Heterogeneity of autoreactive t cell clones specific for the e2 component of the pyruvate dehydrogenase complex in primary biliary cirrhosis

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

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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 V3 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 El-and E2-specific components. We also examined the phenotype, lymphokine profile, and V3 usage of PDC-specific T cell clones 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 3' production from individual liver-derived autoantigen-specific T cell clones suggests that both T helper cell Thl-and Th2-1ike clones are present in the liver. Moreover, there was considerable heterogeneity in the T cell receptor for antigen (TCIk) V3 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 V-repertoire. Thus, our data suggest that in human organ-specific autoimmune diseases, such as PBC, the TClk V3 repertoire is heterogenous.

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

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