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At least 19 recordsLinked to original sources
PubMed1994

Insulin as a target antigen in autoimmune diabetes: a natural repertoire as the source of antibody response.

A solid-phase immunoenzymatic technique with B1- or B29-biotinylated insulin coupled to avidin-coated wells was used to characterize serum anti-insulin antibodies and to locate insulin antibody-producing B lymphocytes in different organs of mice. Low natural serum anti-insulin IgM and IgG antibodies were found in ten different healthy inbred strains of mice. Prediabetic non-obese diabetic (NOD) mice had significantly higher measurements than BALB/c mice (P < 0.05). Anti-insulin IgM antibody-producing B lymphocytes were found in bone marrow and spleen of NOD mice and healthy strains of mice, but not in peripheral lymph nodes, thymus, blood or pancreas. B29-fixed insulin was more frequently recognized than B1-fixed insulin. There was no relationship to the MHC or to other immune markers. IgG insulin antibody-producing cells were not detected. IgG insulin antibody-producing cells appeared in the draining lymph node and in the blood 10 days after immunization with insulin. IgM insulin-recognizing cells in the spleen were reduced in number during the same period (P < 0.05-0.01 for BALB/c, DBA2, B10.D2 and NOD), suggesting migration of these cells. This was tested by in vivo staining of spleens with the red-fluorescent membrane linker PKH-26 on day 7 after immunization. Cells from immunized lymph nodes were FACS-sorted on day 10. Insulin antibody-producing B lymphocytes with red-fluorescence were found, indicating a splenic origin. Examination of IgG subclasses showed preferential production of complement-fixing IgG2b in sera and lymph node cells of immunized NOD mice (P < 0.05 vs BALB/c).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Sjögren's syndrome-like disease of C57BL/6.NOD-Aec1 Aec2 mice: gender differences in keratoconjunctivitis sicca defined by a cross-over in the chromosome 3 Aec1 locus.

Sjögren's syndrome (SjS) is a systemic autoimmune disease in which an immunological attack primarily against the salivary and lacrimal glands results in loss of acinar cell tissue and function leading to stomatitis sicca and keratoconjunctivitis sicca. In recent years, the NOD mouse has become an accepted model of SjS, exhibiting a spontaneously developing disease that strongly mimics the human condition. Two genetic regions, one on chromosome 1 (designated Aec2) and the second on chromosome 3 (designated Aec1) of NOD mice, have been shown to be necessary and sufficient to recapitulate SjS-like disease in non-susceptible C57BL/6 mice. Here we describe a newly derived strain, C57BL/6.NOD-Aec1R1Aec2, in which a recombination in Aec1 has resulted in reducing this genetic region to less than 20 cM from 48.5 cM. Profiling of this recombinant inbred strain has revealed that male mice maintain a full SjS-like disease, whereas female mice exhibit stomatitis sicca in the absence of detectable keratoconjunctivitis sicca. These data suggest SjS-like disease in the NOD mouse shows gender-specific regulation determined by autosomal genes.

Animals↗
PubMed1996

Animal models for autoimmune disease-associated xerostomia and xerophthalmia.

Numerous models of exocrine tissue pathology related to autoimmune initiation of disease have been described, primarily by either immunohistology or histopathology. These model systems include inbred mouse strains that develop systemic lupus erythematosus, rheumatoid arthritis, graft vs. host disease, and diabetes. Commonly observed features of these mice include organized lymphocytic foci, composed of CD4+ and CD8+ T-cells, in both the salivary and the lacrimal glands. However, only the diabetic mouse model (NOD) undergoes a corresponding loss in exocrine gland function related to the presence of lymphocytic infiltrates. As we define the underlying pathophysiology of Sjögren's syndrome, the future of animal models for this disease will involve genetic exploration of candidate genes for development of autoimmune exocrinopathy.

Animals↗
PubMed2003

A susceptibility allele from a non-diabetes-prone mouse strain accelerates diabetes in NOD congenic mice.

