Granulocyte-dendritic cell unbalance in the non-obese diabetic mice

Morin, Jean Paul; Chimènes, Amélie; Boîtard, Christian; Berthier, R; Boudaly, Sarah

doi:10.1016/s0008-8749(03)00154-0

Cited by 16 publications

(8 citation statements)

References 41 publications

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“…[6][7][8][9][10][11][12][13][14][15][16][17][18][19] These abnormalities appear to reflect cell-intrinsic defects in myeloid cells, resulting in altered numbers or maturation of dendritic cells, macrophages, and granulocytes. However, the contribution of these defects, if any, to diabetes pathogenesis remained unclear.…”

Section: Discussionmentioning

confidence: 99%

“…5 Among the phenotypic abnormalities observed in patients with T1D and NOD mice are the impaired responses of hematopoietic cells to granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3). [6][7][8][9][10][11][12][13][14][15][16][17][18][19] Alterations in the number and/or function of dendritic cells, macrophages, and granulocytes derived from cultures of hematopoietic precursors in GM-CSF and IL-3 have been described, but the contribution of these cytokine defects to altered antigen presenting cell function in vivo and the pathogenesis of diabetes remains unclear.We previously established roles for GM-CSF and IL-3 in the maintenance of immune homeostasis through promoting the efficient phagocytosis of apoptotic cells by macrophages. 20 Consistent with other strains of mice that display an impaired uptake of dying cells, 21 aged GM-CSF and, to a greater extent, GM-CSF/IL-3 doubly deficient mice developed a systemic lupus erythematous (SLE)-like disorder characterized by anti-double-stranded DNA antibodies and immune complex-mediated glomerulonephritis.…”

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confidence: 99%

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Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of β cells

Enzler

Gillessen

Dougan

et al. 2007

Blood

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The pathogenesis of type 1 diabetes (T1D) involves the immune-mediated destruction of insulin-producing ␤ cells in the pancreatic islets of Langerhans. Genetic analysis of families with a high incidence of T1D and nonobese diabetic (NOD) mice, a prototypical model of the disorder, uncovered multiple susceptibility loci, although most of the underlying immune defects remain to be delineated. Here we report that aged mice doubly deficient in granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) manifest insulitis, destruction of insulin-producing ␤ cells, and compromised glucose homeostasis. Macrophages from mutant mice produce increased levels of p40 after LPS stimulation, whereas concurrent ablation of interferon-␥ (IFN-␥) ameliorates the disease. The administration of antibodies that block cytotoxic T lymphocyte associated antigen-4 (CTLA-4) to young mutant mice precipitates the onset of insulitis and hyperglycemia. These results, together with previous reports of impaired hematopoietic responses to GM-CSF and IL-3 in patients with T1D and in NOD mice, indicate that functional deficiencies of these cytokines contribute to diabetes. IntroductionType 1 diabetes (T1D) is a chronic autoimmune disease in which a loss of tolerance to insulin-producing ␤ cells in the pancreatic islets results in impaired glucose homeostasis. 1 T1D clusters in families and is frequently associated with other autoimmune disorders, suggesting that an underlying genetic susceptibility compromises tolerance to multiple normal tissues. Nonobese diabetic (NOD) mice are widely used as a model for T1D because they display many similar aspects of disease pathogenesis and harbor a general predisposition to autoimmunity, which is modulated by genetic background. 2 In NOD mice, the development of diabetes proceeds from an initial phase of insulitis, characterized by T and B cell infiltrates in the absence of ␤-cell damage, to an aggressive stage in which ␤ cells are destroyed and glucose homeostasis is disrupted.Extensive linkage analysis of families with T1D and NOD mice yielded more than 20 genetic susceptibility loci. 3 Among these, the major histocompatibility (MHC) class II locus exerts the most potent influence on disease development. Several non-MHCrelated genes have also been implicated, including insulin, CTLA-4, IL-2, CD25, the protein tyrosine phosphatase PTPN22, and the membrane transporter NRAMP-1. Nonetheless, multiple additional loci remain to be identified, although characterization of these gene products has been hampered by the large number of immune defects associated with disease and a limited understanding of the key pathogenic mechanisms.Antigen-presenting cells are thought to play an important role in the development of diabetes. 4 Dendritic cells and macrophages contribute to the maintenance of tolerance through central deletion of autoreactive thymocytes and the induction of recessive and dominant modes of suppression in the periphery. 5 Among the phenotypic abnormalities observed in patients ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of β cells

Enzler

Gillessen

Dougan

et al. 2007

Blood

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“…However, the authors' used the DC properties of low buoyant density and adherence to glass to isolate and enrich for DCs (14). A variety of factors may influence the number of DCs in a tissue or animal at a given time, including infection, chronic disease states such as diabetes, hormones such as estradiol, nutrients such as vitamins A and D, as well as others (15)(16)(17)(18)(19)(20). However, previous methods used to analyze DCs have used enrichment techniques from pooled samples, either multiple tissue or animal sources, to obtain sufficient numbers of cells for analysis leading to potentially high variability and inaccurate DC number assessments.…”

