ABSTRACT
Multiple genes are involved in susceptibility to autoimmune and infectious diseases. However, the human leucocyte antigen (HLA) immune response genes frequently contribute one of the strongest effects. This is the case for many of the diseases believed to have an autoimmune aetiology, including ankylosing spondylitis, which is strongly associated with particular HLA class I alleles, and Type 1 diabetes, associated with specific HLA class II alleles. The normal role of the HLA gene products in binding antigen and presenting it to T-lymphocytes offers clues as to the possible mechanisms underlying these disease associations. However,
> 30 years after the initial associations were first noted, we still lack definitive models to explain these disease mechanisms or to use as the basis for the design of rational, specific therapies. The impact of gene cloning and transgenesis technologies in this field allows the expression of disease-predisposing genes in transgenic mice in the hope of creating better disease models. Transgenic mice expressing HLA genes and other disease-associated molecules, including T-cell receptors and co-stimulatory molecules, can be used to explore models of disease susceptibility. These transgenics can thus be used for approaches that would be impossible using either cultured cells from human patients or normal laboratory mice. HLA-restricted epitopes can be defined from antigens implicated in the activation of pathogenic T-lymphocytes. Furthermore, the conditions leading to HLA-dependent induction of autoimmune disease can be dissected, leading to the design of specific therapies which are capable of blocking pathogenic immune responses without causing global immunosuppression. This approach has been used to
Objectives • Overview • Introduction • Human leucocyte antigen disease associations • Human leucocyte antigen transgenic mice • Conclusions • Glossary • References
investigate models of several diseases including ankylosing spondylitis, multiple sclerosis and Type 1 diabetes. As Human Genome Project initiatives offer further candidate disease genes of known or unknown function to be tested, these transgenic disease models should form an important starting baseline for experiments to build a composite picture of genetic susceptibility.
