|Budget Amount *help
¥2,000,000 (Direct Cost : ¥2,000,000)
Fiscal Year 1994 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1993 : ¥1,300,000 (Direct Cost : ¥1,300,000)
With respect to immunogenetic backgrounds, the association of primary biliary cirrhosis (PBC) with major histocompatibility complex (MHC) antigens has been controversial. Recently, a strong association of PBC with HLA DR8 has been reported in Caucasians and Japanese. Furthermore, an association between PBC and immunoregulatory alleles including TNFalpha, C4B2, and B-associated transcript, which are located in the vicinity of the MHC genes, has been also reported in Caucasians. We investigated MHC genes and its vicinity in Japanese PBC,including HLA DRB1, B3, B4, B5, DQA1 and B1, TNFalpha, gamma and transporter associated with antigen processing (TAP2).
[Methods] Genotypes of HLA DRB,DQA,and DQB were determined by PCR-SSOP method. Polymorphism of TNFalpha was investigated by restriction fragment length polymorphism (RFLP) with Ncol. The Ile * Val substitution at position 379 in the transmembrane domain of TAP2 was determined by PCR-SSO analysis.
[Results] (1) Gene frequency of the DRB1^*0
803 was significantly increased in patients with PBC (gf : 35.5%, relative risk : 6.84, p<0.0001). DRB1^*0803 showed, however, no association with any clinical or laboratory findings includings histological stages, major symptoms (jaundice and/or pruritus), and AMA titers. DQA1^*0103 and DQB1^*0601 were also increased in PBC due to strong linkage disequilibrium with DRB1^*0803 on the same haplotype. In contrast, DQA1^*0102 was significantly less frequent (p<0.05). (2) Differing from the published observation from Danish PBC,the significant decreased frequency of the 10.5kb Ncol fragment of TNFalpha was not found in Japnaese PBC.(3) No significant differences in the amino acid substitution of TAP2 were not observed between PBC and normal controls.
[Conclusions] HLA DRB1^*0803 itself may be the primary gene responsible for predisposition to PBC among Japanese individuals. In the context of antigen presentation and recognition through HLA class II antigens, identification of target antigens on biliary epithelial cells and analysis of cellular interaction through DRB1^*0803 will be important. Less