STRUCTURAL STUDY OF HLA-DQ2 AND AN ASSOCIATED COMPLEX

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This study is aimed at understanding the mechanism of HLA-DQ2 interaction with other molecules. The human major histocompatibility complex (MHC), encoded on chromosome 6, is associated with susceptibility to many immunopathological diseases. One of the diseases with the strongest association with particular MHC alleles is celiac disease, for which there is also mechanistic insight into the basis for the human leukocyte antigen (HLA) association. Celiac disease is caused by an inappropriate intestinal immune response to wheat gluten (consisting of the gliadin and glutenin subcomponents) and the related proteins of rye and barley. Patients with celiac disease have gluten-reactive CD4+ T cells in their small intestinal mucosa, but healthy controls do not. Most patients with celiac disease carry the HLA-DQ2 variant DQ2.5, which is encoded by the DQA1*0501 and DQB1*0201 genes of the DR3-DQ2 haplotype. Most of the few remaining patients express HLA-DQ8. The gluten-reactive T cells of patients with celiac disease recognize a diverse set of gluten epitopes presented in context of DQ2.5 or DQ8 MHC molecules but not in the context of other MHC class II molecules expressed by the patients. 'Preferential' presentation of gluten peptides by the DQ2.5 and DQ8 molecules thus seems to explain the association of HLA with celiac disease.