Advances in the immunogenetics of coeliac disease. Clues for understanding the pathogenesis and disease heterogeneity

Abstract

Recent studies using the technique of the human genome screening in families with multiple siblings suffering from coeliac disease have suggested the presence of at least four different chromosomes in the predisposition to suffer from coeliac disease. Two loci in chromosome 6 appear to be important in disease susceptibility. Other studies based on cytokine gene polymorphisms have found a strong association with a particular haplotype in the TNF locus. This haplotype carries a gene for a high secretor phenotype of TNFalpha. The finding may be important in understanding the heterogeneity of inflammatory response. Evidence has 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 been shown to produce IFN-gamma, which appears to be an indispensable cytokine in the damage to enterocytes encountered in the small intestine, since the histological changes can be blocked by anti-IFN-gamma antibodies 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 enterocytes. In the lamina propria this leads to an increased expression of adhesion molecules such as ICAM-1 on T lymphocytes and macrophages. Th1 cells also activate cytotoxic CD8+ T cells that migrate in the epithelial layer, and stimulate further LPL macrophages to produce IFN-gamma and TNF-alpha enhancing the inflammatory response. During this process autoreactive T cells proliferate, creating a situation which is very similar to the process that takes place in autoimmune diseases. Occasionally, 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 in addition to a gluten-free diet.