Ignorance of hepatic autoantigen in thymus and periphery enables the development of autoimmune liver disease

Background/Aims: The liver has a distinct capacity to induce immune tolerance, which seems to be actively maintained by various regulatory mechanisms including Tregs and inhibitory T cell stimulation. However under yet unclear conditions, hepatic tolerance can be broken, enabling the development of autoimmune liver disease.

Methods: To learn how loss of hepatic tolerance might occur we have generated mice, which express an MHC class II-restricted immunodominant T cell epitope of the Lymphocytic Choriomeningitis Virus glycoprotein (GP61 – 80) specifically on hepatocytes. We constructed a mutated invariant chain (Ii) in which the CLIP peptide sequence was replaced by the GP61 – 80 peptide sequence, and inserted the mutated gene flanked by loxP sites into the ROSA26 gene, as has been done before with a similar construct (Frommer F et al. J Immunol 2008). Conditional expression in hepatocytes was achieved by breeding with Alb-Cre x Smarta mice, which were also transgenic for a T cell receptor recognizing the GP61 – 80 peptide. Alternatively, conditional expression was achieved in macrophages by breeding with LysM-Cre x Smarta mice.

Results: Conditional expression of the GP61 – 80 peptide in macrophages resulted in deletion of autoreactive CD4 T cells in the thymus and virtual absence of antigen-specific CD4 T cells from the periphery. In contrast, conditional expression of GP61 – 80 in hepatocytes did not cause thymic deletion, resulting in abundance of autoreactive CD4 T cells in the periphery. Nonetheless, the majority of these cells were not activated in vivo and most mice did not develop autoimmune pathology. However at 20 – 30 weeks of age, about 25% of these mice spontaneously developed autoimmune liver inflammation, marked by elevated serum ALT levels (mean: 593 U/l versus 62 U/l in littermate controls; P = 0.031), periportal inflammatory infiltrates on liver histology as well as splenomegaly.

Conclusion: Ignorance of liver autoantigens bears a significant risk for accidental activation of autoreactive CD4 T cells. In the absence of active control mechanisms that effectively limit T cell activity, such accidental T cell activation can cause the development of autoimmune liver inflammation.