Implication of the CD47 pathway in autoimmune diabetes

Dugas, Véronique; Beauchamp, Claudine; Chabot‐Roy, Geneviève; Hillhouse, Erin E.; Lesage, Sylvie

doi:10.1016/j.jaut.2010.01.002

Cited by 35 publications

(64 citation statements)

References 67 publications

(87 reference statements)

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“…Interestingly, this region of chromosome 9 is comprised within the Idd2 diabetesresistance locus. As we have previously shown that 3A9 DN T cells can confer resistance to diabetes (22), it is tempting to suggest that the regulation of DN T cell proportion contributes to the diabetes-resistant trait conferred by the Idd2 locus. Moreover, the distal region of chromosome 2, which encompasses the Idd13 locus known to partially restore DN T cell number (24), exceeded the suggestive threshold along with five other genetic regions, namely, on chromosomes 1, 4, 12, and two regions on chromosome 6 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In nontransgenic mice, immunoregulatory DN T cells compose ∼1-3% of total T cells (22,(35)(36)(37). The low number of these cells not only presents a challenge for their isolation and characterization, but limits the sensitivity in detection necessary to perform a linkage analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Because of these challenges, we instead opted to take advantage of the 3A9 TCR transgenic mouse model, in which the TCR recognizes a peptide from HEL in the context of I-A k (29), allowing to investigate the genetic regulation of the proportion of DN T cells in secondary lymphoid organs. Indeed, as for other TCR transgenic systems (15,(38)(39)(40)(41)(42)(43), the 3A9 TCR transgenes enhance the proportion of DN T cells in peripheral lymphoid organs and preclude the differentiation of potentially contaminating NKT cells, increasing the sensitivity of detection of DN T cells (22)(23)(24). We thus performed an F2 out- cross of the 3A9 TCR B10.BR and 3A9 TCR NOD.H2 k parental strains, because they exhibit a significant difference in the proportion of 3A9 DN T cells in the lymph nodes (22 k ) mice varies from 5 to 34% and presents with a Gaussian distribution (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, autoimmune-prone mice carry fewer DN T cells, and injection of DN T cells has been shown to be sufficient to reduce the incidence of autoimmune diabetes in two distinct TCR transgenic mouse models (21,22). Importantly, a low DN T cell proportion, rather than defects in DN T cell function, associates with diabetes susceptibility (22)(23)(24). Together, these observations suggest that variations in DN T cell proportion correlate with susceptibility to autoimmune diabetes.…”

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confidence: 97%

“…Indeed, regulatory DN T cells have been shown to promote allograft and xenograft tolerance (12)(13)(14)(15)(16)(17), limit the incidence of graft versus host disease (17)(18)(19)(20), as well as provide resistance to autoimmune diabetes development in different animal models (21)(22)(23). Specifically, autoimmune-prone mice carry fewer DN T cells, and injection of DN T cells has been shown to be sufficient to reduce the incidence of autoimmune diabetes in two distinct TCR transgenic mouse models (21,22). Importantly, a low DN T cell proportion, rather than defects in DN T cell function, associates with diabetes susceptibility (22)(23)(24).…”

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confidence: 99%

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The Mouse Idd2 Locus Is Linked to the Proportion of Immunoregulatory Double-Negative T Cells, a Trait Associated with Autoimmune Diabetes Resistance

Collin

Dugas

Pelletier

et al. 2014

The Journal of Immunology

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Autoimmune diseases result from a break in immune tolerance. Various mechanisms of peripheral tolerance can protect against autoimmunity, including immunoregulatory CD4−CD8− double-negative (DN) T cells. Indeed, we have previously shown that diabetes-prone mouse strains exhibit a low proportion of DN T cells relative to that of diabetes-resistant mice, and that a single autologous transfer of DN T cells can impede autoimmune diabetes development, at least in the 3A9 TCR transgenic setting. In this study, we aim to understand the genetic basis for the difference in DN T cell proportion between diabetes-resistant and diabetes-prone mice. We thus perform an unbiased linkage analysis in 3A9 TCR F2 (NOD.H2k × B10.BR) mice and reveal that a locus on chromosome 9, which coincides with Idd2, is linked to the proportion of DN T cells in the lymph nodes. We generate two NOD.H2k.B10-Chr9 congenic mouse strains and validate the role of this genetic interval in defining the proportion of DN T cells. Moreover, we find that the increased proportion of DN T cells in lymphoid organs is associated with a decrease in both diabetes incidence and serum IgG Ab levels. Together, the data suggest that Idd2 is linked to DN T cell proportion and that a physiological increase in DN T cell number may be sufficient to confer resistance to autoimmune diabetes. Altogether, these findings could help identify new candidate genes for the development of therapeutic avenues aimed at modulating DN T cell number for the prevention of autoimmune diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

