Immunization with a xenobiotic 6-bromohexanoate bovine serum albumin conjugate induces antimitochondrial antibodies.
The E2 subunit of pyruvate dehydrogenase complex (PDC-E2) is the major autoantigen recognized by antimitochondrial Abs (AMA) in primary biliary cirrhosis (PBC). Recently, we replaced the lipoic acid moiety of PDC-E2 with a battery of synthetic structures designed to mimic a xenobiotically modified lipoyl hapten on a 12-aa peptide that was found within the immunodominant autoepitope of PDC-E2 and demonstrated that AMA in PBC reacted against several organic modified mimotopes as well as, or sometimes significantly better than, the native lipoyl domain. Based on this data, we immunized rabbits with one such xenobiotic organic compound, 6-bromohexanoate, coupled to BSA. One hundred percent of immunized rabbits developed AMA that have each and every characteristic of human AMAs with reactivity against PDC-E2, E2 subunit of branched chain 2-oxo-acid dehydrogenase, and E2 subunit of 2-oxoglutarate dehydrogenase complex. The rabbit AMA also inhibited enzymatic function of PDC-E2 and, importantly, binds to peptide sequences not present in the xenobiotic carrier immunogen. In contrast, BSA-immunized controls did not produce such activity. Our observation that animals immunized with a xenobiotic BSA complex produce autoantibodies that react not only with the xenobiotic, but also with mitochondrial autoantigens recognized by autoimmune PBC sera, suggests that environmental xenobiotic agents can be a risk factor for the induction of PBC.
Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA 95616, USA.
Patrick S C
PS
Leung
Chao
C
Quan
Ogyi
O
Park
Judy
J
Van de Water
Mark J
MJ
Kurth
Michael H
MH
Nantz
Aftab A
AA
Ansari
Ross L
RL
Coppel
Kit S
KS
Lam
M Eric
ME
Gershwin
D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood / Q000502:physiology; D001324:Autoantigens / Q000276:immunology; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D000939:Epitopes / Q000097:blood / Q000276:immunology; D005260:Female; D006241:Haptens / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000008:administration & dosage / Q000276:immunology*; D007114:Immunization / Q000379:methods; D008105:Liver Cirrhosis, Biliary / Q000201:enzymology / Q000276:immunology; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism; D018716:Molecular Mimicry / Q000276:immunology; D011768:Pyruvate Dehydrogenase Complex / Q000032:analysis / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology; D011817:Rabbits; D017634:Self Tolerance; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000276:immunology*; D015262:Xenobiotics / Q000008:administration & dosage / Q000276:immunology*
D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D006241:Haptens; D006842:Hydrocarbons, Brominated; D011768:Pyruvate Dehydrogenase Complex; D015262:Xenobiotics; D012710:Serum Albumin, Bovine; D051047:Dihydrolipoyllysine-Residue Acetyltransferase