Furthermore, the identification of alleles of the TNF-beta gene which differ in one unique amino acid, and in the production of TNF-beta after phytohaemagglutinin stimulation, has prompted the idea of a possible linkage between the impaired TNF-beta response in PBC and the genetic prevalence of a certain TNF haplotype.
A major issue in the study of the pathogenesis of primary biliary cirrhosis is whether the E2 subunit of the pyruvate dehydrogenase complex (PDH-E2), the major autoantigen in the disease, exists as a tissue-specific isoform. cDNA clones spanning a segment of the 3'-catalytic region of PDH-E2 (nt 1158-1361) have been isolated from human kidney, placenta and bile epithelium cells.
The restriction fragment length polymorphism of the two human HLA-B-associated transcripts (BATs) genes, BAT1 and BAT2, identifying polymorphic bands of 12, 8, 2.5, and 1.1 kb, and at 3.3, 2.7, 2.3, and 0.9 kb, respectively, was investigated in patients with primary biliary cirrhosis (PBC), systemic lupus erythematosus (SLE), pauciarticular juvenile rheumatoid arthritis (P-JRA), rheumatoid arthritis (RA), and primary Sjögren's syndrome (pSS), and in healthy Danes.
The associations between PBC and B8, DR3, DQA1*0501, and DQB1*0201, which are frequently found together on the same haplotype, are at variance with recent reports on associations between PBC and Drw8.
The following genetic markers were found with increased frequencies in PBC: HLA-B8 (relative risk, RR = 2.4, P less than 0.05, 'corrected' P greater than 0.05), HLA-DR3 (RR = 3.4, P less than 0.01, 'corrected' P less than 0.05), the DRB3*01/02/03 (DRw52) associated DRB Bgl II 9.1 kilobase (kb) fragment (RR = 2.9; P less than 0.05, 'corrected' P greater than 0.05), the DQA1*0501 associated DQA Taq I 4.8 kb fragment (RR = 3.1; P less than 0.05, 'corrected' P greater than 0.05), the DQB1*0201 (DQw2) associated DQB Hin dIII 11.5 kb fragment (RR = 3.1; P less than 0.05, 'corrected' P greater than 0.05).
Comparative analysis of amino acid sequences from DPB1 alleles indicated that a Leu at position 35 of the DPB1 chain likely contributes to the susceptibility to primary biliary cirrhosis among the Japanese.
Six human monoclonal IgG Fab clones (LC1-LC6) specific for the major autoantigen of PBC--dihydrolipoamide acetyltransferase, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2)--were isolated, appearing at a frequency of 0.01% in the combinatorial immunoglobulin library.
Studies were carried out to test the hypothesis that the GSTM1 null phenotype at the mu (mu) class glutathione S-transferase 1 locus is associated with an increased predisposition to primary biliary cirrhosis.
As the GSTM1 phenotype might be changed by the disease process, the polymerase chain reaction was used to amplify the exon 4-exon 5 region of GSTM1 and show that in 13 control subjects and 11 patients with primary biliary cirrhosis, GSTM1 positive and negative genotypes were associated with corresponding GSTM1 expressing and non-expressing phenotypes respectively.