The nonobese diabetic (NOD) mouse is genetically predisposed for the spontaneous development of type 1 diabetes. Linkage analyses have identified at least 19 susceptibility loci (Idd1-Idd19) that contribute to disease pathogenesis in which lymphocytes mediate the specific destruction of insulin-producing beta-cells. Interestingly, nondiabetic mouse strains have been shown to confer susceptibility alleles to affected progeny in NOD outcrosses for some of the Idd loci. In particular, we noted that diabetic backcross progeny, derived from NOD and C57BL/6 (B6) mouse strains, demonstrated increased heterozygousity for an interval encompassing Idd14 on chromosome 13. This result suggested that B6 mice harbor a more diabetogenic allele(s) than NOD mice for this locus. To confirm this observation, a NOD congenic mouse strain, containing a B6-derived interval covering the majority of chromosome 13, was generated. Adding to the combination of already potent susceptibility alleles elsewhere in the NOD genome, the chromosome 13 B6-derived interval was able to increase the overall risk of developing type 1 diabetes, which resulted in an earlier onset and increased incidence of type 1 diabetes in congenic mice as compared with NOD mice. Furthermore, this B6-derived interval, in combination with the NOD genetic background, was able to overcome environmental conditions that typically suppressed type 1 diabetes in the NOD mouse strain.

Alleles↗
PubMed2003

Erythrocyte-replaced mouse model for Haemoparasite studies: comparison of NOD/shi-scid and C.B-17/Jcl-scid mouse upon acceptability of human erythrocytes.

The erythrocyte-exchanged chimera mouse model has become to be a significant tool for studying animal and human (hu) protozoan haemoparasites, though the usefulness of this model varies depending primarily on the acceptability of xenogeneic red blood cells (RBC). To find a superior recipient in comparison with C.B-17/Jcl mouse with severe combined immuno-deficiency (scid) mutation, we examined in this report the non-obese diabetes (NOD)/shi-scid mouse, a recently available strain of SCID. When 2.5 x 10(8) of fluorescent dye-labeled hu-RBCs were transfused, C.B-17scid mouse eliminated them logarithmically by a simple linear regression, while NOD-scid mouse eradicated hu-RBCs by a unique two-step fashion, i.e., a potent but only briefly functioning RBC eradication followed by a weak steadily functioning step. The means of regression line constance +/- their standard deviations (SD) of 205 C.B-17scid and of 213 NOD-scid mice for their short- and long-lasting steps were -0.73 +/- 0.63, -0.53 +/- 0.25 and -0.16 +/- 0.10, respectively. Hu-RBC half-lives determined from these means of C.B-17scid mice and of NOD-scid mice for the short- and long-living steps were 3.6, 4.9 and 16.3 hr, respectively. Higher hu-RBC acceptability of NOD-scid mouse, especially at their long-lasting step, was also demonstrated under at an activated state of mouse innate immunity. Treatment with 1.0 mg heat-killed Candida cells caused an acceleration of hu-RBC elimination in both mouse strains but the magnitudes for the short- and long-living steps of NOD-scid mice evaluated by "stimulation index" were only 1/2.6 and 1/7.6 of C.B-17scid mice, respectively.

Animals↗
PubMed2002

Tumor necrosis factor-alpha regulation of CD4+CD25+ T cell levels in NOD mice.

The mechanism by which tumor necrosis factor-alpha (TNF) differentially modulates type I diabetes mellitus in the nonobese diabetic (NOD) mouse is not well understood. CD4+CD25+ T cells have been implicated as mediators of self-tolerance. We show (i) NOD mice have a relative deficiency of CD4+CD25+ T cells in thymus and spleen; (ii) administration of TNF or anti-TNF to NOD mice can modulate levels of this population consistent with their observed differential age-dependent effects on diabetes in the NOD mouse; (iii) CD4+CD25+ T cells from NOD mice treated neonatally with TNF show compromised effector function in a transfer system, whereas those treated neonatally with anti-TNF show no alteration in ability to prevent diabetes; and (iv) repeated injection of CD4+CD25+ T cells into neonatal NOD mice delays diabetes onset for as long as supplementation occurred. These data suggest that alterations in the number and function of CD4+CD25+ T cells may be one mechanism by which TNF and anti-TNF modulate type I diabetes mellitus in NOD mice.

Adoptive Transfer↗
PubMed1999

Disorganization of thymic medulla precedes evolution towards diabetes in female NOD mice.

