congresos y reuniones científicas
The most severe forms of type I autoimmune hepatitis are associated with genetically determinated levels of TGF-Ò1
N PALADINO, AC FLORES, A CHER&NTILDE;AVSKY, G CONSTANZO, L ARRUVITO, M CUARTEROLO, J GO&NTILDE;I, C GALOPPO, MC CA&NTILDE;ERO-VELASCO, D LEVI, H FAINBOIM, AND L FAINBOIM
Río de Janeiro, Brasil
Congreso; 15th Histocompatibility and Immunogenetics Conference; 2008
Type I autoimmune hepatitis (AH) is a progressive liver disease characterized by the presence of circulating anti-nuclear and/or anti-smooth muscle autoantibodies, hypergammaglobulinemia and by its response to immunosuppressive treatment. We previously reported that pediatric (PAH) and adult (AAH) forms have different HLA-associations, and clinical characteristics, in particular, PAH in spite of the requirement of higher dose of immunosuppression have a more severe outcome. TGF-b1 is an immunoregulatory cytokine, which through its potent fibrogenic capability was previously associated with liver fibrosis in AAH patients. We first investigated the mRNA levels of TGF-b1 by RT-PCR and Southern blot in liver biopsies form PAH and found that the expression of the TGF-b1 mRNA was clearly upregulated in untreated PAH samples when compared with control liver (PAH: 729 ¡Ó 172.20, n=11 vs. CL: 119.40 ¡Ó 48.74, n=7; p=0.014). Additionally we retrospectively analyzed in 101 PAH, 69 AAH and 183 control individuals the functional genetic polymorphisms of codon 25 (Arg25Pro) of TGF-b1 gene, by PCR-SSOP. In comparison with normal controls, PAH showed a strong significant decreased frequency of the low producer 25Pro allele (p=0.0011, OR=0.2, CI=0.07-0.54) that was even more significant when compared with AAH (p=0.0006, OR=0.16, CI=0.05-0.48). A similar retrospective analysis of the functional IL-10 promoter polymorphisms (positions: -1082A/G, -819A/C and -592A/C) in PAH, AAH and healthy controls, did not show differences in haplotype and genotype frequencies. In conclusion, these results provide support for an association between TGF-b1 and the observed more severe outcome in the pediatric forms of AH. Additionally, the genetic polymorphism analysis of IL-10 confirmed our previous report at the mRNA level, of the lack of association of this cytokine with the pathogenesis of AH.