title: The multifactorial nature of MHC-linked susceptibility to insulin-dependent diabetes.
abstract: Several lines of evidence suggest that major histocompatibility complex (MHC)-linked susceptibility to insulin-dependent diabetes mellitus (IDDM) is not restricted to the presence or absence of any single gene product. The existence of population-specific haplotypes associated with IDDM supports the concept that distinct combinations of MHC alleles interact synergistically to induce disease when other environmental and genetic factors are present. MHC-controlled peptide transport and binding to MHC molecules as well as the levels of MHC class I and class II expression in the thymus and pancreatic beta cells may also play significant roles in the outbreak of IDDM. These intrinsic factors shape the T-cell receptor (TCR) repertoire during T-cell ontogeny in the thymus and later influence the efficiency of potentially autoreactive T cells in the periphery. Several extrinsic factors, such as viruses or dietary proteins, may be directly involved in the TCR/MHC interaction at the cell surface; furthermore viruses can alter the regulatory mechanisms of peptide/MHC interaction and expression. We propose that these intrinsic and extrinsic factors need not be mutually exclusive and might even be interdependent: a given virus may act deleteriously only when certain autoreactive T cells and combinations of MHC alleles are present in the individual. IDDM would develop if pathogenic T-cells are activated and an appropriate target MHC/peptide is expressed in pancreatic beta cells. Future knowledge of the host-virus relationships influenced by the MHC genes, the function of their encoded proteins and the polymorphic gene structure of well-established susceptibility MHC haplotypes will help delineate an overall picture of this issue.
authors.affiliation: Institute of Immunology, University of Munich, Germany.
authors.forename: O G
authors.initials: OG
authors.lastname: Segurado
authors.forename: A
authors.initials: A
authors.lastname: Arnaiz-Villena
authors.forename: R
authors.initials: R
authors.lastname: Wank
authors.forename: D J
authors.initials: DJ
authors.lastname: Schendel
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006681:HLA-D Antigens / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex; D051379:Mice; D008954:Models, Biological; D051381:Rats; D017634:Self Tolerance; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014777:Virus Diseases / Q000150:complications / Q000276:immunology
chemical_list: D005819:Genetic Markers; D006681:HLA-D Antigens