Diabetes is Associated with Autoimmunity in the New Zealand Obese (NZO) Mouse

Melez, Kathleen A.; Harrison, Len C.; Gilliam, James N.; Steinberg, Alfred D.

doi:10.2337/diacare.20.10.835

Cited by 38 publications

(22 citation statements)

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“…Because of the early development of obesity, the strain is difficult to breed and has not been widely studied. Thus, despite their relatedness to the autoimmune-prone NZB and NZW strains, only limited analysis of the immune system of NZO mice has been reported previously (Melez et al, 1980(Melez et al, , 1985. These studies indicated that NZO shared some of the classic autoimmune abnormalities found in the NZB strain, and suggested that diabetes development might be associated with the autoimmunity.…”

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confidence: 78%

“…In diabetic males, this peri-insulitic lesion includes plasma cells, a feature not reported in autoimmune T cell-mediated diabetes in either NOD mice or BB rats. Other immune anomalies shared by NZO mice with (NZB x NZW) F1 mice include development of autoantibodies to both native and denatured single-strand DNA, as well as deposition of IgG antibodies on the glomerular basement membrane (Melez et al, 1980(Melez et al, , 1985. The progressive microcytic anemia discovered in the NZO/ HlLt mouse, with age-associated declines in reticulocytes and red cell size to levels comparable to those observed in NZB mice, indicates that this strain may be developing autoantibodies similar in origin but distinct in function to those developing in NZB mice.…”

Section: Discussionmentioning

confidence: 99%

“…These studies indicated that NZO shared some of the classic autoimmune abnormalities found in the NZB strain, and suggested that diabetes development might be associated with the autoimmunity. Among the immune anomalies reported were the development of IgM autoantibodies to native and single-stranded DNA as well as IgM immune complex deposition in kidney (Melez et al, 1980). Another immune anomaly shared with the NZB strain was splenic hypertrophy with increased basal splenocyte proliferation in vitro, but reduced mitogenstimulated proliferation.…”

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confidence: 99%

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The Diabetes-Prone NZO/HlLt Strain. I. Immunophenotypic Comparison to the Related NZB/BlNJ and NZW/LacJ Strains

Haskell

Flurkey

Duffy

et al. 2002

Laboratory Investigation

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SUMMARY:New Zealand Obese (NZO)/HlLt male mice exhibit a polygenic obesity and approximately 50% develop type 2 diabetes. This strain is known to produce a variety of autoantibodies, including autoantibodies to the insulin receptor. Because of their relatedness to the autoimmune-predisposed New Zealand Black (NZB) and New Zealand White (NZW) inbred strains, we compared NZO to its two related strains for shared hematologic and immunologic characteristics. Comparison of the three strains by serotyping and genotyping methods indicated that NZO shared with NZW the rare (recombinant) H2 z haplotype at the major histocompatibility complex. Similar to the NZB and NZW strains, spleens from NZO mice contained increased numbers of CD19 ϩ CD43 ϩ IgM ϩ B-1 B cells, a phenotype associated with natural autoantibody production. NZO mice developed a progressive microcytic anemia that was distinguished from NZB hemolytic anemia by absence of demonstrable antierythrocyte antibodies in the former. Outcross of NZO females with NZB males accelerated development of obesity and diabetes in F1 males. NZO males made B-lymphocyte-deficient by a disrupted immunoglobulin heavy chain gene did not become diabetic. These results suggest that NZO mice should be useful to investigators interested in studying the genetic contributions to autoimmunity made by the related NZW and NZB strains. Further, these results, combined with the pancreatic histopathology contained in the companion manuscript, suggest that B lymphocytes may be important contributors to diabetes pathogenesis in the NZO mouse. (Lab Invest 2002, 82:833-842).

