No abstract

Antimitochondrial autoantibodies were found to be present in sera of patients with AIH more frequently than expected, even at very low titer. However, clinical features and histological findings of AIH were not influenced by the AMA status.

It still remains unclear how antimitochondrial autoantibodies (AMA) are involved with immunopathogenesis of primary biliary cirrhosis (PBC). We have suggested the potential role of IgA-AMA in damage to epithelial cells in PBC. In the current study, we investigated whether IgA-AMA were detectable in sera and saliva of PBC patients, to examine the association between detectable IgA-type autoantibodies in sera or saliva and progression of liver diseases. Fifty-three patients with PBC were enrolled, and IgA-AMA in sera and saliva were sought by immunoblotting using pork heart mitochondria as antigens. The progression of PBC was determined as Scheuer's classification consisting of four histological stages. We found IgA-AMA, IgA-anti-PDC-E2, and IgA-anti-E3BP in 43/53 (81%), 37/53 (70%), and 35/53 (66%) sera of patients with PBC, but none of controls. The progression of PBC was statistically associated with presence of IgA-anti-PDC-E2 (P = 0.0124), but neither with IgA-AMA (P = 0.1296) nor anti-IgA-E3BP (P = 0.5973). In saliva, detectable IgA-AMA, IgA-anti-PDC-E2, and IgA-anti-E3BP were noted in 12/26 (46%), 6/26 (23%), and 11/26 (42%), respectively. Detection of IgA-anti-PDC-E2 was strongly associated with progression of PBC (P = 0.0002), whereas detection of IgA-AMA and IgA-anti-E3BP were not associated (P = 0.2145 and P = 0.5118). The current findings suggest that the presence of IgA-anti-PDC-E2 in sera or saliva might be associated with progression of PBC, although a prospective study with PBC patients with detectable IgA-anti-PDC-E2 at early stages will be required to conclude the contribution of IgA-anti-PDC-E2 to the progression of PBC.

To examine the genetics of susceptibility to primary biliary cirrhosis (PBC), genome-wide association studies GWAS have been performed in patients of European ancestry and have shown the significant associations of IL12-related pathways, SPIB, IRF5-TNPO3, and 17q12-21. We tested whether these findings could be extended to a Japanese cohort, 303 Japanese PBC and 298 controls. We failed to detect significant associations at IL12A (rs574808, rs1075498) and IL12RB2 (rs3790567). There was no genetic variance at IRF5-TNPO3 (rs10488631) in Japanese. A single nucleotide polymorphism (SNP) at SPIB (rs3745516) reached nominal significance, but the corrected P value did not reach significance. For the 17q12-21 region, two SNPs had nominally significant associations [GSDMB (rs2305480, P = 0.022) and ZPBP2 (rs11557467, P = 0.021)] and we noted a significant P value at a SNP in IKZF3 (rs939327, P = 0.0024, P(c) = 0.017) after correction for multiple comparisons. Thus, these results indicate a haplotype on 17q12-21 with a similar association in Japanese and European PBC.

A functional variant in the Fc receptor-like 3 (FCRL3) gene is associated with the susceptibility to several autoimmune diseases. In this study, we examined whether the FCRL3 is associated with susceptibility to primary biliary cirrhosis (PBC) by comparing the two different ethnic groups, Japanese and Italians. We enrolled 232 patients with PBC and 230 controls in Japanese, and 216 PBC and 180 controls in Italians. Minor allele frequency of fcrl3_3 (-169 T>C) in the patients with PBC and controls was 0.20 and 0.09 in Japanese and 0.24 and 0.21 in Italians, respectively. We found a significant association of fcrl3_3 with PBC only in Japanese (P = 9.64 × 10(-7) ). These findings support the presence of common FCRL3-related pathological pathways in several autoimmune diseases, especially in Asians.