Autoimmune hepatitis and antigen‐specific T regulatory cells: When can we send in the regulators?

A utoimmune hepatitis (AIH) is a chronic, progressive necroinflammatory disease putatively caused by loss of tolerance to hepatic autoantigens. The current concept of pathogenesis involves initiation by environmental triggers in persons with immunogenetic predisposition reflected by strong human leukocyte antigen (HLA) class II haplotype associations, loss of immunological tolerance to liver autoantigens, generation of an unregulated T-cell– mediated immune attack against those autoantigens, and production of non–species-specific autoantibodies. 3 In the absence of biomarkers, the diagnosis of AIH is based on characteristic histological features of interface hepatitis, clinical and laboratory findings, and the presence of autoantibodies that permit subclassification of AIH into type 1 (anti-nuclear and/or smooth muscle autoantibodies) and type 2 (anti-liver-kidney-microsomal-1 [LKM-1] autoantibodies). Prevention of autoimmunity is achieved through the interaction of professional antigen-presenting cells (APCs), T effector, and T regulatory (Treg) cells (Fig. 1). Autoimmunity primarily results from failure of natural Treg generated in the thymus to prevent initial reactions against autoantigens. Thereafter, organ-specific autoimmunity is driven by interplay between T effector and antigen-specific inducible Treg (iTreg) that determine the duration, extent, and distribution of inflammation within the organ. Complete understanding of the interplay between T effector cells and Treg cells in AIH may lead to novel strategies for therapeutic regulation of the autoimmune response in this and other diseases. The pathogenesis of organ-specific autoimmune diseases involves interplay of CD4 T helper (Th) 1 cells promoting immunopathology through proinflammatory cytokines, CD8 cytotoxic T lymphocyte (CTL) cytotoxicity, CD4 Th2 cells promoting antibody production, Th17 and Th9 cells intensifying inflammation, and the immunoregulatory functions of antigenspecific, inducible Treg cells (Fig. 1). Collectively, they determine the extent of immunopathology through their direct effector functions and activation and recruitment of macrophages, neutrophils, eosinophils, and natural killer (NK) cells. The adaptive immune response of T cells requires processing of antigens into peptides that fit the antigen-binding grooves of major histocompatibility complex (MHC; termed HLA in humans) class I and class II molecules and presentation of the MHC-peptide antigen complexes to T cell receptors (TCR). The TCR of CD8 T cells recognize only class I MHC-antigen complexes, while those of CD4 T cells recognize only class II MHC-antigen complexes. T cell activation is optimal when MHCantigen complexes are presented by professional APC, comprised of activated B cells and macrophages and mature dendritic cells (DCs), because these APC coexpress costimulatory molecules CD80 and CD86. Binding of CD80 and CD86 to the CD28 receptor on both naı̈ve CD4 and CD8 T cells delivers a costimulatory signal required for functional differentiation into CD4 T cell subsets and CD8 CTL (Fig. 1). Treg cells are indispensable for maintenance of selftolerance and regulation of the extent and duration of normal immune responses. T cell precursors traffic to the thymus, where those with TCR with high affinity for autoantigens are deleted. During thymic development of CD4 T cells, a variable proportion express repressor forkhead winged helix transcription factor box (FoxP3) and later differentiate into natural CD4 Treg cells with the phenotype CD4þCD25þhigh CD45ROþhighCD62LþhighCD127lowFoxP3þhigh, where ‘‘high’’ refers to the degree of expression, CD25 is the receptor for the a-chain of the T cell mitogenic Abbreviations: AIH, autoimmune hepatitis; APC, antigen-presenting cell; CTL, cytotoxic T lymphocyte; DC, dendritic cell; FoxP3, forkhead winged helix transcription factor box; HLA, human leukocyte antigen; iDC, immature DC; IFN, interferon; IL, interleukin; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; iTreg, inducible Treg activated by smDC or mDC; LKM-1, liver-kidney-microsomal-1; mDC, mature DC; MHC, major histocompatibility complex; NKT, natural killer T; NK, natural killer; nTreg, natural Treg selected in thymus; PBMC, peripheral blood mononuclear cell; PD-L1, programmed death receptor-ligand-1; PMN, polymorphonuclear neutrophil; SLA, soluble liver antigen; smDC, semimature DC; Tcd, T cells expressing T cell receptors comprised of cd chains; TCR, T cell receptors; TGFb, transforming growth factor b; Th, T helper; Tr1, T regulatory 1; Treg, T regulatory. Address reprint requests to: John M. Vierling, MD, 1709 Dryden, Suite 1500, Houston, TX 77030. E-mail: vierling@bcm.tmc. edu; fax: 713 798 8319. CopyrightVC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.24153 Potential conflict of interest: Nothing to report.