The thymic medulla is a complex microenvironment which plays a crucial role in central tolerance induction. Using a quantitative histological analysis of non-obese diabetic (NOD) mice, we show that the medulla undergoes several structural modifications during the course of the disease in NOD mice. Indeed, the majority of 70-day-old NOD mice show a scattering of medullary epithelial cells in the cortex which is associated with a reduction in the size of the medulla in heavily disorganized thymuses. The severity of this phenotype is shown to correlate with the subsequent appearance of diabetes in older female NOD mice. This trait is mainly controlled by non-major histocompatibility complex NOD genes since C57BL/6 H-2g(7) congenic mice have a normal medulla. It persists in conditions where effector lymphocytes that lead to diabetes are inhibited in periphery. These results suggest that primary alterations of the thymic stroma might play a role in the progression towards diabetes in NOD mice.

Age Factors↗
PubMed2006

Deregulated stress system in non-obese diabetic lymphocyte.

Lymphopenia-induced homeostatic expansion in non-obese diabetic (NOD) mice may lead to autoimmunity. We demonstrated that NOD lymphocytes are more susceptible to apoptosis than those of non-diabetic C57BL/6 or NOD.H2(h4) mice in vivo and in vitro, which may be an underlying mechanism causing lymphopenia in NOD mice. Gene expression profiling identified a set of genes that are differentially expressed between NOD and B6 mice. Identity of these genes suggested that NOD T cells have a deregulated stress response system, especially heat-shock protein family, making them overly sensitive to apoptosis. Thus, we hypothesize that this strain-specific gene expression profile may confer a liability upon NOD T cells making them more susceptible to apoptosis that may lead to lymphopenia in NOD mice and contribute to development of autoimmunity.

Animals↗
PubMed1993

RFLP analysis of the MHC class III region defines unique haplotypes for the non-obese diabetic, cataract Shionogi and the non-obese non-diabetic mouse strains.

The non-obese diabetic (NOD) mouse strain which spontaneously develops diabetes is a model for human Type 1 (insulin-dependent) diabetes mellitus. At least one of several genes controlling diabetes in the NOD mouse has been mapped to the MHC. Although previous experiments have implicated the MHC class II genes in the development of the disease, the existence of other MHC linked susceptibility genes has not been ruled out. In order to identify these susceptibility genes we have further characterized the MHC haplotype of the NOD mouse and two non-diabetic sister strains, the non-obese non-diabetic (NON) and cataract Shionogi (CTS). We have examined the mouse MHC class III region for the presence of homologous genes to 17 newly isolated human MHC class III region genes (G1, G2, G4, G6, G7a/valyl-tRNA synthetase, HSP70, G8, G9, G10, G12, G13, G14, G15, G16, G17 and G18). We detect unique hybridizing DNA fragments for 16 of the 17 genes in six inbred mouse strains (NOD, NON, CTS, B10, BALB/c and CBA/J) indicating that this part of the H-2 region is similar to the human MHC class III region. Using a panel of restriction enzymes we have defined RFLPs for 6 (G2, G6, HSP70, G12, G16, G18) of the 16 cross-hybridizing probes. The RFLPs demonstrate that NOD, NON and CTS mouse strains each have a distinct MHC haplotype in the MHC class III region.

Animals↗
PubMed2004

Sex differences in experimental autoimmune encephalomyelitis in multiple murine strains.

Multiple sclerosis (MS) is more prevalent in women than men. We evaluated seven different mouse strains commonly used in the study of autoimmune diseases, for sex differences in the disease course of experimental autoimmune encephalomyelitis (EAE). Greater severity of EAE was observed in the female SJL immunized with two different peptides of myelin proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) as well as in the female ASW relative to males. Female NZW mice showed a greater incidence of EAE than males. However, male B10.PL and PL/J mice showed more severe disease than females. No sex differences were noted in the C57BL/6 or NOD strains.

Amino Acid Sequence↗
PubMed1994

Molecular analysis of the pathogenesis of autoimmune insulitis in NOD mice.

