Comparative immunoreactivity of anti-trifluoroacetyl (TFA) antibody and anti-lipoic acid antibody in primary biliary cirrhosis: searching for a mimic.
Previous studies documenting the existence of cross-reactivity between the lipoated (but not unlipoated) forms of the inner lipoyl domain (E2L2) of PDC-E2 [the major autoantigen in Primary biliary cirrhosis (PBC)] and trifluoroacetylated (TFA) proteins, led us to hypothesize that PBC may be due to an initial insult with an environmental agent that cross-reacts with TFA. Therefore, we performed a comparative study of the reactivity of rabbit anti-TFA antibody and anti-lipoic acid (LA) antibody against the mitochondrial autoantigens of human PBC and various TFA and LA conjugated proteins. Whereas both anti-TFA and anti-LA reacted with PDC-E2, the wild-type lipoated form of E2L2, OGDC-E2, E3-BP and LA-KLH, neither reacted with BCOADC-E2 or the non-lipoated form of E2L2. Of interest was that while anti-TFA reacted with PDC-E2, TFA-RSA and LA-KLH, it failed to inhibit PDC-E2 enzyme function. In contrast, anti-LA demonstrated cytoplasmic and mitochondrial staining, and inhibited PDC enzyme activity. Hence, although considerable cross reactivity exists between anti-TFA and anti-LA, the molecular nature of the interaction is clearly different. One of 14 PBC sera reacted weakly with TFA-albumin, whereas four of 14 PBC sera reacted with LA-KLH. Immunohistochemically, both anti-TFA and anti-LA antibodies reacted focally with periportal hepatocytes and bile ducts in both PBC and controls. However, anti-LA produced much stronger focalized staining of the bile ducts of diseased liver. This study suggests that while anti-TFA antibody recognizes lipoic acid-linked enzymes and proteins, the epitope recognized differs from that of anti-LA antibody and PBC autoantibodies. It is unlikely that a response to TFA is the triggering event in PBC. Anti-LA antibodies share a higher degree of similarity to PBC sera providing suggestive evidence that anti-LA antibodies or anti-LA like antibodies (mimotopes) may help define the initiator of the autoimmune response.
Division of Rheumatology/Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
M
M
Sasaki
A
A
Ansari
N
N
Pumford
J
J
van de Water
P S
PS
Leung
K M
KM
Humphries
L I
LI
Szweda
Y
Y
Nakanuma
T E
TE
Roche
R L
RL
Coppel
J F
JF
Bach
M E
ME
Gershwin
D000818:Animals; D000937:Antigen-Antibody Reactions; D001323:Autoantibodies / Q000737:chemistry* / Q000378:metabolism*; D002417:Cattle; D003600:Cytosol / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D004791:Enzyme Inhibitors / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005463:Fluoroacetates; D006221:Halothane / Q000008:administration & dosage; D006241:Haptens / Q000276:immunology; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D007106:Immune Sera / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000201:enzymology / Q000276:immunology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018716:Molecular Mimicry / Q000276:immunology*; D008974:Mollusca; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D012709:Serum Albumin / Q000276:immunology; D008063:Thioctic Acid / Q000276:immunology*; D014269:Trifluoroacetic Acid / Q000276:immunology*
D001323:Autoantibodies; D004791:Enzyme Inhibitors; D005463:Fluoroacetates; D006241:Haptens; D007106:Immune Sera; D011768:Pyruvate Dehydrogenase Complex; D012709:Serum Albumin; C053344:trifluoroacetyl-serum albumin; D008063:Thioctic Acid; D006433:Hemocyanins; D014269:Trifluoroacetic Acid; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; C032808:keyhole-limpet hemocyanin; D006221:Halothane