The class II region of the MHC contains genes encoding molecules involved in antigen presentation. These molecules are found on the surface of circulating antigen presenting cells as well as epithelial cells of the thymus. Striking genetic associations have been reported for a number of chronic inflammatory disorders (see Fig. 12.4) but defining the causative gene or variant has proved difficult due to linkage disequilibrium and a paucity of knowledge about the underlying disease mechanism. However recent genetic and pathophysiological studies are providing insights into the relationship between possession of particular HLA alleles and individual disease risk. Of particular note are advances in our knowledge of the structural biology of the MHC class II molecules which are highlighting the importance of genetic diversity in defining the specificity of the peptide binding domain (Jones et al. 2006).
Although the molecular basis for the dramatic HLA association with susceptibility to narcolepsy (Box 12.7) is still incompletely understood, it is striking that two very similar MHC class II alleles, HLA-DQB1*0602 and DQB1*06011, should be strongly associated with risk and protection from the disorder, respectively, and that structural analysis of their respective peptide binding grooves should show specificity for peptides implicated in disease pathogenesis.
The occurrence of narcolepsy in dogs has provided a very important animal model to understand disease pathogenesis. Familial narcolepsy can be bred in Doberman pinschers and Labrador retrievers, comprising an autosomal recessive trait with full penetrance.
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