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Autoimmun Rev. 2011 Feb;10(4):189-93. doi: 10.1016/j.autrev.2010.09.024. Epub 2010 Oct 7.

Autoimmune hepatitis, HLA and extended haplotypes.

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1
Laboratório de Pediatria Clinica (LIM-36), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, São Paulo, Brazil.

Abstract

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease. Characteristic liver-infiltrating immune cells in portal and periportal areas, hypergammaglobulinemia and typical autoantibodies indicate an ongoing autoimmune reaction against liver self antigens, which lead to irreversible cellular damage and ultimately to severe hepatic failure. A significant part of adult, but not pediatric AIH patients, exhibit concurrent autoimmune diseases, further strengthening the immunological etiology of the disease. Genetic susceptibility to autoimmune hepatitis is strongly associated with HLA-DRB1 alleles. In Caucasian European and North American patients, AIH-1 is associated with the presence of DRB1*0301, DRB3*0101 and DRB1*0401 alleles, while AIH-2 is associated with DRB1*0301 or DRB1*07. In Brazil, the primary susceptibility allele for AIH-1 is DRB1*1301, but a secondary association with DRB1*0301 has also been identified. We looked for additional susceptibility factors in the extended MHC region. We genotyped 107 AIH-1 children and up to 326 healthy subjects for TNFA G-308A, TNFA G-238A, LTA A+252G, LTA A+80C, NFKBIL1 T-63A, BAT1 C-348T, BAT1 G-22C, MICA, and HLA-B polymorphisms. The TNFA-308 A allele was significantly increased in AIH-1 when compared with healthy controls, confirming data from other studies. Linkage disequilibrium analysis was carried out. The ancestral haplotype comprising TNFA-308A, TNFA-238G, LTA+252G, LTA+80C, NFKBIL1-63A, BAT1-348C, BAT1-22C, HLA-B*08, MICA*08 was more common in DRB1*03 positive patients than in controls (40% vs. 14%), showing a seven-fold increased risk for the disease [OR=7.8 (95%CI 2.04-29.9.2, p=0.0021). In contrast, the remaining patients carrying DRB1*03 exhibited varied haplotypes. Finally, a variety of class III haplotypes was also present in HLA-DRB1*13 patients, without a predominant pattern. The most common of the 98 haplotypes present in patients were completely absent in controls. The extended haplotype analysis in this sample of AIH-1 patients highlights not only the genetic diversity present in the Brazilian population, but is also in accordance with the previously documented microdiversity within the MHC region. The present knowledge of AIH suggests that the same or a very similar disease can be induced by yet unknown, but different, triggers followed by presentation on different HLA-DR molecules of the epitopes derived from the corresponding autoantigens, characterizing a much more complex disease than previously thought.

PMID:
20933106
DOI:
10.1016/j.autrev.2010.09.024
[Indexed for MEDLINE]
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