The NOD Mouse Beyond Autoimmune Diabetes

Abstract

Autoimmune diabetes arises spontaneously in Non-Obese Diabetic (NOD) mice, and the pathophysiology of this disease shares many similarities with human type 1 diabetes. Since its generation in 1980, the NOD mouse, derived from the Cataract Shinogi strain, has represented the gold standard of spontaneous disease models, allowing to investigate autoimmune diabetes disease progression and susceptibility traits, as well as to test a wide array of potential treatments and therapies. Beyond autoimmune diabetes, NOD mice also exhibit polyautoimmunity, presenting with a low incidence of autoimmune thyroiditis and Sjögren's syndrome. Genetic manipulation of the NOD strain has led to the generation of new mouse models facilitating the study of these and other autoimmune pathologies. For instance, following deletion of specific genes or via insertion of resistance alleles at genetic loci, NOD mice can become fully resistant to autoimmune diabetes; yet the newly generated diabetes-resistant NOD strains often show a high incidence of other autoimmune diseases. This suggests that the NOD genetic background is highly autoimmune-prone and that genetic manipulations can shift the autoimmune response from the pancreas to other organs. Overall, multiple NOD variant strains have become invaluable tools for understanding the pathophysiology of and for dissecting the genetic susceptibility of organ-specific autoimmune diseases. An interesting commonality to all autoimmune diseases developing in variant strains of the NOD mice is the presence of autoantibodies. This review will present the NOD mouse as a model for studying autoimmune diseases beyond autoimmune diabetes.

Keywords: NOD mice; biliary disease; neuropathy; polyautoimmunity; thyroiditis.

Figure 1

The NOD.H2^h4 congenic mouse model. Representation of the mouse chromosome 17 from the parental B10.A(4R) (left), parental NOD (middle), and congenic NOD.H2^h4 (right) strains. By backcrossing NOD mice to B10.A(4R), the thyroiditis-prone H2^h4 MHC locus from chromosome 17 of the parental B10.A(4R) mouse has been selected at each backcross generation to replace in the NOD-derived H2^g7 MHC locus, resulting in the NOD.H2^h4 congenic mouse.

Figure 2

iNKT cell abundance in the spleen. Spleen of NOD/ShiLtJ, NOD.H2^h4 , and BALB/c mice were stained with antibodies to TCRβ and with CD1d tetramer (NIH Tetramer Core Facility). Data was acquired on BD FACSCanto II flow cytometer and analyzed with FlowJo. (A) Representative flow cytometry profiles of iNKT (TCRβ⁺CD1d-Tet⁺) cells in the spleen of NOD/ShiLtJ, NOD.H2^h4 , and BALB/c mice. (B) Compilation of the percentage of iNKT cells in the spleen of NOD/ShiLtJ, NOD.H2^h4 , and BALB/c mice (n = 4). (C) Compilation of absolute number of iNKT cells in the spleen of NOD/ShiLtJ, NOD.H2^h4 , and BALB/c mice (n = 4). One-way ANOVA tests were performed for statistical analysis. Non-significant, NS; P-value > 0.05, and *; P-value = 0.03.

Figure 3

The central role of B cells in autoimmune thyroiditis. By producing anti-thyroglobulin (Tg) and anti-TPO autoantibodies, by activating autoreactive T cells, and by promoting antibody dependent cell cytotoxicity (ADCC), B cells play an important role in the onset and the progression of autoimmune thyroiditis in the NOD mouse.

Figure 4

Disruption of T cell activation signals induce autoimmune neuropathy in the NOD mouse. Autoimmune neuropathy can be induced in the NOD mouse after modulation of one of the three T cell activation signals. More specifically, mutations in AIRE transcription factor expression in medullary thymic epithelial cells (mTECs) indirectly impact signal 1. In addition, disruptions in co-stimulation signals, such as ICOS/ICOSL and CD28/CD80-86 (signal 2), or neutralization of IL-2 (signal 3) induce autoimmune neuropathy in the NOD mouse.

Figure 5

The immunopathogenesis of autoimmune biliary disease. In the NOD congenic mice, T cells play an important role in ABD by activating B cells which will eventually produce AMA, ANA, and anti-Sm autoantibodies.

Figure 6

Polyautoimmunity in the NOD mouse. The NOD mouse can spontaneously develop autoimmune diabetes, autoimmune thyroiditis, and Sjögren’s syndrome (green). Disruptions in peripheral (blue) and central tolerance (pink) exacerbate or induce a wide spectrum of other organ-specific autoimmune diseases.