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.

Activation-induced cytidine deaminase expression by thymic B cells promotes T-cell tolerance and limits autoimmunity

“…In this study, we identified B cell-specific phenotypes in the thymic APC pool of NOD mice, a common mouse model for autoimmune diabetes and other autoimmune syndromes. 16 , 17 , 46 In addition to a B cell-specific deficit of co-stimulation, NOD thymic B cells do not switch to secondary isotypes as efficiently as in other mouse strains, a trait that correlates with a reduction of CD4SP thymocyte tolerance to self-antigens. To investigate the potential impact of isotype switching by thymic B cells on T-cell tolerance and autoimmunity, we generated NOD.AID −/− mice.…”

“…Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β cells. 15 The non-obese diabetic (NOD) mouse strain is autoimmune-prone 16 and spontaneously develops autoimmune diabetes. 17 , 18 , 19 T cells are necessary and sufficient for autoimmune diabetes onset and progression, 20 , 21 , 22 and it has been suggested that defects in central T-cell tolerance in NOD mice contribute to the development of autoimmune diabetes.…”

Mutated Pkhd1 alone is sufficient to cause autoimmune biliary disease on the nonobese diabetic (NOD) genetic background

“…The NOD mouse is best known as a model of spontaneous T1D; however, they develop multiple other spontaneous autoimmune conditions such as thyroiditis and Sjögren’s syndrome. Immunogenetic components contributory to NOD autoimmune disease include the TCR-MHC interaction (signal 1), co-stimulatory molecules (signal 2), and cytokines (signal 3) as reviewed by Aubin et al (Aubin et al 2022 ). The NOD immunogenetic background is susceptible to autoimmunity and to understand the basis of this heightened immunity, congenic mapping experiments were conducted to identify genetic regions responsible for the diabetes phenotype.…”

Epitope-based precision immunotherapy of Type 1 diabetes

“… 1 Second, they may impair general tolerance mechanisms (as suggested by the occurrence of other autoimmune conditions in both T1D patients 2 and its animal model, the non-obese diabetic (NOD) mouse. 3 Administration of exogenous insulin for the last 100 years has saved countless lives; however, it can rarely achieve tight regulation of blood glucose levels, such that episodes of hyper- and hypoglycemia remain commonplace, and their recurrence leads to long-term complications. 4 Even when perfect glycemic control is achieved, there is still a residual 2- to 3-fold hazard ratio of death from any cause, particularly from cardiovascular disease, in T1D vs. non-diabetic individuals.…”