Proteasome is required for class I-restricted presentation by Fcgamma receptor-mediated endocytosis in primary biliary cirrhosis

• Published in: Journal of autoimmunity Vol. 21; no. 2; pp. 175 - 182
• Main Authors: Kita, Hiroto, Ansari, Aftab A, He, Xiao-Song, Lian, Zhe-Xiong, Van de Water, Judy, Coppel, Ross L, Luketic, Velimir, Kaplan, Marshall, Inamori, Hideaki, Isoda, Norio, Sugano, Kentaro, Imawari, Michio, Gershwin, M Eric
• Format: Journal Article
• Language: English
• Published: England 01.09.2003
• Subjects: Acetylcysteine - analogs & derivatives; Acetylcysteine - pharmacology; Antigen Presentation; Cysteine Endopeptidases - physiology; Dendritic Cells - immunology; Dihydrolipoyllysine-Residue Acetyltransferase; Endocytosis; Histocompatibility Antigens Class I - metabolism; Humans; Liver Cirrhosis, Biliary - enzymology; Liver Cirrhosis, Biliary - immunology; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - physiology; Peptide Fragments - genetics; Peptide Fragments - immunology; Proteasome Endopeptidase Complex; Pyruvate Dehydrogenase Complex - genetics; Pyruvate Dehydrogenase Complex - immunology; Receptors, IgG - metabolism; Signal Transduction; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Cytotoxic - immunology
• ISSN: 0896-8411

There is a considerable database on the effector mechanisms for CD8 recognition of PDC-E2 in primary biliary cirrhosis (PBC). In particular, the specific roles of MHC class I, the mitochondrial autoepitope, and the liver-specific T cell precursor frequency, are defined for HLA-A2.1 patients. There is evidence for a role of MHC class I-mediated presentation of exogenous antigens, or cross-presentation, in the development of the antimitochondrial response and a contributory role of Fcgamma receptor-mediated uptake of autoantigen-autoantibody complexes for the induction of a PDC-E2 specific autoreactive CTL response. Based on this background, we examined potential intracellular pathways for processing the immunodominant mitochondrial autoantigen, PDC-E2, by dendritic cells (DC). In particular, we studied the effects of the proteasome inhibitor lactacystin and the endosomal acidification inhibitor bafilomycin on the induction of PDC-E2-specific CTL response in PBC. Importantly, our data indicate that pre-treatment with either lactacystin or bafilomycin inhibits the PDC-E2 immune complex-induced CTL response. The processing and presentation of PDC-E2 by CD8(+)T cells is mediated by proteasomes and facilitated by Fcgamma receptor-mediated endocytosis. This data reflects another layer of interaction between components of the immune system in the development of autoimmunity. Further characterization of autoantigen uptake and processing may lead to potential therapeutic intervention.