TNF-Producing Th1 Cells Are Selectively Expanded in Liver Infiltrates of Patients with Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that is believed to be driven by a CD4(+) T cell response to liver Ags. However, the pathogenic function of CD4(+) effector T cells in AIH is not fully understood. To characterize liver-infiltrating lymphocytes in AIH, we determined the cytokine production of infiltrating cells obtained from biopsy material by quantitative RT-PCR and flow cytometry. A cytokine quantitiative RT-PCR array of AIH specimens revealed that TNF was the most strongly upregulated cytokine, as compared with control livers. To confirm this finding, we determined the frequencies of TNF-producing CD4(+) T cells in peripheral blood and in liver biopsy specimens in comparison with those of CD4(+) T cells producing IFN-gamma or IL-17. In AIH, TNF-producing CD4(+) T cells were significantly expanded, both in blood and liver, whereas IL-17-producing CD4(+) T cells were not. However, the majority of the TNF-producing CD4(+) T cells in AIH also produced IFN-gamma, suggesting that TNF producers might represent a pathogenic activation state of Th1 cells. Ag-specific stimulation of PBMC from AIH patients with the AIH-associated autoantigen SEPSECS resulted in significant TNF production only in patients manifesting SLA/LP autoantibodies targeting SEPSEC but not in healthy individuals who do not manifest this reactivity. Taken together, our findings indicated that TNF-producing CD4(+) T cells are expanded in AIH, both in blood and in liver. TNF-producing CD4(+) T cells in AIH seem to be aberrantly activated Th1 cells. Our findings provide a rationale for therapeutic efforts using TNF blockade in AIH.