EVIDENCE FOR THE TARGETING BY 2-OXO-DEHYDROGENASE ENZYMES IN THE T-CELL RESPONSE OF PRIMARY BILIARY-CIRRHOSIS
Details
Publication Year 1991-01-01,Volume 146,Issue #1,Page 89-94
Journal Title
JOURNAL OF IMMUNOLOGY
Publication Type
Journal Article
Abstract
Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease that includes the presence of lymphoid infiltrates in portal tracts, high titer autoantibodies against pyruvate dehydrogenase-E2 (PDH-E2) and branched chain ketoacid dehydrogenase-E2 (BCKD-E2), and biliary tract destruction. The mechanism by which the autoimmune response is induced, the specificity of damage to the biliary epithelium, and the role of T cells in PBC are still unknown. To address these issues, we have taken advantage of a mouse mAb, coined C355.1, and studied its reactivity against a panel of liver tissue from normal subjects as well as a panel of liver specimens from patients with PBC, progressive sclerosing cholangitis, and chronic active hepatitis (CAH). C355.1, much like human autoantibodies to PDH-E2, reacts exclusively by immunoblotting with PDH-E2, binds to the inner lipoyl domain of the protein, and inhibits PDH-E2 activity in vitro. In addition, we have also attempted to develop cloned T cell lines that react with PDH-E2 and/or BCKD-E2 using liver biopsies from patients with PBC, compared with CAH. Although monoclonal C355.1 produced typical mitochondrial fluorescence on sections of normal liver, pancreas, lung, heart, thyroid, and kidney, it produced a distinct and intense reactivity when used to stain the bile ducts of patients with PBC. Nine of 13 PBC liver biopsies studied herein contained bile ducts on light microscopy, all of which reacted intensely at a 1:100 culture supernatant dilution of monoclonal C355.1. In contrast, although bile ducts of liver specimens from normals, CAH, and progressive sclerosing cholangitis also reacted with C355.1, such reactivity was exclusively mitochondrial and readily detectable only at a dilution of 1:2. More importantly, we generated CD4+, CD8-, alpha-beta-TCR+ cloned T cell lines from patients with PBC, but not from CAH, that produced IL-2 specifically in response to PDH-E2 or BCKD-E2.
Publisher
AMER ASSOC IMMUNOLOGISTS
Keywords
MITOCHONDRIAL AUTO-ANTIGEN; BILE-DUCT EPITHELIUM; HLA-DR ANTIGENS; DIHYDROLIPOAMIDE ACETYLTRANSFERASE; AUTOIMMUNE ENCEPHALOMYELITIS; DEHYDROGENASE COMPLEX; AUTOANTIBODIES; IMMUNIZATION; RECOGNITION; ANTIBODIES
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Creation Date: 1991-01-01 12:00:00
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