Autoreactivity to Lipoate and a Conjugated Form of Lipoate in Primary Biliary Cirrhosis

Sylvaine F A Bruggraber, Patrick S Leung, Katsushi Amano, Chao Quan, Mark J. Kurth, Michael H. Nantz, Gordon D. Benson, Judith A Van de Water, Velimer Luketic, Thomas E. Roche, Aftab A. Ansari, Ross L. Coppel, M. Eric Gershwin

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Abstract

Background & Aims: Although considerable effort has been directed toward the mapping of peptide epitopes by autoantibodies, the role of nonprotein molecules has been less well studied. The immunodominant autoantigen in primary biliary cirrhosis (PBC), E2 components of pyruvate dehydrogenase complexes (PDC-E2), has a lipoate molecule bonded to the domain to which autoantibodies are directed. Methods: We examined sera from patients with PBC (n = 105), primary sclerosing cholangitis (n = 70), and rheumatoid arthritis (n = 28) as well as healthy volunteers (n = 43) for reactivity against lipoic acid. The lipoic acid hapten specificity of the reactive antibodies in PBC sera was determined following incubation of aliquots of the sera with human serum albumin (HSA), lipoylated HSA (HSA-LA), PDC-E2, lipoylated PDC-E2, polyethylene glycol (PEG), lipoylated PEG, free lipoic acid, and synthetic molecular mimics of lipoic acid. Results: Anti-lipoic acid specific antibodies were detected in 81% (79 of 97) of antimitochondrial antibody (AMA)-positive patients with PBC but not in controls. Two previously unreported specificities in AMA-positive sera that recognize free lipoic acid and a carrier-conjugated form of lipoic acid were also identified. Conclusions: We hypothesize that conjugated form(s) of native or xenobiotic lipoic acid mimics contribute to the initiation and perpetuation of autoimmunity by at first breaking self-tolerance and participating in subsequent determinant spreading. The variability in the immunoreactive carrier/lipoate conjugates provides an experimental framework on which potential mechanisms for the breakdown of self-tolerance following exposure to xenobiotics can be investigated. The data have implications for patients taking lipoic acid as a dietary supplement.

Original languageEnglish (US)
Pages (from-to)1705-1713
Number of pages9
JournalGastroenterology
Volume125
Issue number6
DOIs
StatePublished - Dec 2003

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Thioctic Acid
Biliary Liver Cirrhosis
Self Tolerance
Xenobiotics
Serum
Serum Albumin
Autoantibodies
Antibodies
Dihydrolipoyllysine-Residue Acetyltransferase
Epitope Mapping
Sclerosing Cholangitis
Peptide Mapping
Antibody Specificity
Haptens
Autoantigens
Dietary Supplements
Autoimmunity
Rheumatoid Arthritis
Healthy Volunteers

ASJC Scopus subject areas

  • Gastroenterology

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Autoreactivity to Lipoate and a Conjugated Form of Lipoate in Primary Biliary Cirrhosis. / Bruggraber, Sylvaine F A; Leung, Patrick S; Amano, Katsushi; Quan, Chao; Kurth, Mark J.; Nantz, Michael H.; Benson, Gordon D.; Van de Water, Judith A; Luketic, Velimer; Roche, Thomas E.; Ansari, Aftab A.; Coppel, Ross L.; Gershwin, M. Eric.

In: Gastroenterology, Vol. 125, No. 6, 12.2003, p. 1705-1713.

