HLA alleles are known to be associated with susceptibility to develop autoimmune hepatitis (AH), and hepatitis A virus (HAV) infection is postulated as a putative trigger for AH. We investigated whether HLA may influence the outcome of the HAV infection by studying 67 children with self-limited and 39 children with protracted forms of this infection. HLA typing of the uncomplicated forms showed no significant increase of any HLA class I or II alleles. In contrast, DRB1*1301 was present in 46.1% of the children with protracted forms (vs. 9.8% in healthy controls; relative risk [RR]: 7.6; 2 ‫؍‬ 33.3; P ‫؍‬ 2 ؋ 10 ؊9 ). In uncomplicated hepatitis, 45% developed anti-smooth muscle antibody (SMA)/actin antibodies, but only 1 child had detectable antibodies after 3 months of infection onset. In contrast, after 1 year, 69% of the patients suffering protracted forms had titers of anti-SMA/actin antibodies that ranged between 1:40 and 1:160. Within their follow-up, 2 patients developed a Hashimoto's thyroiditis, but the remaining patients showed no signs of developing autoimmune hepatitis. We conclude that the DRB1*1301 haplotype is strongly associated with the protracted forms of HAV infection and suggest that the infection allows a sustained release of liver self-antigens. However, other still-unknown susceptibility genes are required for the full development of pediatric AH. (HEPATOLOGY 2001;33:1512-1517

In natural killer cells, killer immunoglobulin-like receptors (KIRs) loci code for either inhibitory or activating receptors, and according to the number of genes present in each individual, it is possible to identify a high rate of polymorphism in the populations. We performed KIR typing by polymerase chain reaction-sequence-specific oligonucleotide probing in 402 Argentinean Caucasoid and in two Amerindian populations (101 Wichis and 54 Chiriguanos) from the North of Argentina. KIR2DL4, KIR3DL2, KIR3DL3 and KIR3DP1 were always present, whereas the frequencies of KIR2DL1, KIR2DL3, KIR2DS4, KIR3DL1 and KIR2DP1 ranged between 84% and 96%. The frequencies of KIR2DS2, KIR2DL2, KIR2DL5, KIR2DS5, KIR2DS1 and KIR3DS1 ranged between 41% and 62%. The KIR2DS3 with a frequency of 29% in Argentinean Caucasoid population was present at a very low frequency in Amerindian populations. Haplotype segregation studies performed in 10 Wichi families showed the presence of only three haplotypes: A, B5 and B1. The Amerindian populations showed several similarities to Asian but not to Caucasoid populations with regard to the frequency of KIR2DS3, full-length KIR2DS4 gene and KIR2DL4 alleles.

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We have previously reported a strong association between HLA-DRB1*1301 and type 1 pediatric autoimmune hepatitis (PAH) and between HLA-DR*0405 and adult autoimmune hepatitis (AAH). Because human killer cell immunoglobulin-like receptors are known to be associated with susceptibility to autoimmune diseases, we investigated the frequencies of HLA-A, B, C, DRB1 and KIR genes in 144 type 1 PAH and 86 AAH patients, which were compared with 273 healthy controls. We demonstrated in PAH the increased frequency of the functional form of KIR2DS4-Full Length (KIR2DS4-FL), which in combination with HLA-DRB1*1301 revealed a strong synergistic effect (odds ratio=36.5). PAH-KIR2DS4-FL+ subjects have shown an increased frequency of their putative HLA-C*02, 04 and 06 ligands. KIR analysis of PAH also revealed a decreased frequency of KIR2DL2 gene and its ligand. In contrast, AAH cases have shown a weaker increased frequency of KIR2DS4-FL, a lack of synergistic effect with HLA class II antigens and a moderate association with HLA-DRB1*0405. Of note, we demonstrated that liver T cells have a unique pattern of KIR expression. These results show a KIR gene involved in autoimmune hepatitis and suggest a stronger genetic influence for the early onset type I autoimmune hepatitis.