TY - JOUR
T1 - Heterogeneity of autoreactive T cell clones specific for the E2 component of the pyruvate dehydrogenase complex in primary biliary cirrhosis
AU - Van de Water, Judith A
AU - Ansari, Aftab
AU - Prindiville, Thomas P
AU - Coppel, Ross L.
AU - Ricalton, Nancy
AU - Kotzin, Brian L.
AU - Liu, Shengjiang
AU - Roche, Thomas E.
AU - Krams, Sheri M.
AU - Munoz, Santiago
AU - Gershwin, M. Eric
PY - 1995/2/1
Y1 - 1995/2/1
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.181.2.723
DO - 10.1084/jem.181.2.723
M3 - Article
C2 - 7836925
AN - SCOPUS:0028936405
VL - 181
SP - 723
EP - 733
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 2
ER -