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confidence: 99%

“…Despite numerous publications quantifying DCs in tissues and animals, accurate analysis relies on in vivo expansion of DC before isolation, enrichment techniques, or positive or negative selection procedures (16,(21)(22)(23). Also DC identification using flow cytometry has been documented in Cytometry, Part A (24)(25)(26)(27).…”

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confidence: 99%

The identification and enumeration of dendritic cell populations from individual mouse spleen and Peyer's patches using flow cytometric analysis

Duriancik

Hoag

2009

Cytometry Pt A

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Dendritic cell (DC) research currently involves pooling of tissues from multiple animals followed by enrichment techniques to obtain sufficient numbers of DCs for analysis. Enrichment techniques take advantage of DC adherence, buoyant density properties, and/or positive or negative selection of cell populations using monoclonal antibodies. However, enrichment techniques may significantly change the maturation and/or activation status of DCs or selectively eliminate one or more subpopulations of DCs. To overcome these drawbacks, we designed a multicolor flow cytometric technique for simultaneous analysis of DC populations from tissues of individual mice. The spleens and Peyer's patches were mechanically and enzymatically digested, then incubated with a panel of six monoclonal antibody-fluorochrome direct conjugate reagents. A BD 1 Biosciences LSR II flow cytometer and FCS Express 1 software were used to identify three subtypes of mature DCs (myeloid, lymphoid, and plasmacytoid), precursor DCs, polymorphonuclear neutrophils, B lymphocytes, and Gr-1 1 /CD8a 1 memory T lymphocytes in the spleen. Likewise, we also identified these DC subpopulations and B lymphocytes in the Peyer's patches. The three key parameters in analysis of the DC populations were bi-exponential plotting in data analysis, collection of a minimum of 50,000 total events, and accurate color compensation. This procedure to analyze DCs from individual mice can lead to further understanding of the role of DCs in many other model systems as well as better understanding of how dietary or physiological factors may affect in vivo DC homeostasis. ' 2009 International Society for Advancement of Cytometry

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“…Like many cytokines involved in hemopoiesis, GM-CSF uses Jak2 activation of the signal transduction/transcriptional regulator proteins, STAT5A and STAT5B, to influence gene regulation (6 -14). In immature myeloid cells and unactivated monocytes, GM-CSF can induce signaling through both full-length STAT5A (94 -96K) and STAT5B (94 -92k) isoforms as well as through post-translationally modified truncated isoforms (77K and 80K) (8,9,(15)(16)(17). During cytokine-induced differentiation, truncated STAT5 isoforms can act as repressors of gene transcription in immature/unactivated cells, whereas full-length STAT5 isoforms induced in mature/activated cells act as gene transcription activators (7,8,(15)(16)(17).…”

mentioning

confidence: 99%

Nonobese Diabetic Mouse Congenic Analysis Reveals Chromosome 11 Locus Contributing to Diabetes Susceptibility, Macrophage STAT5 Dysfunction, and Granulocyte-Macrophage Colony-Stimulating Factor Overproduction

Litherland

Grebe

Belkin

et al. 2005

The Journal of Immunology

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Unstimulated monocytes of at-risk/type 1 diabetic humans and macrophages of the NOD mouse have markedly elevated autocrine GM-CSF production and persistent STAT5 phosphorylation. We analyzed the relationship between GM-CSF production and persistent STAT5 phosphorylation in NOD macrophages using reciprocal congenic mouse strains containing either diabetes-susceptible NOD (B6.NODC11), or diabetes-resistant C57L (NOD.LC11) loci on chromosome 11. These intervals contain the gene for GM-CSF (Csf2; 53.8 Mb) and those for STAT3, STAT5A, and STAT5B (Stat3, Stat5a, and Stat5b; 100.4–100.6 Mb). High GM-CSF production and persistent STAT5 phosphorylation in unactivated NOD macrophages can be linked to a region (44.9–55.7 Mb) containing the Csf2 gene, but not the Stat3/5a/5b genes. This locus, provisionally called Idd4.3, is upstream of the previously described Idd4.1 and Idd4.2 loci. Idd4.3 encodes an abundance of cytokine genes that use STAT5 in their macrophage activation signaling and contributes ∼50% of the NOD.LC11 resistance to diabetes.

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Granulocyte-dendritic cell unbalance in the non-obese diabetic mice

Cited by 16 publications

References 41 publications

Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of β cells

Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of β cells

The identification and enumeration of dendritic cell populations from individual mouse spleen and Peyer's patches using flow cytometric analysis

Nonobese Diabetic Mouse Congenic Analysis Reveals Chromosome 11 Locus Contributing to Diabetes Susceptibility, Macrophage STAT5 Dysfunction, and Granulocyte-Macrophage Colony-Stimulating Factor Overproduction

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