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The Mouse Idd2 Locus Is Linked to the Proportion of Immunoregulatory Double-Negative T Cells, a Trait Associated with Autoimmune Diabetes Resistance

Collin

Dugas

Pelletier

et al. 2014

The Journal of Immunology

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Regulation of antigen‐expressing dendritic cells by double negative regulatory T cells

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CD47 deficiency ameliorates autoimmune nephritis in Fas^lpr mice by suppressing IgG autoantibody production

Shi

Bian

Chen

et al. 2015

The Journal of Pathology

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CD47, a self-recognition marker, plays an important role in both innate and adaptive immune response. To explore the potential role of CD47 in activation of autoreactive T and B cells and the production of autoantibodies in autoimmune disease, especially systemic lupus erythematosus (SLE), we have generated CD47 knockout Faslpr (CD47−/−–Faslpr) mice and examined histopathologic changes in the kidneys, cumulative survival rates, proteinuria, extent of splenomegaly and autoantibodies, serum chemistry and immunologic parameters. In comparison with Faslpr mice, CD47−/−–Faslpr mice exhibit a prolonged lifespan and delayed autoimmune nephritis including glomerular cell proliferation, basement membrane thickening, acute tubular atrophy and vacuolization. CD47−/−–Faslpr mice have lower levels of proteinuria, associated with reduced deposition of complement C3 and C1q, and IgG but not IgM in the glomeruli, compared to the age-matched Faslpr mice. Serum levels of antinuclear antibodies and anti-double-stranded DNA antibodies are significantly lower in CD47−/−–Faslpr mice than in Faslpr mice. CD47−/−–Faslpr mice also display less pronounced splenomegaly than Faslpr mice. The mechanistic studies further suggest that CD47 deficiency impairs the antigenic challenge-induced production of IgG but not IgM, and that this effect is associated with reduction of T follicular cells and impairment of germinal center development in lymphoid tissues. In conclusion, our results demonstrate that CD47 deficiency ameliorates lupus nephritis in Faslpr mice via suppression of IgG autoantibody production.

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Implication of the CD47 pathway in autoimmune diabetes

Cited by 35 publications

References 67 publications

The Mouse Idd2 Locus Is Linked to the Proportion of Immunoregulatory Double-Negative T Cells, a Trait Associated with Autoimmune Diabetes Resistance

The Mouse Idd2 Locus Is Linked to the Proportion of Immunoregulatory Double-Negative T Cells, a Trait Associated with Autoimmune Diabetes Resistance

Regulation of antigen‐expressing dendritic cells by double negative regulatory T cells

CD47 deficiency ameliorates autoimmune nephritis in Fas^lpr mice by suppressing IgG autoantibody production

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Implication of the CD47 pathway in autoimmune diabetes

Cited by 35 publications

References 67 publications

The Mouse Idd2 Locus Is Linked to the Proportion of Immunoregulatory Double-Negative T Cells, a Trait Associated with Autoimmune Diabetes Resistance

The Mouse Idd2 Locus Is Linked to the Proportion of Immunoregulatory Double-Negative T Cells, a Trait Associated with Autoimmune Diabetes Resistance

Regulation of antigen‐expressing dendritic cells by double negative regulatory T cells

CD47 deficiency ameliorates autoimmune nephritis in Faslpr mice by suppressing IgG autoantibody production

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CD47 deficiency ameliorates autoimmune nephritis in Fas^lpr mice by suppressing IgG autoantibody production