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Recognition of uridine diphosphate glucuronosyl transferases by LKM-3 antibodies in chronic hepatitis D
T Philipp1, M Durazzo, C Trautwein
1Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany.
Abstract:
Patients with chronic hepatitis D often have liver-kidney microsomal antibodies type 3 (LKM-3). These antibodies react with several microsomal antigens that have a molecular weight of 55 KDa and an isoelectric point of about 8. We studied the molecular nature of the antigen and, by immunoscreening a human liver cDNA expression library with KM-3 sera, found that uridine diphosphate glucuronosyl transferases (UGT) appeared as candidate antigens. We confirmed the identity of UGT as an antigen by reacting the sera with recombinant rabbit liver UGT proteins. Some sera reacted with rabbit UGT-2 proteins, but UGT-1 proteins were more sensitive and specific in detecting LKM-3 autoantibodies in patient sera. Anti-UGT-1 antibodies were detected in all LKM-3 positive sera from patients with hepatitis D and 1 out of 11 patients with autoimmune hepatitis type 2. Sera from patients who had hepatitis B only did not react with UGT proteins. The UGT proteins are part of the phase II enzymes of drug metabolism and are the first such enzymes to be identified as human autoantigens.
Insights
Patients with chronic hepatitis D frequently develop liver-kidney microsomal antibodies type 3 (LKM-3). This study identifies uridine diphosphate glucuronosyl transferases (UGT) as the specific autoantigens targeted by these antibodies.
Area of Science:
- Hepatology
- Immunology
- Biochemistry
Background:
- Chronic hepatitis D patients often exhibit liver-kidney microsomal antibodies type 3 (LKM-3).
- These LKM-3 antibodies target microsomal antigens with specific molecular weight and isoelectric point characteristics.
Purpose of the Study:
- To elucidate the molecular identity of the autoantigens recognized by LKM-3 antibodies.
- To investigate the role of uridine diphosphate glucuronosyl transferases (UGT) as potential LKM-3 autoantigens.
Main Methods:
- Immunoscreening of a human liver cDNA expression library using LKM-3 patient sera.
- Confirmation of antigen identity by testing sera against recombinant rabbit liver UGT proteins.
- Assessing the sensitivity and specificity of UGT-1 and UGT-2 in detecting LKM-3 autoantibodies.
Main Results:
- Uridine diphosphate glucuronosyl transferases (UGT) were identified as candidate antigens.
- Recombinant UGT proteins confirmed UGT as the target antigen for LKM-3 antibodies.
- Anti-UGT-1 antibodies were present in all LKM-3 positive hepatitis D sera and in one patient with autoimmune hepatitis type 2.
Conclusions:
- UGT proteins are identified as the specific autoantigens for LKM-3 antibodies.
- UGT-1 is a sensitive and specific marker for LKM-3 autoantibodies in hepatitis D.
- This discovery marks the first identification of phase II drug metabolism enzymes as human autoantigens.