scholarly journals Nonobese Diabetic (NOD) Mice Lack a Protective B-Cell Response against the “Nonlethal” Plasmodium yoelii 17XNL Malaria Protozoan

2016 ◽  
Vol 2016 ◽  
pp. 1-9
Author(s):  
Mirian Mendoza ◽  
Luis Pow Sang ◽  
Qi Qiu ◽  
Sofia Casares ◽  
Teodor-D. Brumeanu
Keyword(s):  
B Cell ◽  
Nod Mice ◽  
Treg Cells ◽  
Plasmodium Yoelii ◽  
Mouse Strains ◽  
Nonobese Diabetic ◽  
Blood Stage Infection ◽  
Protective Antibodies ◽  
Antibody Secretion

Background. Plasmodium yoelii 17XNL is a nonlethal malaria strain in mice of different genetic backgrounds including the C57BL/6 mice (I-Ab/I-Enull) used in this study as a control strain. We have compared the trends of blood stage infection with the nonlethal murine strain of P. yoelii 17XNL malaria protozoan in immunocompetent Nonobese Diabetic (NOD) mice prone to type 1 diabetes (T1D) and C57BL/6 mice (control mice) that are not prone to T1D and self-cure the P. yoelii 17XNL infection. Prediabetic NOD mice could not mount a protective antibody response to the P. yoelii 17XNL-infected red blood cells (iRBCs), and they all succumbed shortly after infection. Our data suggest that the lack of anti-P. yoelii 17XNL-iRBCs protective antibodies in NOD mice is a result of parasite-induced, Foxp3+ T regulatory (Treg) cells able to suppress the parasite-specific antibody secretion. Conclusions. The NOD mouse model may help in identifying new mechanisms of B-cell evasion by malaria parasites. It may also serve as a more accurate tool for testing antimalaria therapeutics due to the lack of interference with a preexistent self-curing mechanism present in other mouse strains.

scholarly journals Foxp3+Regulatory T Cells in Mouse Models of Type 1 Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Cathleen Petzold ◽  
Julia Riewaldt ◽  
Deepika Watts ◽  
Tim Sparwasser ◽  
Sonja Schallenberg ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Mouse Models ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Treg Cells ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models ◽  
Nonobese Diabetic ◽  
Human Type 1 Diabetes

Studies on human type 1 diabetes (T1D) are facilitated by the availability of animal models such as nonobese diabetic (NOD) mice that spontaneously develop autoimmune diabetes, as well as a variety of genetically engineered mouse models with reduced genetic and pathogenic complexity, as compared to the spontaneous NOD model. In recent years, increasing evidence has implicated CD4+CD25+regulatory T (Treg) cells expressing the transcription factor Foxp3 in both the breakdown of self-tolerance and the restoration of immune homeostasis in T1D. In this paper, we provide an overview of currently available mouse models to study the role of Foxp3+Treg cells in the control of destructiveβcell autoimmunity, including a novel NOD model that allows specific and temporally controlled deletion of Foxp3+Treg cells.

scholarly journals Rodent Models for Investigating the Dysregulation of Immune Responses in Type 1 Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Feng-Cheng Chou ◽  
Heng-Yi Chen ◽  
Shyi-Jou Chen ◽  
Mei-Cho Fang ◽  
Huey-Kang Sytwu
Keyword(s):  
Type 1 Diabetes ◽  
Animal Studies ◽  
Genetic Manipulation ◽  
Nod Mice ◽  
Environmental Parameters ◽  
Conditional Knockout ◽  
Therapeutic Approaches ◽  
Nonobese Diabetic ◽  
Genetically Manipulated

Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells that selectively destroy the insulin-producingβcells. Previous reports based on epidemiological and animal studies have demonstrated that both genetic factors and environmental parameters can either promote or attenuate the progression of autoimmunity. In recent decades, several inbred rodent strains that spontaneously develop diabetes have been applied to the investigation of the pathogenesis of T1D. Because the genetic manipulation of mice is well developed (transgenic, knockout, and conditional knockout/transgenic), most studies are performed using the nonobese diabetic (NOD) mouse model. This paper will focus on the use of genetically manipulated NOD mice to explore the pathogenesis of T1D and to develop potential therapeutic approaches.

