Non-major histocompatibility complex-linked diabetes susceptibility loci on chromosomes 4 and 13 in a backcross of the DP-BB/Wor rat to the WF rat.

Martin, A.-M.; Blankenhorn, Elizabeth P.; Maxson, M. N.; Zhao, Meng; Leif, Jean; Mordes, J P; Greiner, Dale L.

doi:10.2337/diabetes.48.1.50

Cited by 41 publications

(58 citation statements)

References 54 publications

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“…For this reason, we performed parallel analyses in the BBDR rat, which does not share the lymphopenia mutation of the BBDP rat but remains susceptible to the induction of diabetes as a function of other shared genetic loci (25,36,37). We document that these animals have normal numbers of IELs, but even before treatment to induce diabetes, they appear to be deficient in IENK cell number and function.…”

Section: Discussionmentioning

confidence: 99%

Deficiencies in Gut NK Cell Number and Function Precede Diabetes Onset in BB Rats

Todd

Forsberg

Greiner

et al. 2004

The Journal of Immunology

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Defects in the intestinal immune system may contribute to the pathogenesis of autoimmune diseases. Intraepithelial lymphocytes represent a substantial fraction of gut-associated lymphocytes, but their function in mucosal immunity is unclear. A newly described population of NK cells that spontaneously secrete IL-4 and IFN-γ is present in the intraepithelial lymphocyte compartment of the rat. We hypothesized that defects in the number or function of these cells would be present in rats susceptible to autoimmunity. We report that the number of NKR-P1A+CD3− intraepithelial NK (IENK) cells is deficient before onset of spontaneous autoimmune diabetes in diabetes-prone BB (BBDP) rats. The absolute number of recoverable IENK cells was only ∼8% of that observed in WF rats. Bone marrow transplantation from histocompatible WF donors reversed the IENK cell deficiency (and prevented diabetes) in these animals, suggesting a hemopoietic origin for their IENK cell defect. Analysis of diabetes-resistant BB rats, which develop autoimmune diabetes only after perturbation of the immune system, revealed IENK cell numbers intermediate between that of BBDP and WF rats. IENK cells were selectively depleted during treatment to induce diabetes. Prediabetic BBDP and diabetes-resistant BB animals also exhibited defective IENK cell function, including decreased NK cell cytotoxicity and reduced secretion of IL-4 and IFN-γ. IENK functional defects were also observed in LEW and BN rats, which are susceptible to induced autoimmunity, but not in WF, DA, or F344 rats, which are resistant. Defects in IENK cell number and function may contribute to the pathogenesis of autoimmune diseases including type 1 diabetes.

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Section: Discussionmentioning

confidence: 99%

Deficiencies in Gut NK Cell Number and Function Precede Diabetes Onset in BB Rats

Todd

Forsberg

Greiner

et al. 2004

The Journal of Immunology

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“…A second non-MHC locus strongly associated with diabetes susceptibility present on chromosome 4 has been termed iddm4 [39]. The homozygous presence of the lymphopenia gene (lyp) on chromosome 4 (iddm1) appears to remove regulatory T-cells, thus permitting the susceptibility for diabetes determined by iddm2 and iddm4 to be expressed [39,40]. In the absence of regulation due to the homozygous presence of lyp, T-cell-mediated b-cell destruction and overt hyperglycemia ensues.…”

Section: Discussionmentioning

confidence: 99%

Thymic expression of insulin-related genes in an animal model of autoimmune type 1 diabetes

Kecha-Kamoun

Achour

Martens

et al. 2001

Diabetes Metab. Res. Rev.

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Background Insulin and multiple other autoantigens have been implicated in the pathogenesis of autoimmune type 1 diabetes, but the origin of immunological self-reactivity specifically oriented against insulin-secreting islet b-cells remains obscure. The primary objective of the present study was to investigate the hypothesis that a defect in thymic central T-cell selftolerance of the insulin hormone family could contribute to the pathophysiology of type 1 diabetes. This hypothesis was investigated in a classic animal model of type 1 diabetes, the Bio-Breeding (BB) rat.

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“…As shown in Table III ϩ cells expressing CD25 in lymphoid tissues of BBDR and WF rats. These strains share the same MHC haplotype, but only the BBDR rat can readily be induced to express autoimmune diabetes (1,24,30,32). We therefore tested the hypothesis that differences in CD4 ϩ CD25 ϩ cells could contribute to this difference in diabetes susceptibility.…”

Section: Cd4mentioning

confidence: 99%

A Regulatory CD4+ T Cell Subset in the BB Rat Model of Autoimmune Diabetes Expresses Neither CD25 Nor Foxp3

Hillebrands

Whalen

Visser

et al. 2006

The Journal of Immunology

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Biobreeding (BB) rats model type 1 autoimmune diabetes (T1D). BB diabetes-prone (BBDP) rats develop T1D spontaneously. BB diabetes-resistant (BBDR) rats develop T1D after immunological perturbations that include regulatory T cell (Treg) depletion plus administration of low doses of a TLR ligand, polyinosinic-polycytidylic acid. Using both models, we analyzed CD4+CD25+ and CD4+CD45RC− candidate rat Treg populations. In BBDR and control Wistar Furth rats, CD25+ T cells comprised 5–8% of CD4+ T cells. In vitro, rat CD4+CD25+ T cells were hyporesponsive and suppressed T cell proliferation in the absence of TGF-β and IL-10, suggesting that they are natural Tregs. In contrast, CD4+CD45RC− T cells proliferated in vitro in response to mitogen and were not suppressive. Adoptive transfer of purified CD4+CD25+ BBDR T cells to prediabetic BBDP rats prevented diabetes in 80% of recipients. Surprisingly, CD4+CD45RC−CD25− T cells were equally protective. Quantitative studies in an adoptive cotransfer model confirmed the protective capability of both cell populations, but the latter was less potent on a per cell basis. The disease-suppressing CD4+CD45RC−CD25− population expressed PD-1 but not Foxp3, which was confined to CD4+CD25+ cells. We conclude that CD4+CD25+ cells in the BBDR rat act in vitro and in vivo as natural Tregs. In addition, another population that is CD4+CD45RC−CD25− also participates in the regulation of autoimmune diabetes.

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Non-major histocompatibility complex-linked diabetes susceptibility loci on chromosomes 4 and 13 in a backcross of the DP-BB/Wor rat to the WF rat.

Cited by 41 publications

References 54 publications

Deficiencies in Gut NK Cell Number and Function Precede Diabetes Onset in BB Rats

Deficiencies in Gut NK Cell Number and Function Precede Diabetes Onset in BB Rats

Thymic expression of insulin-related genes in an animal model of autoimmune type 1 diabetes

A Regulatory CD4+ T Cell Subset in the BB Rat Model of Autoimmune Diabetes Expresses Neither CD25 Nor Foxp3

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