Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease.
There have been important advances in defining effector mechanisms for several human autoimmune diseases. However, for most human autoimmune diseases, the induction stage is less well defined and there are very few clues on etiology. Our laboratory has focused on defining the molecular basis of autoantibody recognition and epitope modification in primary biliary cirrhosis (PBC). Our work has demonstrated that antibodies to mitochondria, the hallmark of disease, are directed against a very conserved site of pyruvate dehydrogenase, the E2 subunit of pyruvate dehydrogenase (PDC-E2). We have also demonstrated that several chemical xenobiotics, chosen based on quantitative structural activity relationship analysis and rigorous epitope analysis, when coupled to the lysine residue that normally binds the lipoic acid cofactor of PDC-E2, reacts as well or better to PBC sera than native autoantigen. In the present studies, we immunized C57BL/6 mice with one such xenobiotic, 2-octynoic acid, coupled to bovine serum albumin and we followed the mice for 24 weeks. Animals were studied for appearance of histologic lesions as well as appearance of antibodies to PDC-E2, serum levels of tumor necrosis factor-alpha and interferon-gamma, and splenic and liver lymphoid phenotyping by flow cytometry. Mice immunized with 2-octynoic acid manifest autoimmune cholangitis, typical mitochondrial autoantibodies, increased liver lymphoid cell numbers, an increase in CD8(+) liver infiltrating cells, particularly CD8(+) T cells that coexpress CD44, and finally an elevation of serum tumor necrosis factor-alpha and interferon-gamma.


CONCLUSIONS
these data provide a persuasive argument in favor of an environmental origin for human PBC.
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
Kanji
K
Wakabayashi
Zhe-Xiong
ZX
Lian
Patrick S C
PS
Leung
Yuki
Y
Moritoki
Koichi
K
Tsuneyama
Mark J
MJ
Kurth
Kit S
KS
Lam
Katsunori
K
Yoshida
Guo-Xiang
GX
Yang
Toshifumi
T
Hibi
Aftab A
AA
Ansari
William M
WM
Ridgway
Ross L
RL
Coppel
Ian R
IR
Mackay
M Eric
ME
Gershwin
D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D016516:CD4-CD8 Ratio; D002761:Cholangitis / Q000276:immunology* / Q000473:pathology; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000276:immunology*; D000939:Epitopes; D005229:Fatty Acids, Monounsaturated / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000187:drug effects*; D007114:Immunization; D007070:Immunoglobulin A / Q000096:biosynthesis / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood; D008099:Liver / Q000473:pathology; D008221:Lymphoid Tissue / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000276:immunology; D010641:Phenotype; D012710:Serum Albumin, Bovine / Q000276:immunology; D013154:Spleen / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015262:Xenobiotics / Q000276:immunology*
D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D005229:Fatty Acids, Monounsaturated; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D014409:Tumor Necrosis Factor-alpha; D015262:Xenobiotics; D012710:Serum Albumin, Bovine; C060855:2-octynoic acid; D007371:Interferon-gamma; D051047:Dihydrolipoyllysine-Residue Acetyltransferase