Autoimmune syndromes in major histocompatibility complex (MHC) congenic strains of nonobese diabetic (NOD) mice. The NOD MHC is dominant for insulitis and cyclophosphamide-induced diabetes.

Abstract

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

An Interval Tightly Linked to but Distinct From the H2 Complex Controls Both Overt Diabetes (Idd16) and Chronic Experimental Autoimmune Thyroiditis (Ceat1) in Nonobese Diabetic Mice

“…Such protection was expected for R2 mice because they carry the protective B6 MHC alleles. In addition, it was previously shown that the H2 b haplotype confers nearly dominant protection against diabetes, with almost complete penetrance in the heterozygous state (27,28). As shown in Fig.…”

Genetic Disassociation of Autoimmunity and Resistance to Costimulation Blockade-Induced Transplantation Tolerance in Nonobese Diabetic Mice

“…In another study, NOD mice were crossed with diabetes-and insulitis-free NOD.H2 b mice. Approximately 50% of (NOD ϫ NOD.H2 b )F 1 mice developed insulitis, a low percentage (3%) of female F 1 mice spontaneously developed diabetes, and ϳ20% become diabetic after treatment with cyclophosphamide (77). These data argue for a "genetic threshold" model for expression of autoimmunity.…”

Innate stimulation of B1a cells enhances the autoreactive IgM repertoire in the NOD mouse: implications for type 1 diabetes

“…While the detection of antitype-1-diabetes-AAg IgG is widely accepted as an early disease marker in clinical practice and is generally considered to be a by-product of the T-cell-mediated destruction of beta cells [32,33], autoreactive IgM comprises the pool of NAbs, the first antibodies to arise during ontogeny, produced in the absence of exogenous stimuli [34]. Analysis of MHC congenic strains [35] showed that, unlike IgG, IgM reactivity observed in the NOD cells is independent of T cell help and disease progression, and is consistent with the hypothesis that an increased autoreactivity in the NOD NAb compartment would contribute to the initiation of autoimmunity [26]. This suggested the possibility that IgM reactivities would also be altered in human type 1 diabetes and we have preliminary evidence that common genetic variants (single-nucleotide polymorphisms) in the IgM locus control the levels of anti-GAD serum IgM and are associated with disease in a collection of type 1 diabetes patients (I. Rolim, G. Barata, J. Raposo, M. Catarino, C. Penha-Gonçalves, unpublished results).…”