Abstract
Emerging evidence has suggested environmental factors as causative agents in the pathogenesis of primary biliary cirrhosis (PBC), We have hypothesized that in PBC the lipoyl domain of the immunodominant E2 component of pyruvate dehydrogenase (PDC-E2) is replaced by a chemical xenobiotic mimic, which is sufficient to break self-tolerance. To address this hypothesis, based upon our quantitative structure-activity relationship data, a total of 107 potential xenobiotic mimics were coupled to the lysine residue of the immunodominant 15 amino acid peptide of the PDC-E2 inner lipoyl domain and spotted on microarray slides. Sera from patients with PBC (n = 47), primary sclerosing cholangitis (n = 15), and healthy volunteers (n = 20) were assayed for Ig reactivity. PBC sera were subsequently absorbed with native lipoylated PDC-E2 peptide or a xenobiotically modified PDC-E2 peptide, and the remaining reactivity analyzed. Of the 107 xenobiotics, 33 had a significantly higher IgG reactivity against PBC sera compared with control sera. In addition, 9 of those 33 compounds were more reactive than the native lipoylated peptide. Following absorption, 8 of the 9 compounds demonstrated cross-reactivity with lipoic acid. One compound, 2-octynoic acid, was unique in both its quantitative structure-activity relationship analysis and reactivity. PBC patient sera demonstrated high Ig reactivity against 2-octynoic acid-PBC-E2 peptide. Not only does 2-octynoic acid have the potential to modify PDC-E2 in vivo but importantly it was/is widely used in the environment including perfumes, lipstick, and many common food flavorings.
| Original language | English |
|---|---|
| Pages (from-to) | 5874-5883 |
| Number of pages | 10 |
| Journal | Journal of Immunology |
| Volume | 174 |
| Issue number | 9 |
| Publication status | Published - May 1 2005 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology
Cite this
Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis : Identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid. / Amano, Katsushi; Leung, Patrick S C; Rieger, Roman; Quan, Chao; Wang, Xiaobing; Marik, Jan; Suen, Yat Fan; Kurth, Mark J.; Nantz, Michael H.; Ansari, Aftab A.; Lam, Kit S.; Zeniya, Mikio; Matsuura, Eiji; Coppel, Ross L.; Gershwin, M. Eric.
In: Journal of Immunology, Vol. 174, No. 9, 01.05.2005, p. 5874-5883.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis
T2 - Identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid
AU - Amano, Katsushi
AU - Leung, Patrick S C
AU - Rieger, Roman
AU - Quan, Chao
AU - Wang, Xiaobing
AU - Marik, Jan
AU - Suen, Yat Fan
AU - Kurth, Mark J.
AU - Nantz, Michael H.
AU - Ansari, Aftab A.
AU - Lam, Kit S.
AU - Zeniya, Mikio
AU - Matsuura, Eiji
AU - Coppel, Ross L.
AU - Gershwin, M. Eric
PY - 2005/5/1
Y1 - 2005/5/1
N2 - Emerging evidence has suggested environmental factors as causative agents in the pathogenesis of primary biliary cirrhosis (PBC), We have hypothesized that in PBC the lipoyl domain of the immunodominant E2 component of pyruvate dehydrogenase (PDC-E2) is replaced by a chemical xenobiotic mimic, which is sufficient to break self-tolerance. To address this hypothesis, based upon our quantitative structure-activity relationship data, a total of 107 potential xenobiotic mimics were coupled to the lysine residue of the immunodominant 15 amino acid peptide of the PDC-E2 inner lipoyl domain and spotted on microarray slides. Sera from patients with PBC (n = 47), primary sclerosing cholangitis (n = 15), and healthy volunteers (n = 20) were assayed for Ig reactivity. PBC sera were subsequently absorbed with native lipoylated PDC-E2 peptide or a xenobiotically modified PDC-E2 peptide, and the remaining reactivity analyzed. Of the 107 xenobiotics, 33 had a significantly higher IgG reactivity against PBC sera compared with control sera. In addition, 9 of those 33 compounds were more reactive than the native lipoylated peptide. Following absorption, 8 of the 9 compounds demonstrated cross-reactivity with lipoic acid. One compound, 2-octynoic acid, was unique in both its quantitative structure-activity relationship analysis and reactivity. PBC patient sera demonstrated high Ig reactivity against 2-octynoic acid-PBC-E2 peptide. Not only does 2-octynoic acid have the potential to modify PDC-E2 in vivo but importantly it was/is widely used in the environment including perfumes, lipstick, and many common food flavorings.
AB - Emerging evidence has suggested environmental factors as causative agents in the pathogenesis of primary biliary cirrhosis (PBC), We have hypothesized that in PBC the lipoyl domain of the immunodominant E2 component of pyruvate dehydrogenase (PDC-E2) is replaced by a chemical xenobiotic mimic, which is sufficient to break self-tolerance. To address this hypothesis, based upon our quantitative structure-activity relationship data, a total of 107 potential xenobiotic mimics were coupled to the lysine residue of the immunodominant 15 amino acid peptide of the PDC-E2 inner lipoyl domain and spotted on microarray slides. Sera from patients with PBC (n = 47), primary sclerosing cholangitis (n = 15), and healthy volunteers (n = 20) were assayed for Ig reactivity. PBC sera were subsequently absorbed with native lipoylated PDC-E2 peptide or a xenobiotically modified PDC-E2 peptide, and the remaining reactivity analyzed. Of the 107 xenobiotics, 33 had a significantly higher IgG reactivity against PBC sera compared with control sera. In addition, 9 of those 33 compounds were more reactive than the native lipoylated peptide. Following absorption, 8 of the 9 compounds demonstrated cross-reactivity with lipoic acid. One compound, 2-octynoic acid, was unique in both its quantitative structure-activity relationship analysis and reactivity. PBC patient sera demonstrated high Ig reactivity against 2-octynoic acid-PBC-E2 peptide. Not only does 2-octynoic acid have the potential to modify PDC-E2 in vivo but importantly it was/is widely used in the environment including perfumes, lipstick, and many common food flavorings.
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UR - http://www.scopus.com/inward/citedby.url?scp=20944443874&partnerID=8YFLogxK
M3 - Article
C2 - 15845458
AN - SCOPUS:20944443874
VL - 174
SP - 5874
EP - 5883
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 9
ER -