Carbon Chapter 126 The NOD IDD9

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Journal of Autoimmunity

Idd-linked genetic regulation of TACIhigh expressing B cells in NOD mice

Author links open overlay panelMiaSundströmKristinaLejon

In NOD mice, B cells play a key role in the initiation of type 1 diabetes pathogenesis. We have identified a novel NOD-specific B cell-related trait, i.e. the increased percentage of TACIhigh-expressing splenic B cells, by comparing NOD mice with non-autoimmune C57BL/6 mice. Using athymic NOD mice, we determined that this trait was T cell independent. We mapped the loci contributing to the increased proportion of TACIhigh expressing splenic B cells and found that the control of TACI expression was strongly linked to chromosome 1, in a region which includes the insulin-dependent diabetes (Idd) 5 loci. Moreover, another locus potentially involved was detected in the vicinity of Idd22 on chromosome 8. Interestingly, when analyzing age-dependent contribution to the obtained LOD scores we observed that the linkage to chromosome 8 was explained solely by mice ≥61 days of age, suggesting a temporal genetic regulation of TACI expression. In addition, analysis of genetic interaction between chromosome 1 and chromosome 8 indicated that the two loci acted in an additive fashion. Our findings corroborate the notion that B cell deviations contribute to type 1 diabetes development, and suggest a temporal regulation of TACIhigh expression, possibly influenced by the ongoing autoimmune process.

The nonobese diabetic (NOD) mouse is a model of human autoimmune insulin-dependent diabetes mellitus. The NOD mouse also serves as a model for studying complex polygenic diseases because at least fourteen different loci are linked to disease development. The first Idd locus recognized, Idd1, is linked to the major histocompatibility complex (MHC), and its inheritance and expression are a paradigm for the other non-MHC Idd genes. The NOD allele at Idd1 does not behave as a recessive diabetes susceptibility gene, as it was originally thought to be, but instead it acts as a dominant gene with varying degrees of penetrance for the phenotypes of insulitis, a prediabetic inflammatory lesion, and spontaneous diabetes. MHC congenic strains of mice have shown that the NOD MHC is essential but, by itself, not sufficient for developing diabetes. The contributions of non-MHC Idd loci have also been assessed with NOD congenic strains derived by replacing NOD-specific chromosomal segments with those from diabetes-resistant strains of mice. While only partial protection from disease is provided by resistance alleles at single non-MHC Idd loci, epistatic interaction between two of the loci, Idd3 and Idd10, produced nearly complete protection from diabetes. Identifying Idd genes and defining their biologic functions should further our understanding of autoimmune disease pathogenesis and facilitate development of new treatments for diabetes.

The NOD mouse was discovered and established as an inbred strain in Japan. If is an excellent animal model for human Type 1 (insulin-dependent) diabetes mellitus in many aspects, including genetics, immunology, virology, and prevention and therapy. The diabetes and/or insulitis is controlled by at least 10 genes and results from the T cell-mediated destruction of β cells. Retrovirus might also play a role in the pathogenesis. Insulitis and/or diabetes of the mice is easily prevented by a number of agents or manipulations, suggesting that diabetes of the mice develops only when many diabetogenic factors assemble. Some of the intervention trials using the mice are hoped to be applied to human Type 1 diabetes.

Factor DNA Nod

Abstract

Previous analyses of NOD mice have shown that some genes control the development of both insulitis and diabetes, while other loci influence diabetes without reducing insulitis. Evidence for the existence of a gene only influencing diabetes, Idd9 on mouse chromosome 4, is provided here by the development of a novel congenic mouse strain, NOD.B10 Idd9. NOD.B10 Idd9 mice display profound resistance to diabetes even though nearly all develop insulitis. Subcongenic analysis has demonstrated that alleles of at least three B10 genes, Idd9.1, Idd9.2, and Idd9.3 are required to produce Idd9-mediated diabetes resistance. Candidate genes with amino acid differences between the NOD and B10 strains have been localized to the 5.6 cM Idd9.2 interval (Tnfr2, Cd30) and to the 2.0 cM Idd9.3 interval (Cd137).

Introduction

The NOD mouse spontaneously develops type 1 diabetes as well as other autoimmune syndromes such as inflammation of the thyroid, submandibular, and lacrimal glands (46, 33, 34, 11). Analysis of MHC congenic strains has shown that the NOD MHC (H2g7) is required for the development of insulin-dependent diabetes. However the non-MHC genes present on the NOD background are responsible for the breakdown of self-tolerance and the abnormal accumulation of inflammatory cells. For example, accumulation of T cells within the thyroid does not require the NOD MHC. In fact, the thyroid inflammation is more pronounced in the presence of the H2h4 MHC haplotype (33, 11). Thus, many of the non-MHC genes that contribute to diabetes are likely to be autoimmunity genes, and their identification will facilitate our understanding of the molecular basis of autoimmune disease.

Linkage analysis of the NOD genome has revealed the location of several of the non-MHC genes (42, 9, 17). They fall into two classes: genes with disease resistance alleles that reduce the development of both insulitis (T cell inflammation of pancreatic islets, evaluated by conventional histological staining with hematoxylin and eosin) and diabetes, and genes that prevent diabetes without reducing the amount of insulitis (Ghosh et al. 1993). The identification of these two patterns of protection suggests that genes of the latter class exert their effects despite the accumulation of inflammatory cells. NOD congenic strains containing specific segments of B6 chromosome 3 have been constructed and prove the existence of one of the former class of genes controlling both insulitis and diabetes (Wicker et al. 1994b). In addition, the strains show that the original linkage is due to at least four separate loci (Idd3, Idd10, Idd17, and Idd18) (45, 29,Podolin et al. 1998). In addition to reducing the frequency of spontaneous diabetes and insulitis, Idd3 also mediates protection from experimental autoimmune encephalomyelitis (EAE). Idd3 has now been mapped to a 0.15 cM interval encompassing the variant candidate gene Il2 (Lyons et al. 2000). Combined, these data support the hypothesis that Idd3 is an autoimmunity gene that contributes to the accumulation of self-reactive cells (43, 8).

In our initial genome scan, we obtained evidence for several genes that were only linked to diabetes, not to insulitis. We now provide evidence that one of these, Idd9 on chromosome 4, is a true locus. The B10 allele of Idd9 does not prevent the development of insulitis but does prevent the development of infiltrates expressing cytokines associated with β cell destruction such as IFNγ and TNFα. Insulitis in Idd9 mice is instead characterized by the presence of cells expressing CD30 and secreting IL-4. The Idd9 resistance phenotype contrasts sharply with that of NOD mice protected by a set of linked resistance alleles on chromosome 3 (Idd3, Idd17, Idd10, and Idd18), which severely restrict the accumulation of leukocytes in the islet, and defines a second mechanism of naturally occurring genetically programmed protection from autoimmune disease (Wicker et al. 1994b). We also provide evidence that the Idd9 locus is actually composed of at least three separate Idd loci: Idd9.1, Idd9.2, and Idd9.3. In the genetic interval containing Idd9.2 and Idd9.3, three variant TNFR family members have now been identified and represent functional candidate genes for mediating the diabetes-protective effects of this region.

Results

NOD.B10 Idd9 Mice Are Highly Protected from Spontaneous Diabetes

Earlier linkage studies with the B10 and B6 strains demonstrated that a gene, Idd9, located in the distal portion of chromosome 4 in the NOD strain, contributes to the development of spontaneous diabetes (9, 35). With the eventual goal of characterizing and fine-mapping Idd9, we developed a congenic strain on the NOD background containing approximately 48 cM of introgressed B10-derived genetic material (Table 1). Female and male NOD.B10 Idd9 mice were monitored for the development of diabetes and were found to be highly resistant (p < 10−4) to the development of disease as compared to the NOD parental strain (Figure 1). Thus, the existence of a diabetes resistance gene, Idd9, on chromosome 4 was confirmed by these observations.

The non-obese diabetic (NOD) mouse is susceptible to the development of autoimmune diabetes but also multiple other autoimmune diseases. Over twenty susceptibility loci linked to diabetes have been identified in NOD mice and progress has been made in the definition of candidate genes at many of these loci (termed Idd for insulin-dependent diabetes). The susceptibility to multiple autoimmune diseases in the NOD background is a unique opportunity to examine susceptibility genes that confer a general propensity for autoimmunity versus susceptibility genes that control individual autoimmune diseases. We previously showed that NOD mice deficient for the costimulatory molecule B7-2 (NOD-B7-2KO mice) were protected from diabetes but spontaneously developed an autoimmune peripheral neuropathy. Here, we took advantage of multiple NOD mouse strains congenic for Idd loci to test the role of these Idd loci the development of neuropathy and determine if B6 alleles at Idd loci that are protective for diabetes will also be for neuropathy. Thus, we generated NOD-B7-2KO strains congenic at Idd loci and examined the development of neuritis and clinical neuropathy. We found that the NOD-H-2g7 MHC region is necessary for development of neuropathy in NOD-B7-2KO mice. In contrast, other Idd loci that significantly protect from diabetes did not affect neuropathy when considered individually. However, we found potent genetic interactions of some Idd loci that provided almost complete protection from neuritis and clinical neuropathy. In addition, defective immunoregulation by Tregs could supersede protection by some, but not other, Idd loci in a tissue-specific manner in a model where neuropathy and diabetes occurred concomitantly. Thus, our study helps identify Idd loci that control tissue-specific disease or confer general susceptibility to autoimmunity, and brings insight to the Treg-dependence of autoimmune processes influenced by given Idd region in the NOD background.

The prevention of insulin-dependent diabetes (IDD) in humans remains an elusive goal, despite the broad spectrum of therapeutic interventions that prevent the development of IDD in the non-obese diabetic (NOD) mouse. Can an animal model in which spontaneous autoimmune pathology is interrupted so easily serve as an archetype for the design of clinical trials aimed at the prevention of IDD in humans? In this article, Mark Bowman, Edward Leiter and Mark Atkinson review the intervention strategies that prevent IDD in the NOD mouse and indicate why these studies may well be relevant to the prevention of IDD in humans.

Type 1 diabetes (T1D) is an autoimmune disease characterized by immunological destruction of insulin-producing pancreatic β-cells and subsequent hyperglycemia. The non-obese diabetic (NOD) mouse strain spontaneously develops a disease similar to human T1D and is commonly used as an animal model for studying this disease. We have previously shown that the administration of B7-H4-immunoglobulin fusion protein (B7-H4.Ig), a newly identified T-cell co-inhibitory signaling molecule, blocks the onset of diabetes in NOD mice. However, the mechanism(s) by which B7-H4 protects NOD mice from T1D is not fully understood. IL-17 is a pro-inflammatory cytokine, produced by Th17 cells, that activates T cells and other immune cells to produce a variety of cytokines and chemokines. Increasing evidence has shown that therapeutic agents targeting the IL-17 molecule or directly inhibiting IL-17-producing cells regulate autoimmune diabetes in NOD mice, suggesting that IL-17 is involved in the pathogenesis of this disease. In this study, we investigate whether B7-H4.Ig treatment inhibits the generation of Th17 cells which subsequently decreases IL-17 production and prevents the onset of T1D in NOD mice. Pre-diabetic female NOD mice were injected intraperitoneally with control mouse IgG or B7-H4.Ig starting at 4 weeks of age for 12 weeks. Our data showed that the frequency of Th17 cells in B7-H4.Ig-treated mice was significantly decreased. In addition, our data showed that B7-H4.Ig-treated mice had decreased levels of pro-inflammatory cytokines and Th17-associated cytokines, and an increased level of the potent Th17 inhibitor IFN-γ. To further investigate the effect of B7-H4.Ig on differentiation of Th17 cells, we co-cultured splenocytes with Th17-polarizing cytokines in the absence or presence of B7-H4.Ig. Our results indicated that splenocytes, under the Th17 driving conditions in the presence of B7-H4.Ig, had significantly decreased the numbers of Th17 cells compared to cells co-cultured in the absence of B7-H4.Ig. Together, this study suggests that blocking the generation of Th17 cells with the administration of B7-H4.Ig effectively inhibits the development of T1D in NOD mice.

Type 1 Diabetes (T1D) is an autoimmune disease characterized by the pancreatic infiltration of immune cells resulting in T cell-mediated destruction of the insulin-producing beta cells. The successes of the Non-Obese Diabetic (NOD) mouse model have come in multiple forms including identifying key genetic and environmental risk factors e.g. Idd loci and effects of microorganisms including the gut microbiota, respectively, and how they may contribute to disease susceptibility and pathogenesis. Furthermore, the NOD model also provides insights into the roles of the innate immune cells as well as the B cells in contributing to the T cell-mediated disease. Unlike many autoimmune disease models, the NOD mouse develops spontaneous disease and has many similarities to human T1D. Through exploiting these similarities many targets have been identified for immune-intervention strategies. Although many of these immunotherapies did not have a significant impact on human T1D, they have been shown to be effective in the NOD mouse in early stage disease, which is not equivalent to trials in newly-diagnosed patients with diabetes. However, the continued development of humanized NOD mice would enable further clinical developments, bringing T1D research to a new translational level. Therefore, it is the aim of this review to discuss the importance of the NOD model in identifying the roles of the innate immune system and the interaction with the gut microbiota in modifying diabetes susceptibility. In addition, the role of the B cells will also be discussed with new insights gained through B cell depletion experiments and the impact on translational developments. Finally, this review will also discuss the future of the NOD mouse and the development of humanized NOD mice, providing novel insights into human T1D.

NOD

Type 1 diabetes

Gut microbiota

B cells

Humanized mice

Trends in Endocrinology & Metabolism

Volume 7, Issue 7, September 1996, Pages 252-257

Brief review

Immunotherapies in diabetes

Author links open overlay panelVijayakumar K.RamiyaNoel K.Maclaren

Outline

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https://doi.org/10.1016/S1043-2760(96)00116-6Get rights and content

Abstract

Insulin-dependent diabetes (IDD) is a serious, life-long disease replete with life-threatening complications that are not preventable through conventional insulin replacement therapies. The prolonged prodromal period of autoimmunity to β cell antigens offers multiple intervention opportunities. These can target different steps that precede final destruction of insulin-secreting β cells and clinical onset of the disease. All current and proposed immunotherapies are experimental procedures that have proven to be protective in animal models, especially the nonobese diabetic (NOD) mouse. This brief review deals with a selected list of nonspecific and autoantigen-specific immunotherapies that may bring hope in the near future to individuals at risk of developing the disease. None are yet proven to be effective in humans

Journal of Autoimmunity

Volume 3, Issue 3, June 1990, Pages 289-298

Restriction fragment length polymorphisms in the major histocompatibility complex of the non-obese diabetic mouse

Author links open overlay panelTorbenLund★†AnneCooke★

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https://doi.org/10.1016/0896-8411(90)90147-KGet rights and content

Abstract

The inbred non-obese diabetic (NOD) mouse is a spontaneous model for insulin-dependent diabetes mellitus (IDDM). As in man and BB rats, IDDM in the NOD mouse has an autoimmune aetiology. The disease is controlled by several genes, one of which, Idd-1, has been mapped to the major histocompatibility complex (MHC) on chromosome 17. However, Idd-1 has not yet been identified. To facilitate the identification of Idd-1 we have further analysed the MHC region for restriction fragment length polymorphisms and we find that the NOD mouse has a distinct haplotype: H-2K1nod Kd Aβnod Aαd Eβnod Eαnod TNF-αb. In addition, the NOD mouse shows some similarities with the H-2b haplotype in the Q region, in that either the Q7 or the Q9 gene seems to be like that in the b-haplotype and that the Qa2 antigen is expressed, while other parts of this region are distinct from the b- as well as the d-haplotype. In contrast, the sister strain, the non-obese normal (NON) mouse, derived from the same cataract-prone line of mice as the NOD mouse, has an MHC Class I region indistinguishable from the b-haplotype, but the MHC Class II region is distinct from the NOD mouse as well as the b-, d- and k-haplotype.

Clinical Immunology and Immunopathology

Volume 53, Issue 2, November 1989, Pages S92-S98

Insulin dependent diabetes mellitus, an autoimmune disorder?☆

Author links open overlay panelWilliam J.Riley

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https://doi.org/10.1016/0090-1229(89)90074-3Get rights and content

Abstract

During the last 25 years the concept of a chronic autoimmune process leading to the development of insulin dependent diabetes (IDD) has emerged. The presence of two animal models for IDD, the BB rat and the NOD mouse, has improved our ability to understand the process leading to β cell destruction. The hallmark of an autoimmune disease is the characteristic pathologic lesion of mononuclear infitration of the pancreatic islets. Further histologic studies of the diabetic pancreas have identified the type of cells infiltrating the islets and led to the concept of pancreatic β cells capable of presenting antigen. The initial description of linkage disequilibrium of HLA DR3 and DR4 alleles with IDD has now progressed to the molecular level with the identification of residue 57 of the HLA DQ β chain as crucial to the genetic predisposition to IDD. Autoantibodies to cytoplasmic antigens (ICA), surface antigens, or a membrane protein of 64 kDa identified by immunoprecipitation, autoantibodies to secreted products such as insulin and proinsulin, and autoantibodies that are cytotoxic to cultured β cells are islet specific autoantibodies that have been described. Some are probably only markers of immunologic activity; others might participate in the destruction itself. The use of ICA as a screening tool has been successful in identifying individuals prior to the onset of IDD. Widespread cellular immunological defects have been identified both in animal models and in man. In the BB rat, a seeming paradox of severe immunodeficiency occurs in an animal with autoaggressive destruction of β cells. More subtle defects in immuno-regulation have been described in the NOD mouse and in human IDD. The response of IDD in both animal models and in man to immunomodulation and to immunosuppression offers further evidence of an immunologically mediated disease. However, some therapies in the animal models, not typically considered immunologic, such as protein restriction and insulin therapy, have prevented IDD. The possibility of intervening prior to the onset of clinical disease at the level either of the initial process of recognition of the pancreatic β cell as a target organ or of the effector mechanism is approaching a reality in human IDD.

Chapter 126 - The NOD IDD9

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