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 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 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 V beta 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 V beta 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 gamma 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) V beta 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 beta repertoire. Thus, our data suggest that in human organ-specific autoimmune diseases, such as PBC, the TCR V beta repertoire is heterogenous.
Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California Davis 95616.
J
J
Van de Water
A
A
Ansari
T
T
Prindiville
R L
RL
Coppel
N
N
Ricalton
B L
BL
Kotzin
S
S
Liu
T E
TE
Roche
S M
SM
Krams
S
S
Munoz
M E
ME
Gershwin
D000328:Adult; D000368:Aged; D015551:Autoimmunity; D002999:Clone Cells; D005260:Female; D006801:Humans; D008099:Liver / Q000276:immunology / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000201:enzymology / Q000276:immunology*; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D010641:Phenotype; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D011768:Pyruvate Dehydrogenase Complex; D011948:Receptors, Antigen, T-Cell