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confidence: 78%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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The Diabetes-Prone NZO/HlLt Strain. I. Immunophenotypic Comparison to the Related NZB/BlNJ and NZW/LacJ Strains

Haskell

Flurkey

Duffy

et al. 2002

Laboratory Investigation

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“…They may be prone to autoimmune disease as the kidneys exhibit light microscopic features of both diabetic and lupus nephropathies: Glomerular proliferation, mesangial deposits, mild basement membrane thickening, and glomerulosclerosis (144). Eosinophilic nodules may be seen in some glomeruli, with occasional hyalinization of the glomerular arterioles and healing arteriolar inflammation (144).…”

Section: New Zealand Obese Micementioning

confidence: 99%

Mouse Models of Diabetic Nephropathy

Breyer¹,

Böttinger²,

Brosius³

et al. 2005

Journal of the American Society of Nephrology

483

516

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Mice provide an experimental model of unparalleled flexibility for studying mammalian diseases. Inbred strains of mice exhibit substantial differences in their susceptibility to the renal complications of diabetes. Much remains to be established regarding the course of diabetic nephropathy (DN) in mice as well as defining those strains and/or mutants that are most susceptible to renal injury from diabetes. Through the use of the unique genetic reagents available in mice (including knockouts and transgenics), the validation of a mouse model reproducing human DN should significantly facilitate the understanding of the underlying genetic mechanisms that contribute to the development of DN. Establishment of an authentic mouse model of DN will undoubtedly facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans.J (1), with costs for care of these patients projected to be $12 billion/yr by 2010 (1). Despite the high prevalence of DN, only 20 to 40% of all diabetic patients are prone to developing kidney failure, and family-based studies suggest that a significant genetic component confers risk for DN (2-4). Studies of diabetic mice suggest that, like people, mice exhibit differential susceptibility to diabetes and renal and cardiovascular diseases (5-7). In mice, identification of a strain that is prone to disease provides the relevant discriminator rather than identification of an individual who is at risk for diabetic complications. However, in contrast to people, each inbred mouse strain represents a genetically homogeneous and readily replenished resource that is amenable to repeated experimental study.Biomedical experimentation in mice affords significant advantages over experimentation in other species. These advantages include the development of diverse and unique genetic resources, including completion of a detailed map of murine genomic sequence that is freely available through the internet, as well as Ͼ450 inbred strains of mice that have been generated over the past century, with each strain genetically being homogeneous and offering a unique array of phenotypes (8,9). The availability of murine embryonic stem cells has also provided the ability to disrupt the expression and function of specific preselected genes (10 -12). Finally, repositories of mice that bear multiple mutations that alter function in each known gene are gradually being assembled (13-15). These unique resources have the potential to significantly facilitate studies into the pathogenesis of disease in mice. Through the use of the unique genetic reagents that are available in mice (including knockouts and transgenics), the identification of a robust mouse model of DN should significantly facilitate understanding of the underlying genetic mechanisms that contribute to the development of DN in people as well as in mice. Establishment of a valid mouse model of DN should also facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans. Workin...

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“…These characteristics are concomitant with poor breeding performance due to ovarian degeneration [97] and diabetic nephropathy expressed as glomerular proliferation, mesangial deposits, mild thickening of basement membrane, glomerular eosinophilic nodules and glomerulosclerosis [98][99][100]. There are research which concluded that the obesity develops independently to dietary content, the onset of diabetes being recorded earlier in mice fed with carbohydrates and fat reach diet [101].…”

Section: Animal Models Of Non-insulin Dependent Diabetes Mellitus (Nimentioning

confidence: 99%

Development of Improved Animal Models for the Study of Diabetes

Ciobotaru¹

2013

Diabetes Mellitus - Insights and Perspectives

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Diabetes is Associated with Autoimmunity in the New Zealand Obese (NZO) Mouse

Cited by 38 publications

References 0 publications

The Diabetes-Prone NZO/HlLt Strain. I. Immunophenotypic Comparison to the Related NZB/BlNJ and NZW/LacJ Strains

The Diabetes-Prone NZO/HlLt Strain. I. Immunophenotypic Comparison to the Related NZB/BlNJ and NZW/LacJ Strains

Mouse Models of Diabetic Nephropathy

Development of Improved Animal Models for the Study of Diabetes

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