Heterogeneity of autoreactive T cell clones specific for the E2 component of the pyruvate dehydrogenase complex in primary biliary cirrhosis

Judith A Van de Water, Aftab Ansari, Thomas P Prindiville, Ross L. Coppel, Nancy Ricalton, Brian L. Kotzin, Shengjiang Liu, Thomas E. Roche, Sheri M. Krams, Santiago Munoz, M. Eric Gershwin

Research output: Contribution to journalArticle

114 Scopus citations

Abstract

The extraordinary specificity of bile duct destruction in primary biliary cirrhosis (PBC) and the presence of T cell infiltrates in the portal tracts have suggested that biliary epithelial cells are the targets of an autoimmune response. The immunodominant antimitochondrial humoral response in patients with PBC is directed against the E2 component of pyruvate dehydrogenase (PDC- E2). Hitherto, there have only been limited reports on the characterization and Vβ usage of PDC-E2-specific cloned T cell lines. In this study, we examined peripheral blood mononuclear cells (PBMC) for their reactivity to the entire PDC complex as well as to the E1- and E2-specific components. We also examined the phenotype, lymphokine profile, and Vβ usage of PDC- specific T cell dories isolated from cellular infiltrates from the livers of PBC patients. We report that PBMC from 16/19 patients with PBC, but not 12 control patients, respond to the PDC-E2 subunit. Interestingly, this response was directed to the inner and/or the outer lipoyl domains, despite the serologic observation that the autoantibody response is directed predominantly to the inner lipoyl domain. Additionally, lymphokine analysis of interleukin (IL) 2/IL-4/interferon γ production from individual liver- derived autoantigen-specific T cell clones suggests that both T helper cell Th1- and Th2-like clones are present in the liver. Moreover, there was considerable heterogeneity in the T cell receptor for antigen (TCR) Vβ usage of these antigen-specific autoreactive T cell clones. This is in contrast to murine studies in which animals are induced to develop autoimmunity by specific immunization and have an extremely limited T cell Vβ repertoire. Thus, our data suggest that in human organ-specific autoimmune diseases, such as PBC, the TCR Vβ repertoire is heterogenous.

Original languageEnglish (US)
Pages (from-to)723-733
Number of pages11
JournalJournal of Experimental Medicine
Volume181
Issue number2
DOIs
StatePublished - Feb 1 1995

ASJC Scopus subject areas

  • Immunology

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