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

Hiroto Kita, Aftab A. Ansari, Xiaosong He, Zhe Xiong Lian, Judith A Van de Water, Ross L. Coppel, Velimir Luketic, Marshall Kaplan, Hideaki Inamori, Norio Isoda, Kentaro Sugano, Michio Imawari, M. Eric Gershwin

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

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 Fcγ 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 Fcγ 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.

Original languageEnglish (US)
Pages (from-to)175-182
Number of pages8
JournalJournal of Autoimmunity
Volume21
Issue number2
DOIs
StatePublished - Sep 2003

Keywords

  • Dendritic cells
  • Primary biliary cirrhosis
  • Proteasome

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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    Kita, H., Ansari, A. A., He, X., Lian, Z. X., Van de Water, J. A., Coppel, R. L., Luketic, V., Kaplan, M., Inamori, H., Isoda, N., Sugano, K., Imawari, M., & Gershwin, M. E. (2003). Proteasome is required for class I-restricted presentation by Fcγ receptor-mediated endocytosis in primary biliary cirrhosis. Journal of Autoimmunity, 21(2), 175-182. https://doi.org/10.1016/S0896-8411(03)00089-1