Aberrancies in the differentiation and maturation of dendritic cells from bone-marrow precursors are linked to various genes on chromosome 4 and other chromosomes of the BB-DP rat

Sommandas, Vinod; Rutledge, Elizabeth A.; Yserloo, Brian Van; Fuller, Jessica; Lernmark, Åke; Drexhage, Hemmo A.

doi:10.1016/j.jaut.2005.05.002

Cited by 12 publications

(6 citation statements)

References 51 publications

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“…In line with this, in a previous study by our group, we observed no clear phenotypic or functional abnormalities in DCs isolated from NOD mouse LNs and spleen, whereas such abnormalities could be detected easily when studying DCs generated from NOD BM precursors or NOD circulating monocytes [31,33]. In these studies, DC precursors isolated from the BM of NOD mice showed proliferation/differentiation abnormalities, while in vitro, these precursors gave rise to DCs with a spontaneous, high proinflammatory profile [34,35]. These abnormal DCs have a high level of NF-B, high IL-12, and low IL-10 expression [36][37][38][39], and such DCs are incapable of sufficiently sustaining the proliferation of Treg populations [40].…”

Section: Discussionsupporting

confidence: 84%

Reduced numbers of dendritic cells with a tolerogenic phenotype in the prediabetic pancreas of NOD mice

Welzen-Coppens

Helden-Meeuwsen

Leenen

et al. 2012

Journal of Leukocyte Biology

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The NOD mouse is a widely used animal model of autoimmune diabetes. Prior to the onset of lymphocytic insulitis, DCs accumulate at the islet edges. Our recent work indicated that these DCs may derive from aberrantly proliferating local precursor cells. As CD8α(+) DCs play a role in tolerance induction in steady-state conditions, we hypothesized that the autoimmune phenotype might associate with deficiencies in CD8α(+) DCs in the prediabetic NOD mouse pancreas. We studied CD8α(+) DCs in the pancreas and pLNs of NOD and control mice, focusing on molecules associated with tolerance induction (CD103, Langerin, CLEC9A, CCR5). mRNA expression levels of tolerance-modulating cytokines were studied in pancreatic CD8α(+) DCs of NOD and control mice. In the NOD pancreas, the frequency of CD8α(+)CD103(+)Langerin(+) cells was reduced significantly compared with control mice. NOD pancreatic CD8α(+)CD103(+)Langerin(+) DCs expressed reduced levels of CCR5, CLEC9A, and IL-10 as compared with control DCs. These alterations in the CD8α(+)CD103(+)Langerin(+) DC population were not present in pLNs. We demonstrate local abnormalities in the CD8α(+) DC population in the prediabetic NOD pancreas. These data suggest that abnormal differentiation of pancreatic DCs contributes to loss of tolerance, hallmarking the development of autoimmune diabetes.

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Section: Discussionsupporting

confidence: 84%

Reduced numbers of dendritic cells with a tolerogenic phenotype in the prediabetic pancreas of NOD mice

Welzen-Coppens

Helden-Meeuwsen

Leenen

et al. 2012

Journal of Leukocyte Biology

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“…DC precursors in BM of NOD mice and BB-DP rats also show proliferation/differentiation abnormalities and from these precursors abnormal ''steady state'' DCs arise with a spontaneous high pro-inflammatory set point [29,30]. These abnormal DCs have a high level of NF-kB and a high acid phosphatase, high IL-12 and low IL-10 expression [31][32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

et al. 2011

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The non-obese diabetic (NOD) mouse is a widely used animal model for the study of human diabetes. Before the start of lymphocytic insulitis, DC accumulation around islets of Langerhans is a hallmark for autoimmune diabetes development in this model. Previous experiments indicated that an inflammatory influx of these DCs in the pancreas is less plausible. Here, we investigated whether the pancreas contains DC precursors and whether these precursors contribute to DC accumulation in the NOD pancreas. Fetal pancreases of NOD and control mice were isolated followed by FACS using ER-MP58, Ly6G, CD11b and Ly6C. Sorted fetal pancreatic ER-MP58 1 cells were cultured with GM-CSF and tested for DC markers and antigen processing. CFSE labeling and Ki-67 staining were used to determine cell proliferation in cultures and tissues. Ly6C hi and Ly6C low precursors were present in fetal pancreases of NOD and control mice. These precursors developed into CD11c 1 MHCII 1 CD86 1 DCs capable of processing DQ-OVA. ER-MP58 1 cells in the embryonic and pre-diabetic NOD pancreas had a higher proliferation capacity. Our observations support a novel concept that pre-diabetic DC accumulation in the NOD pancreas is due to aberrant enhanced proliferation of local precursors, rather than to aberrant ''inflammatory infiltration'' from the circulation. IntroductionThe non-obese diabetic (NOD) mouse is used as a spontaneous model to study the development of type 1 diabetes [1]. Lymphocytes accumulate around and in the islets of Langerhans in NOD mice from around 6 weeks of age onwards, which results in the destruction of b-cells followed by a decrease in insulin production leading to diabetes. Prior to T-and B-cell accumulation the number of DCs increases in the pancreas and concentrates around the islets (from the age of 5 weeks onwards) [2,3]. DCs are potent APCs capable of stimulating both naïve and memory T cells [4]. The observation that DCs are the first immune cells to increase in number in the NOD pancreas points to a crucial role for DCs in the initiation of the islet autoimmune reaction. Such a role was recently proven by the demonstration that a temporal depletion of DCs totally abrogated the development of insulitis and diabetes in the NOD mouse model [5].Early studies have shown that BM precursors give rise to monocytes in blood, which circulate for a few days before they migrate into tissue where they develop into different types of DCs and macrophages. Blood monocytes can be subdivided into at least two subsets based on their Ly6C expression: classical and The nonclassical monocytes, which are Ly6C low , patrol the endothelium of the blood vessels and are required for rapid tissue invasion at the site of an infection [7]. Ly6C low monocytes are considered CD11c À , but some studies have reported the expression of CD11c on these cells [6,8]. Both types of monocytes are F4/80 1 and CD86 À [6].Data are accumulating on the presence of local tissue precursors for DCs and macrophages and the contribution of these precursors to DC and ma...

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“…lyp/lyp T-and B-lymphocytes, as well as macrophages and dendritic cells (12,13,15,16). Genome-wide linkage analysis for the diabetes phenotype have identified additional loci after crossing different inbred BB rats with DA rats (Iddm3 on chromosome 18) (17), WF rats (Iddm4 and Iddm5 on chromosomes 4 and 13, respectively) (18,19), and SHR rats (Iddm6 on the X chromosome) (20).…”

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Introgression of F344 Rat Genomic DNA on BB Rat Chromosome 4 Generates Diabetes-Resistant Lymphopenic BB Rats

et al. 2006

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Aberrancies in the differentiation and maturation of dendritic cells from bone-marrow precursors are linked to various genes on chromosome 4 and other chromosomes of the BB-DP rat

Cited by 12 publications

References 51 publications

Reduced numbers of dendritic cells with a tolerogenic phenotype in the prediabetic pancreas of NOD mice

Reduced numbers of dendritic cells with a tolerogenic phenotype in the prediabetic pancreas of NOD mice

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

Introgression of F344 Rat Genomic DNA on BB Rat Chromosome 4 Generates Diabetes-Resistant Lymphopenic BB Rats

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