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.

Elevated levels of interleukin 10 (IL-10) were previously described for chronically hepatitis C virus (HCV)-infected patients. We determined by a sequence-specific oligonucleotide probing technique the IL-10 promoter genotypes in 286 Argentinean HCV patients grouped according to disease outcome. The GG genotype (position ؊1082) is known to be associated with high IL-10 production, GA is considered an intermediate producer, and AA is associated with low IL-10 production. We found an increase in frequency of the GG genotype in female patients who do not eliminate the virus (RNA ؉ ). In these patients, the GG frequency was 0.19, versus 0.10 in controls (P ‫؍‬ 0.03). This association became more significant in those RNA ؉ female patients with elevated hepatic transaminases (GG frequency of 0.25; P ‫؍‬ 0.0013). Additionally, this genotype frequency was higher in noncirrhotic female patients than in controls (GG frequency for noncirrhotic female patients was 0.31; P ‫؍‬ 0.009). In RNA ؊ patients, the GA frequency was elevated compared with that in controls (GA frequency of 0.76 in RNA ؊ patients versus 0.48 in controls; P ‫؍‬ 0.01), that in all HCV patients (GA frequency of 0.43; P ‫؍‬ 0.001), and that in RNA ؉ patients (GA frequency of 0.40; P ‫؍‬ 0.0005). We conclude that a gender effect is observed with women carrying the GG high IL-10 producer genotype. The higher levels of IL-10 present in those individuals are associated with a higher risk of an inefficient clearance of the HCV and the development of a chronic HCV infection together with a lower risk of progression to cirrhosis in female patients.

This study was designed to investigate the role of killer immunoglobulin-like receptor (KIR) genes in the outcome of hepatitis C virus (HCV) infection. In patients who cleared the virus (HCV RNA-) we found a decrease of 2DL2 (P= 0.04), and 2DS2 (P= 0.014) accompanied by an increase of 2DS5 (P= 0.04). Those RNA+ patients with elevated levels of hepatic transaminases (HCV RNA+ elevated alanine aminotransferase) showed an increased frequency of 2DS3 (P= 0.018). Additionally, in cirrhotic patients we found an increased frequency of individuals having two copies of 3DS1 and HLA-Bw4 (P= 0.016). We conclude that higher natural killer cytotoxicity might be associated with a worse progression of the HCV infection.

No abstract

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.

The South American group of rodents known as Graomys griseoflavus comprises two sibling species differing only in diploid chromosomal complement: G. griseoflavus (2n = 36, 37 and 38) and G. centralis (2n=42). Reproductive barriers comprising postzygotic as well as precopulatory mechanisms prevent gene exchange between these species. We have studied genetic polymorphism in two populations of G. centralis and four of G. griseoflavus by means of gel electrophoresis of enzymes and other proteins giving information on a total of 30 loci. Values of interspecific genetic identity were similar to those obtained for conspecific populations, suggesting that fixation of Robertsonian fusions would have occurred without significant bottlenecks. It would also indicate that the cladogenetic process must be relatively recent. FIS values showed no evidence of inbreeding. Fixation indices (FST) for the ancestral species showed a tendency to form demes with very low gene flow among them, while in the derived species such tendency was not shown. However, because of the characteristics of the region they occupy, populations are of moderate size, and genic flow is low. Lack of correlation between gene flow levels and geographical distance between population pairs would indicate a recent and fast colonization of its distribution areas by the derived species. It is possible that fixation of Robertsonian fusions occurred in a marginal deme of the ancestral species, e.g. in a parapatric geographical context.

Graomys griseoflavus is a South American murid rodent showing a high degree of chromosomal polymorphism. We have recently demonstrated that cytotypes 2n = 36-38 form a complex reproductively isolated from the kariomorph 2n = 42, and that they may be considered separate species. Given the importance of olfactory perception for precopulatory recognition, we have investigated the ability of G. griseoflavus females to distinguish between odiferous stimuli from conspecific and heterospecific males by means of olfactory discrimination tests. Results show that females are able to recognize olfactory stimuli from males of compatible chromosome complement and those from males with whom they would not produce viable descendants or would produce sterile hybrids. This discrimination ability is only evident during the estrus phase, suggesting that this capacity is related to the precopulatory recognition and could act as a premating reproductive isolation mechanism. o 1996 Wiley-Liss, Inc.The South American murid rodent Graomys griseoflavus shows a high degree of chromosomal polymorphism (Ortells et al., '89; Zambelli et al., '94). Chromosome complements 2n = 36, 37, 38, and 42 have been found in individuals which so far had been considered members of a single species (Wainberg and Gentile de Fronza, '74; Pearson and Patton, '76; Zambelli et al., '94). Different karyomorphs are morphologically indistinguishable. In Argentina citotypes 2n = 36, 37, and 38 cohabit in the phytogeographic area known as "monte." Although individuals 2n = 42 are found preferentially in the phytogeographic region designated "espinal'' (Fig. l), their distribution area overlaps with that of 2n = 36-38 in borderlands.Allozymic analysis of different populations of Graomys griseoflavus showed that the cytotypes 2n = 42 and those 2n = 36-38 have undergone almost no divergence from the point of view of structural genes (Theiler and Gardenal, '94). Ge- This is an example of speciation through sequential chromosomal rearrangements.It has been observed that the 2n = 36, 37, and 38 cytotypes are interfertile, belonging to a single species complex (Theiler and Blanco, '96).Crosses performed in the laboratory between 2n = 42 females and 2n = 36-38 males were unproductive, while 95% of the reciprocal crosses produced viable but sterile hybrids. These hybrids, with 2n = 40 or 39, could not be found in field populations in regions where the distribution areas of the species 2n = 42 and 2n = 36-38 overlap (Theiler and Blanco, '96). This suggests that hybrids are not produced or are very rare in natural conditions. Thus, it is possible that some mechanism of premating reproductive isolation prevents interspecific crosses.Given the importance of the olfactory perception for precopulatory recognition between members of the same and related species (Bowers and Alexander, '67; Doty, '73; Moore, '65; Nevo et al., '76; Nevo and Heth, '76; Parkes and Bruce, '61; Smith, '65), we have investigated the ability of