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Lookup NU author(s): Dr Jeremy Palmer, Dr Amanda Robe, Professor Alastair BurtORCiD, Emeritus Professor John Kirby, Professor David Jones
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The autoimmune liver disease primary biliary cirrhosis (PBC) is characterized by the breakdown of normal immune self tolerance to pyruvate dehydrogenase complex (PDC). How tolerance is broken to such a central and highly conserved self antigen in the initiation of autoimmunity remains unclear. One postulated mechanism is that reactivity arises to an altered form of self antigen with subsequent cross-reactivity to native self. In this murine study, we set out to examine whether sensitization with a covalently modified form of self PDC can give rise to the pattern of breakdown of B-cell and T-cell tolerance to self PDC seen in PBC patients. The notion that altered self can lead to tolerance breakdown was studied by sensitizing SJL/J mice with a covalently modified (biotinylated) preparation of self murine PDC (mP/O-B). Subsequently, antibody and T-cell reactivities to unmodified self mP/O were studied. Sensitization with mP/O-B elicited high-titre, high-affinity antibody responses reactive with both the mP/O-B immunogen and, importantly, native mP/O. In addition, significant MHC class II restricted splenic T-cell responses to native mP/O (i.e., true autoimmune responses) were seen in mP/O-B sensitized animals. The breakdown of T-cell self tolerance to mP/O was not seen in animals sensitized with irrelevant biotinylated antigens. In conclusion, this study provides evidence to support the concept that exposure to covalently modified self PDC can, in the correct proimmune environment, replicate the full breakdown of B-cell and T-cell immune tolerance to PDC seen in PBC. One potential etiological pathway in PBC therefore could be the breakdown of tolerance to self PDC occurring after exposure to self antigen covalently modified in the metabolically active environment of the liver.
Author(s): Palmer JM, Robe AJ, Burt AD, Kirby JA, Jones DEJ
Publication type: Article
Publication status: Published
Journal: Hepatology
Year: 2004
Volume: 39
Issue: 6
Pages: 1583-1592
ISSN (print): 0270-9139
ISSN (electronic): 1527-3350
Publisher: John Wiley & Sons, Inc.
URL: http://dx.doi.org/10.1002/hep.20248
DOI: 10.1002/hep.20248
PubMed id: 15185299
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