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Biology Articles » Genetics » Clinical Genetics » Genetics of inflammatory bowel disease: The role of the HLA complex » Classical HLA class II genes

Classical HLA class II genes
- Genetics of inflammatory bowel disease: The role of the HLA complex

 
The classical class HLA genes encode cell-surface glycoproteins which are expressed on antigen presenting cells, including dendritic cells and macrophages. Their major role is to present peptides to T cell receptors, as a prelude to T cell activation. There are three types of HLA Class molecules expressed by a single cell, namely HLA-DR, HLA-DQ and HLA-DP. These are each made up of ab heterodimers: the b chains are encoded by the DRB1, DQB1 and DPB1 genes respectively, all of which are highly polymorphic. The a chains for DPA and DQA are also highly polymorphic, while the DRA gene is invariant.  In addition, gene duplication events have occurred on certain haplotypes producing additional DRB3, 4 and 5 genes. When present, these are expressed at low levels in conjunction with the DRA chain.
 
The mechanism by which classical HLA class genes exert their influence in IBD is unclear, although a number of hypotheses have been postulated. Polymorphism in these molecules is concentrated around specific pockets of the binding groove that interact with critical side-chains or 'anchor' residues of a peptide. Thus different HLA molecules may bind preferentially to different peptides, or bind the same peptide with varying affinity. In IBD, cross reactivity (known as "molecular mimicry") may exist between the peptides derived from bacterial luminal flora and from self antigens present in the gut. This may lead to the generation of auto reactive T cells which contribute to disease pathogenesis through either stimulation or inhibition of the immune system. This mechanism is supported by identification of murine MHC-restricted CD4+ T cells reactive to enteric bacterial antigens that are able to induce colitis by adoptive transfer[13].
HLA-DRB1 is the most extensively studied gene in IBD. Convincing evidence of association has been described for a number of alleles, some of which confer risk, whilst others are protective. Many of these were highlighted in a 1999 meta-analysis of 29 association studies published between 1966 and 1998[14]. Since publication of this report, more detailed genotype-phenotype analyses of this locus have been conducted in larger, accurately characterised, patient cohorts leading to the realisation that genetic variation within this region may explain some of the disease heterogeneity of IBD. The most consistently replicated associations are described below.

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