Research output: Contribution to journalArticle

Bruggraber, SFA, Leung, PS, Amano, K, Quan, C, Kurth, MJ, Nantz, MH, Benson, GD, Van de Water, JA, Luketic, V, Roche, TE, Ansari, AA, Coppel, RL & Gershwin, ME 2003, 'Autoreactivity to Lipoate and a Conjugated Form of Lipoate in Primary Biliary Cirrhosis', Gastroenterology, vol. 125, no. 6, pp. 1705-1713. https://doi.org/10.1053/j.gastro.2003.09.034
Bruggraber, Sylvaine F A ; Leung, Patrick S ; Amano, Katsushi ; Quan, Chao ; Kurth, Mark J. ; Nantz, Michael H. ; Benson, Gordon D. ; Van de Water, Judith A ; Luketic, Velimer ; Roche, Thomas E. ; Ansari, Aftab A. ; Coppel, Ross L. ; Gershwin, M. Eric. / Autoreactivity to Lipoate and a Conjugated Form of Lipoate in Primary Biliary Cirrhosis. In: Gastroenterology. 2003 ; Vol. 125, No. 6. pp. 1705-1713.
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abstract = "Background & Aims: Although considerable effort has been directed toward the mapping of peptide epitopes by autoantibodies, the role of nonprotein molecules has been less well studied. The immunodominant autoantigen in primary biliary cirrhosis (PBC), E2 components of pyruvate dehydrogenase complexes (PDC-E2), has a lipoate molecule bonded to the domain to which autoantibodies are directed. Methods: We examined sera from patients with PBC (n = 105), primary sclerosing cholangitis (n = 70), and rheumatoid arthritis (n = 28) as well as healthy volunteers (n = 43) for reactivity against lipoic acid. The lipoic acid hapten specificity of the reactive antibodies in PBC sera was determined following incubation of aliquots of the sera with human serum albumin (HSA), lipoylated HSA (HSA-LA), PDC-E2, lipoylated PDC-E2, polyethylene glycol (PEG), lipoylated PEG, free lipoic acid, and synthetic molecular mimics of lipoic acid. Results: Anti-lipoic acid specific antibodies were detected in 81{\%} (79 of 97) of antimitochondrial antibody (AMA)-positive patients with PBC but not in controls. Two previously unreported specificities in AMA-positive sera that recognize free lipoic acid and a carrier-conjugated form of lipoic acid were also identified. Conclusions: We hypothesize that conjugated form(s) of native or xenobiotic lipoic acid mimics contribute to the initiation and perpetuation of autoimmunity by at first breaking self-tolerance and participating in subsequent determinant spreading. The variability in the immunoreactive carrier/lipoate conjugates provides an experimental framework on which potential mechanisms for the breakdown of self-tolerance following exposure to xenobiotics can be investigated. The data have implications for patients taking lipoic acid as a dietary supplement.",
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AU - Bruggraber, Sylvaine F A

AU - Leung, Patrick S

AU - Amano, Katsushi

AU - Quan, Chao

AU - Kurth, Mark J.

AU - Nantz, Michael H.

AU - Benson, Gordon D.

AU - Van de Water, Judith A

AU - Luketic, Velimer

AU - Roche, Thomas E.

AU - Ansari, Aftab A.

AU - Coppel, Ross L.

AU - Gershwin, M. Eric

PY - 2003/12

Y1 - 2003/12

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AB - Background & Aims: Although considerable effort has been directed toward the mapping of peptide epitopes by autoantibodies, the role of nonprotein molecules has been less well studied. The immunodominant autoantigen in primary biliary cirrhosis (PBC), E2 components of pyruvate dehydrogenase complexes (PDC-E2), has a lipoate molecule bonded to the domain to which autoantibodies are directed. Methods: We examined sera from patients with PBC (n = 105), primary sclerosing cholangitis (n = 70), and rheumatoid arthritis (n = 28) as well as healthy volunteers (n = 43) for reactivity against lipoic acid. The lipoic acid hapten specificity of the reactive antibodies in PBC sera was determined following incubation of aliquots of the sera with human serum albumin (HSA), lipoylated HSA (HSA-LA), PDC-E2, lipoylated PDC-E2, polyethylene glycol (PEG), lipoylated PEG, free lipoic acid, and synthetic molecular mimics of lipoic acid. Results: Anti-lipoic acid specific antibodies were detected in 81% (79 of 97) of antimitochondrial antibody (AMA)-positive patients with PBC but not in controls. Two previously unreported specificities in AMA-positive sera that recognize free lipoic acid and a carrier-conjugated form of lipoic acid were also identified. Conclusions: We hypothesize that conjugated form(s) of native or xenobiotic lipoic acid mimics contribute to the initiation and perpetuation of autoimmunity by at first breaking self-tolerance and participating in subsequent determinant spreading. The variability in the immunoreactive carrier/lipoate conjugates provides an experimental framework on which potential mechanisms for the breakdown of self-tolerance following exposure to xenobiotics can be investigated. The data have implications for patients taking lipoic acid as a dietary supplement.

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