ADVANCES IN THE IMMUNOGENETICS OF CELIAC-DISEASE - CLUES FOR UNDERSTANDING THE PATHOGENESIS AND DISEASE HETEROGENEITY

Recent studies using the technique of the human genome screening in fa milies with multiple siblings suffering from coeliac disease have sugg ested the presence of at least four different chromosomes in the predi sposition to suffer from coeliac disease. Two loci in chromosome 6 app ear to be important in disease susceptibility. Other studies based on cytokine gene polymorphisms have found a strong association with a par ticular haplotype in the TNF locus. This haplotype carries a gene for a high secretor phenotype of TNF alpha. The finding may be important i n understanding the heterogeneity of inflammatory response. Evidence h as been presented in favour of a predominantly Th1 pattern of cytokine production by the coeliac disease associated HLA-DQ restricted T cell clones. HLA-DQ2 and -DQ8 restricted gliadin-specific T cells have bee n shown to produce IFN-gamma, which appears to be an indispensable cyt okine in the damage to enterocytes encountered in the small intestine, since the histological changes can be blocked by anti-IFN-gamma antib odies in vitro. TNF-alpha, also produced by several T cell clones, may in conjunction with IFN-gamma have a toxic effect or enhance the IFN- gamma-induced increase of HLA-class II expression on surface enterocyt es. In the lamina propria this leads to an increased expression of adh esion molecules such as ICAM-1 on T lymphocytes and macrophages. Th1 c ells also activate cytotoxic CD8+ T cells that migrate in the epitheli al layer, and stimulate further LPL macrophages to produce IFN-gamma a nd TNF-alpha enhancing the inflammatory response. During this process autoreactive T cells proliferate, creating a situation which is very s imilar to the process that takes place in autoimmune diseases. Occasio nally, this inflammatory destruction of the small intestinal integrity initiated by gluten peptides goes further and develops into a proper autoimmune disease which requires the use of immunosuppressive drugs i n addition to a gluten-free dirt.