Apoptosis-associated antigens recognized by autoantibodies in patients with the autoimmune liver disease primary biliary cirrhosis |
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Authors: | Christoph Peter Berg Gerburg Maria Stein Hildegard Keppeler Michael Gregor Sebastian Wesselborg Kirsten Lauber |
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Institution: | (1) Department of Internal Medicine I, Medical Clinic, Eberhard-Karls-University, Otfried-Mueller-Str. 10, 72076 Tuebingen, Germany |
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Abstract: | There is growing evidence that the onset of autoimmune disorders can be linked to the inefficient removal of apoptotic cells.
Since defects in the elimination of apoptotic cells lead to secondary necrosis and subsequent release of intracellular components,
this might explain the generation of autoantibodies against intracellular antigens. Accordingly, we wanted to investigate,
whether antibodies from patients with the autoimmune liver disease primary biliary cirrhosis (PBC) recognize self-proteins
generated and released during apoptosis. Using Western blot analyses we could detect intracellular antigens with serum IgG
from PBC patients but not with serum IgG from healthy donors in lysates of Jurkat T-leukemia, HepG2 hepatoma, and HT-29 colon-carcinoma
cells. Interestingly, PBC serum IgG also recognized caspase substrates in cells undergoing apoptosis induced by staurosporine
or TRAIL (TNF-related apoptosis inducing ligand). In addition to intracellular antigens, serum IgG from PBC patients detected
caspase-dependent antigens in the supernatants of apoptotic (secondary necrotic) cells and antigens on the surface of apoptotic
Jurkat cells. Among the caspase substrates recognized by PBC serum IgG we could identify the components PDC-E2 and -E1β of
the known autoantigen PDC (pyruvate dehydrogenase complex). Thus, caspase-mediated processing of intracellular proteins might
generate de novo autoantigens that upon release contribute to the generation of autoantibodies and autoimmune diseases as PBC.
Christoph Peter Berg and Gerburg Maria Stein contributed equally to this paper and share first authorship.
Sebastian Wesselberg and Kirsten Lauber share equal senior authorship. |
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Keywords: | Antibodies Apoptosis Autoimmunity Pyruvate dehydrogenase complex |
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