Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium.
Infectious and environmental agents have been proposed as immunologic triggers for primary biliary cirrhosis (PBC). Recently, a ubiquitous organism that metabolizes organic compounds and estrogens, Novosphingobium aromaticivorans, has been defined. Importantly, 2 bacterial proteins have homology with the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Sera from 97 patients with PBC, 46 first-degree relatives, 10 spouses, and 195 controls were studied for reactivity against N. aromaticivorans and Escherichia coli. The reactivity was defined by absorption, affinity purification, and using monoclonal antibodies to PDC-E2. Stool samples from 20 patients with PBC and 34 controls were analyzed by polymerase chain reaction (PCR) for the presence of N. aromaticivorans. Sera from 100% of anti-PDC-E2 positive (77/77), 33% of anti-BCOADC E2 positive (1/3), and 12% of antimitochondrial antibody (AMA) negative patients with PBC (2/17) reacted with titers up to 10(-6) against two known lipoylated bacterial proteins (47 and 50 kd) from N. aromaticivorans, including patients with early disease. This titer was approximately 100- to 1,000-fold higher than against E. coli and verified by absorption, use of affinity-purified sera, and monoclonal antibody reagents. Moreover, 78 of 80 AMA-positive and 5 of 17 AMA-negative patients with PBC had antibodies against 3 other N. aromaticivorans proteins. In contrast, 0 of 195 control sera reacted against N. aromaticivorans. Approximately 25% of patients and controls had N. aromaticivorans in their fecal specimens. In conclusion, based on protein homology, capacity to metabolize xenobiotics as well as modulate estrogens, its presence in feces, and specific immunologic response, we propose that N. aromaticivorans is a candidate for the induction of PBC.
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA.
Carlo
C
Selmi
David L
DL
Balkwill
Pietro
P
Invernizzi
Aftab A
AA
Ansari
Ross L
RL
Coppel
Mauro
M
Podda
Patrick S
PS
Leung
Thomas P
TP
Kenny
Judy
J
Van De Water
Michael H
MH
Nantz
Mark J
MJ
Kurth
M Eric
ME
Gershwin
D020561:Alphaproteobacteria / Q000276:immunology* / Q000302:isolation & purification / Q000378:metabolism*; D000595:Amino Acid Sequence / Q000235:genetics; D001424:Bacterial Infections / Q000150:complications; D001426:Bacterial Proteins / Q000235:genetics; D016022:Case-Control Studies; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D005243:Feces / Q000382:microbiology; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000276:immunology* / Q000382:microbiology*; D008297:Male; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D015262:Xenobiotics / Q000378:metabolism*
D001426:Bacterial Proteins; D011768:Pyruvate Dehydrogenase Complex; D015262:Xenobiotics; D051047:Dihydrolipoyllysine-Residue Acetyltransferase