Among diabetes-susceptibility genes in NOD mice, only Idd-1 has been clearly assigned: Idd-1 could be a gene complex composed of class II major histocompatibility complex (MHC) genes, I-A beta and I-E. Employing restriction fragment length polymorphism (RFLP) analysis and nucleotide sequencing, we revealed that ILI and CTS mice, which are nondiabetic but are derived from the same Jcl-ICR mice as NOD mice, share the same class II MHC genes with NOD mice suggesting that both ILI and CTS mice also possess susceptible Idd-1 genotype. This was supported by a breeding study. To compare the usage of T cell receptor (TCR) V beta genes in NOD mice with that in ILI mice, we employed quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) which revealed that TCR V beta usages of these mice were indistinguishable. RT-PCR method also revealed that the V beta transcript of T cells infiltrating into pancreas of NOD mice was not restricted but was rather diverse. Since NOD and ILI mice share the same class I and II MHC antigens, we performed lymphocyte transfer experiments between these mice to examine the mechanism by which ILI mice do not develop insulitis. The results of reciprocal transfer of lymphocytes from NOD to ILI-nu/nu mice or from ILI to young NOD mice suggest that ILI mice exhibit autoantigens responsible for the development of insulitis but do not possess T cells reacting with islets. Of the diabetes-susceptibility genes, only in the case of Idd-1 is there any evidence for the identity of the gene products. ILI mice should provide more information on the products of the other diabetes-susceptibility genes of NOD mice.

Amino Acid Sequence↗
PubMed2003

A mutant Stat5b with weaker DNA binding affinity defines a key defective pathway in nonobese diabetic mice.

A number of cytokines that finely regulate immune response have been implicated in the pathogenesis or protection of type 1 diabetes and other autoimmune diseases. It is, therefore, of pivotal importance to examine a family of proteins that serve as signal transducers and activators of transcription (STATs), which regulate the transcription of a variety of cytokines. We report here a defective gene (Stat5b) located on chromosome 11 within a previously mapped T1D susceptibility interval (Idd4) in the nonobese diabetic (NOD) mice. Our sequencing analysis revealed a unique mutation C1462A that results in a leucine to methionine (L327M) in Stat5b of NOD mice. Leu(327), the first residue in the DNA binding domain of STAT proteins, is conserved in all identified mammalian STAT proteins. Homology modeling predicted that the mutant Stat5b has a weaker DNA binding, which was confirmed by DNA-protein binding assays. The inapt transcriptional regulation ability of the mutated Stat5b is proved by decreased levels of RNA of Stat5b-regulated genes (IL-2Rbeta and Pim1). Consequently, IL-2Rbeta and Pim1 proteins were shown by Western blotting to have lower levels in NOD compared with normal B6 mice. These proteins have been implicated in immune regulation, apoptosis, activation-induced cell death, and control of autoimmunity. Therefore, the Stat5b pathway is a key molecular defect in NOD mice.

Amino Acid Sequence↗
PubMed1994

Non-obese diabetic (NOD) mice display enhanced immune responses and prolonged survival of lymphoid cells.

We report that lymphoid cells originating from the non-obese diabetic (NOD) autoimmune prone mouse strain are resistant to several signals known to induce programmed cell death. In vitro culturing of lymphoid cells of splenic or lymph node origin showed that B cells and T cells of both CD4+ and CD8+ phenotypes from NOD mice display extended survival in vitro. By cytofluorimetric analysis, immature CD4+ CD8+ NOD thymocytes were shown to partially resist in vivo treatment with corticosteroids. Finally, immunization with protein antigens induced enhanced and prolonged immune responses in NOD mice compared with normal C57BL/6, BALB/c, and C3H/Tif control mice. We conclude that the NOD mouse displays a defect in the mechanism(s) mediating programmed cell death in T and B lymphocytes. These findings provide a novel explanation for the B cell aberrations observed in the NOD mouse and may have implications for the understanding of the autoimmune pathogenesis in this mouse strain.

Animals↗
PubMed2002

Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains.

Interleukin (Il)-12 is a heterodimeric cytokine composed of 35 and 40 kD chains that plays a key role in the induction of Th1 cells, a T cell subset involved in many autoimmune diseases. We report here the cDNA sequence encoding the IL-12 p40 subunit from the autoimmune-prone non-obese diabetic (NOD) mouse, which spontaneously develops type 1 diabetes. Compared with the C57BL/6 sequence, there are two base changes that lead to amino acid replacements. Other autoimmune-prone strains, but not the diabetes-resistant NOR strain, share the same allele as NOD. We found both trans- and cis- allele-dependent effects on levels of basal and induced IL-12p40 expression. Furthermore, we show that one of these changes results in a structural change in the p40 molecule, as evidenced by the failure of a monoclonal antibody to bind NOD IL-12. These findings have implications for the predisposition to autoimmune responses in NOD and other autoimmune-prone mouse strains.

Animals↗