1. Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells
- Author
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Kita, Hiroto, Lian, Zhe-Xiong, Van de Water, Judy, He, Xiao-Song, Matsumura, Shuji, Kaplan, Marshall, Luketic, Velimir, Coppel, Ross L, Ansari, Aftab A, and Gershwin, M Eric
- Subjects
Antigen Presentation ,Cytotoxic ,T-Lymphocytes ,cytotoxic T cells ,autoimmunity ,Immunology ,hemic and immune systems ,Pyruvate Dehydrogenase Complex ,macromolecular substances ,Dendritic Cells ,Antigen-Antibody Complex ,epitopes ,Lymphocyte Activation ,Dihydrolipoyllysine-Residue Acetyltransferase ,Medical and Health Sciences ,cholangitis ,HLA-A2 Antigen ,Humans ,Cytokines ,cross-priming ,Oligopeptides - Abstract
Primary biliary cirrhosis (PBC) is characterized by an intense biliary inflammatory CD4(+) and CD8(+) T cell response. Very limited information on autoantigen-specific cytotoxic T lymphocyte (CTL) responses is available compared with autoreactive CD4(+) T cell responses. Using peripheral blood mononuclear cells (PBMCs) from PBC, we identified an HLA-A2-restricted CTL epitope of the E2 component of pyruvate dehydrogenase (PDC-E2), the immunodominant mitochondrial autoantigen. This peptide, amino acids 159-167 of PDC-E2, induces specific MHC class I-restricted CD8(+) CTL lines from 10/12 HLA-A2(+) PBC patients, but not controls, after in vitro stimulation with antigen-pulsed dendritic cells (DCs). PDC-E2-specific CTLs could also be generated by pulsing DCs with full-length recombinant PDC-E2 protein. Furthermore, using soluble PDC-E2 complexed with either PDC-E2-specific human monoclonal antibody or affinity-purified autoantibodies against PDC-E2, the generation of PDC-E2-specific CTLs, occurred at 100-fold and 10-fold less concentration, respectively, compared with soluble antigen alone. Collectively, these data demonstrate that autoantibody, helper, and CTL epitopes all contain a shared peptide sequence. The finding that autoantigen-immune complexes can not only cross-present but also that presentation of the autoantigen is of a higher relative efficiency, for the first time defines a unique role for autoantibodies in the pathogenesis of an autoimmune disease.
- Published
- 2002