HLA and autoimmune hepatitis

The human major histocompatibility (MHC) genomic region at chromosomal position 6p21.3 encodes the human leucocyte antigens (HLA) and many other genes necessary for immune regulation and has been associated with over 100 diseases including various autoimmune disorders, one of which is autoimmune hepatitis (AIH) (1). Investigation of the genetics of complex diseases is increasingly sophisticated: there are many candidate genes of potential interest and, because of their key role in antigen presentation and protein recognition, HLA antigens are clearly important genes to study. Involvement of the HLA system in disease susceptibility, phenotype or progression is considered when one or more of the HLA alleles are found to be statistically significantly and reliably increased or decreased when compared with a control group. However, how many of the HLA associations contribute to the disease processes in AIH remain poorly understood; it is thought that it may relate to the amino-acid sequence encoded by the HLA at the antigen presenting site (1, 2). Those molecules encoded by the HLA are thought to be essential elements in the formation of the ‘immune synapse’ presenting antigens for T cell activation and immune responses (1, 3). AIH is a syndrome and defined by a cluster of clinical, biochemical, immunological and histological features. AIH may, therefore, represent a group of diseases, with different triggers (and many viruses have been suggested as triggers) and different natural histories. However, it is a genetically complex disease with a poorly understood aetiology and is characterised by female predominance, interface hepatitis, hypergammaglobulinaemia and high titre auto-antibodies (2, 5). Although the International Autoimmune Hepatitis Group recommended that there is insufficient data to subtype the condition, most clinicians classify AIH into three subgroups: type 1 AIH, the commonest form, is associated with antinuclear antibodies (ANA) and/or smooth muscle antibodies (SMA), affecting all age groups and is associated with HLA. Type 2 affects mostly children and is characterised by antibodies to liver kidney microsome type 1 (LKM1); and type 3 AIH which is the least established form of the disease is associated with soluble liver antigens (SLA) (5, 6). Among white northern European and Americans there is a well-recognised association between increased susceptibility to AIH and inheritance of HLA DR3 and HLA DR4 (later identified as DRB10301 and DRB10401, respectively) (2–4). The HLA alleles are thought to influence disease expression and also susceptibility (5) with DR3 being associated with younger patients with a higher rate of treatment failure, relapse after treatment withdrawal and liver transplantation (3, 5). DR4 is thought to be associated with a milder disease form seen in older patients which is easier to treat (3, 5). Both the prevalence and the genetic associations vary geographically: it is as yet uncertain whether there is a genetic variability between the different subtypes of AIH. Currently the treatment options for AIH remain the same for all patients irrespective of their subtypes or HLA associations. However, these associations may help shed light on the pathogenesis of disease and offer clues to treatment: translation of data from alleles into aminoacid sequences can lead to models for disease susceptibility/resistance as has been performed for, for instance, Type 1 diabetes (7). Donaldson (8) has suggested three different models: one, for Type 1 AIH is dependent on histidine or other basic amino acid residues at position 13 of the DRb polypeptide; the second is based on the amino acid residue LLEQKR at positions 67–72 of the DRb polypeptide and the third model is based on valine/glycine dimorphism at position 86 (8). Genetic factors account for only a proportion of the disease susceptibility and not all patients with AIH have either DR3 or 4. In this issue, Czaja et al. (9) publish a paper to assess the importance of HLADR13 in those patients with type 1 AIHwho lack DR3 and DR4. Their hypothesis is that in those individuals who are negative for both DR3 and DR4 there is a higher incidence of HLA DR13 when compared with a control group and that this group of patients responds differently to treatment with corticosteroids. Liver International 2006: 26: 509–511 r 2006 The Author Journal compilation r 2006 Blackwell Munksgaard