SummaryThe development of autoimmune diabetes in the nonobese diabetic (NOD) mouse is controlled by multiple genes. At least one diabetogenic gene is linked to the major histocompatibility complex (MHC) of the NOD and is most likely represented by the two genes encoding the c~ and chains of the unique NOD class II molecule. Three other diabetogenic loci have recently been identified in the NOD mouse and are located on chromosomes 1, 3, and 11. In addition to the autoimmune diabetes which is caused by destruction of the insulin-producing B cells in the pancreas, other manifestations of autoimmunity are seen in the NOD mouse. These include mononuclear cell inflammation of the submandibular and lacrimal glands, as well as the presence of circulating autoantibodies. To determine the effect of the non-MHC diabetogenic genes on the development of autoimmunity, we constructed the NOD.B10-H-2 b (NOD.H-2 b) strain, which possesses the non-MHC diabetogenic genes from the NOD mouse, but derives its MHC from the C57BL/10 (B10) strain. The NOD.H-2 ~ strain does not develop insulitis, cyclophosphamide-induced diabetes, or spontaneous diabetes. It does, however, develop extensive lymphocytic infiltrates in the pancreas and the submandibular glands that are primarily composed of Thy 1.2 + T cells and B220 + B cells. In addition, autoantibodies are present in NOD.H-2 ~ mice which recognize the "polar antigen" on the insulin-secreting rat tumor line RINm38. These observations demonstrate that the non-MHC genes in the NOD strain, in the absence of the NOD MHC, significantly contribute to the development of autoimmunity. The contribution of a single dose of the NOD MHC to autoimmunity was assessed with a (NOD x NOD.H-2b)F1 cross. Although only '~3% of F1 females developed spontaneous diabetes, approximately 50% of both female and male F1 mice developed insulitis, and 25% of females and 17% of males became diabetic after treatment with cyclophosphamide. These data demonstrate that the MHC-linked diabetogenic genes of the NOD mouse are dominant with decreasing levels of penetrance for the following phenotypes: insulitis > cyclophosphamide-induced diabetes > spontaneous diabetes.T he nonobese diabetic (NOD) 1 mouse spontaneously develops autoimmune diabetes and is an experimental model of human type I diabetes. We previously determined in out-1 Abbreviation used in this paper: NOD, nonobese diabetic. crosses to the C57BL/10 (B10) strain, that at least one gene linked to the MHC of the NOD and three non-MHC-linked recessive diabetogenic genes present in the NOD mouse were required for the development of diabetes (1). Recently, using an outcross with the B10.NOD-H-2g 7 (B10.H-2g 7) strain (a B10 congenic mouse whose MHC was derived from the NOD

SummaryThe development of type I diabetes in the nonobese diabetic (NOD) mouse is under the control of multiple genes, one or more of which is linked to the major histocompatibility complex (MHC). The MHC class II region has been implicated in disease development, with expression of an I-E transgene in NOD mice shown to provide protection from insulitis and diabetes. To examine the effect of expressing an I-E + or I-E-non-NOD MHC on the NOD background, three I-E + and three I-E-NOD MHC congenic strains (NOD.H-2/s, NOD.H-2 k, and NOD.H-2 h2, and NOD.H-2 h4, NOD.H-2/7, and NOD.H-2 b, respectively) were developed. Of these strains, both I-E + NOD.H-2 h2 and I-E-NOD.H-2 h4 mice developed insulitis, but not diabetes. The remaining four congenic strains were free of insulitis and diabetes. These results indicate that in the absence of the NOD MHC, diabetes fails to develop. Each NOD MHC congenic strain was crossed with the NOD strain to produce I-E + and I-E-F1 mice; these mice thus expressed one dose of the NOD MHC and one dose of a non-NOD MHC on the NOD background. While a single dose of a non-NOD MHC provided a large degree of disease protection to all of the F1 strains, a proportion of I-E + and I-E-F1 mice aged 5-12 mo developed insulitis and cyclophosphamide-induced diabetes. When I-E + F1 mice were aged 9-17 mo, spontaneous diabetes developed as well. These data are the first to demonstrate that I-E + NOD mice develop diabetes, indicating that expression of I-E in NOD mice is not in itself sufficient to prevent insulitis or diabetes. In fact, I-E-F1 strains were no more protected from diabetes than I-E + F1 strains, suggesting that other non-NOD MHC-linked genes are important in protection from disease. Finally, transfer of NOD bone marrow into irradiated I-E + F1 recipients resulted in high incidences of diabetes, indicating that expression of non-NOD MHC products in the thymus, in the absence of expression in bone marrow-derived ceils, is not sufficient to provide protection from diabetes.T he nonobese diabetic (NOD) 1 mouse spontaneously develops autoimmune diabetes (1-4), and is considered an appropriate model for examining the etiology of human type I diabetes. As in human diabetes, the murine disease is associated with lymphocytic infiltration of pancreatic islets (insulitis) (1, 5), the appearance of autoantibodies directed against 3 cell proteins (6-13), the T cell-mediated destruction of 3 cells (14-17), and the presence of both MHC-linked (18-24) and non-MHC-linked (25-30) disease susceptibility genes.As analyzed in an outcross with the C57BL/10SnJ strain, the development of diabetes in the NOD mouse is under poly-1 Abbreviation used in this paper: NOD, nonobese diabetic. genic control (20). At least three non-MHC-linked genes, located on chromosomes 1, 3, and 11 (25, 26), as well as one or more genes in the MHC (18,(20)(21)(22) contribute to disease progression and onset. The MHC class II region has been implicated in disease susceptibility, with the NOD strain expressing a unique I-A B chain (22) a...

Human type 1 (insulin-dependent) diabetes is a common auto-immune disease of the insulin-producing beta cells of the pancreas which is caused by both genetic and environmental factors. Several features of the genetics and immunopathology of diabetes in nonobese diabetic (NOD) mice are shared with the human disease. Of the three diabetes-susceptibility genes, Idd-1 -3 and -4 that have been mapped in mice to date, only in the case of Idd-1 is there any evidence for the identity of the gene product: allelic variation within the murine immune response I-A beta gene and its human homologue HLA-DQB1 correlates with susceptibility, implying that I-A beta is a component of Idd-1. We report here the mapping of Idd-5 to the proximal region of mouse chromosome 1. This region contains at least two candidate susceptibility genes, the interleukin-1 receptor gene and Lsh/Ity/Bcg, which encodes resistance to bacterial and parasitic infections and affects the function of macrophages.

No abstract

No abstract