Autoreactivity to lipoate and a conjugated form of lipoate in primary biliary cirrhosis.
OBJECTIVE
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.
Bruggraber
Sylvaine F A
SF
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis Medical School, 95616, USA.
Leung
Patrick S C
PS
Amano
Katsushi
K
Quan
Chao
C
Kurth
Mark J
MJ
Nantz
Michael H
MH
Benson
Gordon D
GD
Van de Water
Judy
J
Luketic
Velimer
V
Roche
Thomas E
TE
Ansari
Aftab A
AA
Coppel
Ross L
RL
Gershwin
M Eric
ME
D000818:Animals; D000906:Antibodies / Q000097:blood*; D015551:Autoimmunity; D000939:Epitopes; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000097:blood; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology; D011817:Rabbits; D012709:Serum Albumin / Q000276:immunology; D008063:Thioctic Acid / Q000276:immunology*
D000906:Antibodies; D000939:Epitopes; D007132:Immunoglobulin Isotypes; D011768:Pyruvate Dehydrogenase Complex; D012709:Serum Albumin; D008063:Thioctic Acid; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin