Amino acid polymorphisms altering the glycosylation of IL-2 do not protect from type 1 diabetes in the NOD mouse.

Idd3 is one of many gene regions that affect the development of type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse. Idd3 has been localized to a 650-kb region on chromosome 3 containing the IL-2 gene. Exon 1 of the IL-2 gene is polymorphic between the susceptible NOD and the protective C57BL/6 (B6) alleles, causing multiple amino acid changes that have been proposed to be responsible for the differing glycosylation status.

Gene-gene interactions in the NOD mouse model of type 1 diabetes.

Human genome wide association studies (GWAS) have recently identified at least four new, non-MHC-linked candidate genes or gene regions causing type one diabetes (T1D), highlighting the need for functional models to investigate how susceptibility alleles at multiple common genes interact to mediate disease. Progress in localizing genes in congenic strains of the nonobese diabetic (NOD) mouse has allowed the reproducible testing of gene functions and gene-gene interactions that can be reflected biologically as intrapathway interactions, for example, IL-2 and its receptor CD25, pathway-pathway interactions such as two signaling pathways within a cell, or cell-cell interactions. Recent studies have identified likely causal genes in two congenic intervals associated with T1D, Idd3, and Idd5, and have documented the occurrence of gene-gene interactions, including "genetic masking", involving the genes encoding the critical immune molecules IL-2 and CTLA-4.

Commonality in the genetic control of Type 1 diabetes in humans and NOD mice: variants of genes in the IL-2 pathway are associated with autoimmune diabetes in both species.

Variants within the IL-2 (interleukin 2) and CD25 genes are associated with T1DM (Type 1 diabetes mellitus) in mice and humans respectively. Both gene products are essential for optimal immune tolerance and a partial failure to tolerize is linked to the autoimmune responses to insulin and other beta-cell proteins that precede T1DM onset. Gene variants that contribute to common disease susceptibility often alter gene expression only modestly.

Interactions between Idd5.1/Ctla4 and other type 1 diabetes genes.

Two loci, Idd5.1 and Idd5.2, that determine susceptibility to type 1 diabetes (T1D) in the NOD mouse are on chromosome 1.

Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity.

Autoimmune diseases are thought to result from imbalances in normal immune physiology and regulation. Here, we show that autoimmune disease susceptibility and resistance alleles on mouse chromosome 3 (Idd3) correlate with differential expression of the key immunoregulatory cytokine interleukin-2 (IL-2). In order to test directly that an approximately twofold reduction in IL-2 underpins the Idd3-linked destabilization of immune homeostasis, we show that engineered haplodeficiency of Il2 gene expression not only reduces T cell IL-2 production by twofold but also mimics the autoimmune dysregulatory effects of the naturally occurring susceptibility alleles of Il2.

A 20-Mb region of chromosome 4 controls TNF-alpha-mediated CD8+ T cell aggression toward beta cells in type 1 diabetes.

Identification of candidate genes and their immunological mechanisms that control autoaggressive T cells in inflamed environments, may lead to novel therapies for autoimmune diseases, like type 1 diabetes (T1D). In this study, we used transgenic NOD mice that constitutively express TNF-alpha in their islets from neonatal life (TNF-alpha-NOD) to identify protective alleles that control T1D in the presence of a proinflammatory environment. We show that TNF-alpha-mediated breakdown in T cell tolerance requires recessive NOD alleles.

Type 1 diabetes genes and pathways shared by humans and NOD mice.

The identification of causative genes for the autoimmune disease type 1 diabetes (T1D) in humans and candidate genes in the NOD mouse has made significant progress in recent years. In addition to sharing structural aspects of the MHC class II molecules that confer susceptibility or resistance to T1D, genes and pathways contributing to autoimmune pathogenesis are held in common by the two species. There are data demonstrating a similar need to establish central tolerance to insulin.

An autoimmune disease-associated CTLA4 splice variant lacking the B7 binding domain signals negatively in T cells.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) plays a critical role in down-regulating T cell responses. A number of autoimmune diseases have shown genetic linkage to the CTLA4 locus. We have cloned and expressed an alternatively spliced form of CTLA4 that has genetic linkage with type 1 diabetes in NOD mice.

Natural genetic variants influencing type 1 diabetes in humans and in the NOD mouse.

The understanding of the genetic basis of type 1 diabetes and other autoimmune diseases and the application of that knowledge to their treatment, cure and eventual prevention has been a difficult goal to reach. Cumulative progress in both mouse and human are finally giving way to some successes and significant insights have been made in the last few years. Investigators have identified key immune tolerance-associated phenotypes in convincingly reliable ways that are regulated by specific diabetes-associated chromosomal intervals.

Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse.

At least two loci that determine susceptibility to type 1 diabetes in the NOD mouse have been mapped to chromosome 1, Idd5.1 (insulin-dependent diabetes 5.1) and Idd5.

An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) plays a critical role in downregulating T cell responses. A number of autoimmune diseases have shown genetic linkage to the CTLA-4 locus. We have cloned and expressed an alternatively spliced form of CTLA-4 that has genetic linkage with type I diabetes in the NOD mice.