Abstract
Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces anti-mitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl moiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 209-216 |
| Number of pages | 8 |
| Journal | Journal of Autoimmunity |
| Volume | 37 |
| Issue number | 3 |
| DOIs | |
| State | Published - Nov 2011 |
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Keywords
- Anti-mitochondrial antibodies
- Primary biliary cirrhosis
- Pyruvate dehydrogenase
- Xenobiotics
ASJC Scopus subject areas
- Immunology
- Immunology and Allergy
Cite this
Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity. / Naiyanetr, Phornnop; Butler, Jeffrey D.; Meng, Liping; Pfeiff, Janice; Kenny, Thomas P.; Guggenheim, Kathryn G.; Reiger, Roman; Lam, Kit; Kurth, Mark J.; Ansari, Aftab A.; Coppel, Ross L.; López-Hoyos, Marcos; Gershwin, M. Eric; Leung, Patrick S.
In: Journal of Autoimmunity, Vol. 37, No. 3, 11.2011, p. 209-216.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity
AU - Naiyanetr, Phornnop
AU - Butler, Jeffrey D.
AU - Meng, Liping
AU - Pfeiff, Janice
AU - Kenny, Thomas P.
AU - Guggenheim, Kathryn G.
AU - Reiger, Roman
AU - Lam, Kit
AU - Kurth, Mark J.
AU - Ansari, Aftab A.
AU - Coppel, Ross L.
AU - López-Hoyos, Marcos
AU - Gershwin, M. Eric
AU - Leung, Patrick S
PY - 2011/11
Y1 - 2011/11
N2 - Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces anti-mitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl moiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC.
AB - Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces anti-mitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl moiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC.
KW - Anti-mitochondrial antibodies
KW - Primary biliary cirrhosis
KW - Pyruvate dehydrogenase
KW - Xenobiotics
UR - http://www.scopus.com/inward/record.url?scp=80755133531&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80755133531&partnerID=8YFLogxK
U2 - 10.1016/j.jaut.2011.06.001
DO - 10.1016/j.jaut.2011.06.001
M3 - Article
C2 - 21763105
AN - SCOPUS:80755133531
VL - 37
SP - 209
EP - 216
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
SN - 0896-8411
IS - 3
ER -