HETEROGENEITY OF AUTOREACTIVE T-CELL CLONES SPECIFIC FOR THE E2 COMPONENT OF THE PYRUVATE-DEHYDROGENASE COMPLEX IN PRIMARY BILIARY-CIRRHOSIS

The extraordinary specificity of bile duct destruction in primary bili ary cirrhosis (PBC) and the presence of T cell infiltrates in the port al tracts have suggested that biliary epithelial cells are the targets of an autoimmune response. The immunodominant antimitochondrial humor al response in patients with PBC is directed against the E2 component of pyruvate dehydrogenase (PDC-E2). Hitherto, there have only been lim ited reports on the characterization and V beta usage of PDC-E2-specif ic cloned T cell lines. In this study, we examined peripheral blood mo nonuclear 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 V beta usage of PDC-specific T cel l clones isolated from cellular infiltrates from the livers of PBC pat ients. We report that PBMC from 16/19 patients with PBC, but not 12 co ntrol patients, respond to the PDC-E2 subunit. Interestingly, this res ponse was directed to the inner and/or the outer lipoyl domains, despi te the serologic observation that the autoantibody response is directe d predominantly to the inner lipoyl domain. Additionally, lymphokine a nalysis of interleukin (IL) 2/IL-4/interferon gamma production from in dividual liver-derived autoantigen-specific T cell clones suggests tha t both T helper cell Th1- and Th2-like clones are present in the liver . Moreover, there was considerable heterogeneity in the T cell recepto r for antigen (TCR) V beta usage of these antigen-specific autoreactiv e T cell clones. This is in contrast to murine studies in which animal s are induced to develop autoimmunity by specific immunization and hav e an extremely limited T cell V beta repertoire. Thus, our data sugges t that in human organ-specific autoimmune diseases, such as PBC, the T CR V beta repertoire is heterogenous.