibodies to gp210 predict a poor outcome. However, a further understanding of the significance of these autoantibodies has been hampered by limitations in accessing human subjects in a preclinical or early asymptomatic stage. To overcome this limitation, we have taken advantage of transgenic mice with abrogated transforming growth factor‐β signalling in T cells (dnTGF‐βRII) that develop histological features of PBC as well as the same AMA specificity. We studied these mice for serum ANA, including specific autoantibodies against gp210 and sp100. We further examined sera from dnTGF‐βRII mice with concurrent deletions of the genes encoding interleukin (IL)‐12p35, IL‐12p40, IL‐23p19, IL‐17, IL‐6, interferon (IFN)‐γ or tumour necrosis factor (TNF)‐α. Sera from all the dnTGF‐βRII mouse lines contained antibodies against gp210 and sp100. Of significance, mice with germline deletions of the genes encoding IL‐12p40, IL‐23p19, IL‐17, IL‐6 and TNF‐α had significantly lower titres of anti‐gp210 antibodies. These results provide a platform to dissect the mechanisms of gp210 and sp100 autoantibody production in dnTGF‐βRII mice as well as to study the possible role of ANA in the pathophysiology of PBC.