Warning: Undefined variable $zfal in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 525
Deprecated: str_replace(): Passing null to parameter #3 ($subject) of type array|string is deprecated in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 525
Warning: Undefined variable $sterm in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 530
 free
Warning: Undefined variable $sterm in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 531
 free
 free
 
English Wikipedia
Nephropedia Template TP (
Twit Text
DeepDyve
Pubget Overpricing |  
lüll
Antimitochondrial antibody heterogeneity and the xenobiotic etiology of primary biliary cirrhosis Chen RC; Naiyanetr P; Shu SA; Wang J; Yang GX; Kenny TP; Guggenheim KC; Butler JD; Bowlus C; Tao MH; Kurth MJ; Ansari AA; Kaplan M; Coppel RL; Lleo A; Gershwin ME; Leung PSHepatology 2013[Apr]; 57 (4): 1498-508Antimitochondrial antibodies (AMAs) directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2) are detected in 95% of patients with primary biliary cirrhosis (PBC) and are present before the onset of clinical disease. The recent demonstration that AMAs recognize xenobiotic modified PDC-E2 with higher titers than native PDC-E2 raises the possibility that the earliest events involved in loss of tolerance are related to xenobiotic modification. We hypothesized that reactivity to such xenobiotics would be predominantly immunoglobulin M (IgM) and using sera from a large cohort of PBC patients and controls (n = 516), we examined in detail sera reactivity against either 6,8-bis(acetylthio) octanoic acid (SAc)-conjugated bovine serum albumin (BSA), recombinant PDC-E2 (rPDC-E2) or BSA alone. Further, we also defined the relative specificity to the SAc moiety using inhibition enzyme-linked immunosorbent assay (ELISA); SAc conjugate and rPDC-E2-specific affinity-purified antibodies were also examined for antigen specificity, isotype, and crossreactivity. Reactivity to SAc conjugates is predominantly IgM; such reactivity reflects a footprint of previous xenobiotic exposure. Indeed, this observation is supported by both direct binding, crossreactivity, and inhibition studies. In both early and late-stage PBC, the predominant Ig isotype to SAc is IgM, with titers higher with advanced stage disease. We also note that there was a higher level of IgM reactivity to SAc than to rPDC-E2 in early-stage versus late-stage PBC. Interestingly, this finding is particularly significant in light of the structural similarity between SAc and the reduced form of lipoic acid, a step which is similar to the normal physiological oxidation of lipoic acid. CONCLUSION: Specific modifications of the disulfide bond within the lipoic-acid-conjugated PDC-E2 moiety, i.e., by an electrophilic agent renders PDC-E2 immunogenic in a genetically susceptible host.|Antibodies, Anti-Idiotypic/*immunology[MESH]|Antibody Specificity[MESH]|Autoantigens/immunology[MESH]|Case-Control Studies[MESH]|Cholangitis, Sclerosing/blood/immunology[MESH]|Dihydrolipoyllysine-Residue Acetyltransferase/immunology[MESH]|Hepatitis, Autoimmune/blood/immunology[MESH]|Humans[MESH]|Immunoglobulin M/blood[MESH]|Liver Cirrhosis, Biliary/blood/*etiology/*immunology[MESH]|Mitochondria/*immunology[MESH]|Mitochondrial Proteins/immunology[MESH]|Recombinant Proteins/immunology[MESH]|Serum Albumin, Bovine/immunology[MESH]|Xenobiotics/*adverse effects[MESH] |
