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Original Article

Hiroto Kita ¹ , Zhe-Xiong Lian ¹ , Judy Van de Water ¹ , Xiao-Song He ¹ , Shuji Matsumura ¹ , Marshall Kaplan ² , Velimir Luketic ³ , Ross L. Coppel ⁴ , Aftab A. Ansari ⁵ , and M. Eric Gershwin ¹

¹ Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616
² Department of Gastroenterology, Tufts University School of Medicine, Boston, MA 02111
³ Hepatology Section, Medical College of Virginia Commonwealth University, Richmond, VA 23298
⁴ Department of Microbiology, Monash University, Victoria, Clayton, 3168, Australia
⁵ Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322

Address correspondence to M. Eric Gershwin, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, TB 192, One Shields Ave., Davis, CA 95616. Phone: 530-752-2884; Fax: 530-752-4669; E-mail: megershwin{at}ucdavis.edu

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.

Key Words: autoimmunity • cytotoxic T cells • cholangitis • epitopes • cross-priming

^* Abbreviations used in this paper: BCL, Epstein-Barr virus-transformed B lymphoblastoid cell line; BEC, biliary epithelial cell; DC, dendritic cell; Eu, europium; FcR, Fc receptor; HBc, Hepatitis B virus core protein; IC, immune complex; PBC, primary biliary cirrhosis; PDC-E2, E2 component of pyruvate dehydrogenase; rPDC-E2, recombinant PDC-E2; TDA, 2,2':6',2''–terpyridine–6,6''–dicarboxylic acid.

The Rockefeller University Press

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This article has been cited by other articles:

• Amigorena, S. (2002). Fc{gamma} Receptors and Cross-Presentation in Dendritic Cells. JEM 195: F1-F3 [Full Text]  

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