Interface hepatitis, the histological lesion typical of autoimmune hepatitis (AIH), is composed of CD4 and CD8 T lymphocytes and of innate immunity cells, particularly monocytes. Studies in AIH have focused on autoreactive CD4 and CD8 T cells and impairment of CD4ΨCD25Ψ regulatory T cells (T-regs), whereas little is known about the role of monocytes and their relationship with T-regs. We have investigated 51 patients with autoimmune liver disease (AILD) and 27 healthy subjects, finding that monocytes were higher in number (P β«Ψβ¬ 0.044), had a more vigorous spontaneous migration (P < 0.0005 in patients with inactive disease [ID], and P < 0.001 in those with active disease [AD]), displayed a higher tumor necrosis factor alpha (TNF-β£) over interleukin (IL)-10 production (P β«Ψβ¬ 0.07 in ID and P β«Ψβ¬ 0.0005 in AD), and expressed higher levels of Toll-like receptor (TLR) 4 (P β«Ψβ¬ 0.048 in ID and P β«Ψβ¬ 0.03 in AD). Addition of conventional T-regs (cT-regs) in AILD enhanced monocyte migration (P β«Ψβ¬ 0.05 in ID and P β«Ψβ¬ 0.08 in AD), magnified TNF-β£ over IL-10 production (P β«Ψβ¬ 0.0005 in ID and P β«Ψβ¬ 0.006 in AD), and markedly increased TLR4 expression levels (P β«Ψβ¬ 0.01 in ID and P β«Ψβ¬ 0.004 in AD), whereas in normal subjects it either restrained or left unchanged monocyte function. Because a CD127negative subpopulation within CD4ΨCD25Ψ T cells exerts the strongest regulatory activity, we performed additional experiments using purified CD4ΨCD25ΨCD127Ψ T cells (true T-regs [tT-regs]). Addition of tT-regs to monocytes decreased monocyte migration (P β«Ψβ¬ 0.03) and promoted IL-10 production (P β«Ψβ¬ 0.009), leaving unchanged TLR4 expression in healthy subjects, whereas in patients with AILD it induced only a marginal increase in IL-10 production (P β«Ψβ¬ 0.045 in ID and P β«Ψβ¬ 0.13 in AD). Conclusion: Monocyte overactivation and inability of cT-regs and tT-regs to restrain it may contribute to the loss of immune tolerance and perpetuation of the autoimmune attack in AILD. (HEPATOLOGY 2009;50:130-142.)
C ells of the adaptive immune system have been implicated in the pathogenesis of autoimmune hepatitis (AIH), a liver disorder characterized by elevated transaminase levels, circulating autoantibodies, hypergammaglobulinemia, and a histological lesion known as interface hepatitis consisting of portal/periportal mononuclear cell infiltration. [1][2][3][4] In AIH, CD4Ο©CD25Ο© regulatory T cells (Tregs), a lymphocyte subpopulation central to the maintenance of immune homeostasis, are defective in number and unable to restrain CD4 and CD8 T cell proliferation