scholarly journals Histidine Decarboxylase Deficiency Prevents Autoimmune Diabetes in NOD Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Manal Alkan ◽  
François Machavoine ◽  
Rachel Rignault ◽  
Julie Dam ◽  
Michel Dy ◽  
...  
Keyword(s):  
Histidine Decarboxylase ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Wild Type ◽  
Gene Encoding ◽  
Nonobese Diabetic ◽  
Endogenous Histamine ◽  
Wild Type Counterpart

Recent evidence has highlighted the role of histamine in inflammation. Since this monoamine has also been strongly implicated in the pathogenesis of type-1 diabetes, we assessed its effect in the nonobese diabetic (NOD) mouse model. To this end, we used mice (inactivated) knocked out for the gene encoding histidine decarboxylase, the unique histamine-forming enzyme, backcrossed on a NOD genetic background. We found that the lack of endogenous histamine in NOD HDC−/−mice decreased the incidence of diabetes in relation to their wild-type counterpart. Whereas the proportion of regulatory T and myeloid-derived suppressive cells was similar in both strains, histamine deficiency was associated with increased levels of immature macrophages, as compared with wild-type NOD mice. Concerning the cytokine pattern, we found a decrease in circulating IL-12 and IFN-γin HDC−/−mice, while IL-6 or leptin remained unchanged, suggesting that histamine primarily modulates the inflammatory environment. Paradoxically, exogenous histamine given to NOD HDC−/−mice provided also protection against T1D. Our study supports the notion that histamine is involved in the pathogenesis of diabetes, thus providing additional evidence for its role in the regulation of the immune response.

scholarly journals Genetic and functional data identifying Cd101 as a type 1 diabetes (T1D) susceptibility gene in nonobese diabetic (NOD) mice

PLoS Genetics ◽  
2019 ◽  
Vol 15 (6) ◽  
pp. e1008178 ◽  
Author(s):  
Jochen Mattner ◽  
Javid P. Mohammed ◽  
Michael E. Fusakio ◽  
Claudia Giessler ◽  
Carl-Philipp Hackstein ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Functional Data ◽  
Susceptibility Gene ◽  
Nod Mice ◽  
Nonobese Diabetic

scholarly journals Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Mar Gacias ◽  
Sevasti Gaspari ◽  
Patricia-Mae G Santos ◽  
Sabrina Tamburini ◽  
Monica Andrade ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Social Behavior ◽  
Gut Microbiota ◽  
Nod Mice ◽  
Mouse Strains ◽  
Social Avoidance ◽  
Nonobese Diabetic ◽  
Gene Environment ◽  
Transcriptional Changes

Gene-environment interactions impact the development of neuropsychiatric disorders, but the relative contributions are unclear. Here, we identify gut microbiota as sufficient to induce depressive-like behaviors in genetically distinct mouse strains. Daily gavage of vehicle (dH2O) in nonobese diabetic (NOD) mice induced a social avoidance behavior that was not observed in C57BL/6 mice. This was not observed in NOD animals with depleted microbiota via oral administration of antibiotics. Transfer of intestinal microbiota, including members of the Clostridiales, Lachnospiraceae and Ruminococcaceae, from vehicle-gavaged NOD donors to microbiota-depleted C57BL/6 recipients was sufficient to induce social avoidance and change gene expression and myelination in the prefrontal cortex. Metabolomic analysis identified increased cresol levels in these mice, and exposure of cultured oligodendrocytes to this metabolite prevented myelin gene expression and differentiation. Our results thus demonstrate that the gut microbiota modifies the synthesis of key metabolites affecting gene expression in the prefrontal cortex, thereby modulating social behavior.

scholarly journals Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice following Oral Administration

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Susanne W. Bruun ◽  
Knud Josefsen ◽  
Julia T. Tanassi ◽  
Aleš Marek ◽  
Martin H. F. Pedersen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Degradation Products ◽  
Intestinal Barrier ◽  
Nod Mice ◽  
Radioactive Label ◽  
Nonobese Diabetic ◽  
Gliadin Peptide ◽  
Gliadin Peptides

Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates that, even in normal animals, large gliadin fragments can reach the pancreas. If applicable to humans, the increased gut permeability in prediabetes and type 1 diabetes patients could expose beta cells directly to gliadin fragments. Here they could initiate inflammation and induce beta cell stress and thus contribute to the development of type 1 diabetes.

scholarly journals Postnatal Hematopoiesis and Gut Microbiota in NOD Mice Deviate from C57BL/6 Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Dina Silke Malling Damlund ◽  
Stine Broeng Metzdorff ◽  
Jane Preuss Hasselby ◽  
Maria Wiese ◽  
Mia Lundsager ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Adaptive Immunity ◽  
Early Life ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Mouse Strains ◽  
Newborn Mice ◽  
Nonobese Diabetic ◽  
Splenic Cell ◽  
Cell Profile

Neonatal studies in different mouse strains reveal that early life colonization affects the development of adaptive immunity in mice. The nonobese diabetic (NOD) mouse spontaneously develops autoimmune diabetes, but neonatal studies of NOD mice are lacking. We hypothesized that NOD mice deviate from another much used mouse strain, C57BL/6, with respect to postnatal microbiota and/or hematopoiesis and compared this in newborn mice of dams housed under the same conditions. A distinct bacteria profile rich instaphylococciwas found at postnatal days (PND) 1–4 in NOD mice. Furthermore, a distinct splenic cell profile high in a granulocytic phenotype was evident in the neonatal NOD mice whereas neonatal C57BL/6 mice showed a profile rich in monocytes. Neonatal expression ofReg3gandMuc2in the gut was deviating in NOD mice and coincided with fewer bacteria attaching to the Mucosal surface in NOD compared to C57BL/6 mice.

scholarly journals TLR9-deficiency in B cells Promotes Immune Tolerance via IL-10 in a Type 1 Diabetes Mouse Model

2020 ◽  
Author(s):  
Ada Admin ◽  
Sha Sha ◽  
James A Pearson ◽  
Jian Peng ◽  
Youjia Hu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
B Cells ◽  
B Cell ◽  
Nod Mice ◽  
Adaptive Immune ◽  
Immune Molecule ◽  
And Function ◽  
Intrinsic Effect ◽  
Specific Deletion

Toll-like receptor 9 (TLR9) is highly expressed in B cells and B cells are important in the pathogenesis of type 1 diabetes (T1D) development. However, the intrinsic effect of TLR9 in B cells on beta cell autoimmunity is not known. To fill this knowledge gap, we generated non-obese diabetic (NOD) mice with a B cell-specific deficiency of TLR9 (TLR9<sup>fl/fl</sup>/CD19-Cre+ NOD). The B cell-specific deletion of TLR9 resulted in near complete protection from T1D development. Diabetes protection was accompanied by an increased proportion of IL-10-producing B cells. We also found that TLR9-deficient B cells were hyporesponsive to both innate and adaptive immune-stimuli. This suggested that TLR9 in B cells modulates T1D susceptibility in NOD mice by changing the frequency and function of IL-10-producing B cells. Molecular analysis revealed a network of TLR9 with MMPs, TIMP1 and CD40, all of which are inter-connected with IL-10. Our study has highlighted an important connection of an innate immune molecule in B cells to the immuno-pathogenesis of T1D. Thus, targeting the TLR9 pathway, specifically in B cells, may provide a novel therapeutic strategy for T1D treatment.

scholarly journals Reversal of autoimmunity by mixed chimerism enables reactivation of β cells and transdifferentiation of α cells in diabetic NOD mice

2020 ◽  
Vol 117 (49) ◽  
pp. 31219-31230
Author(s):  
Shanshan Tang ◽  
Mingfeng Zhang ◽  
Samuel Zeng ◽  
Yaxun Huang ◽  
Melissa Qin ◽  
...  
Keyword(s):  
Nod Mice ◽  
Lineage Tracing ◽  
Mixed Chimerism ◽  
Cell Regeneration ◽  
Β Cells ◽  
Β Cell ◽  
Nonobese Diabetic ◽  
Autoimmune Destruction ◽  
Epidermal Growth

Type 1 diabetes (T1D) results from the autoimmune destruction of β cells, so cure of firmly established T1D requires both reversal of autoimmunity and restoration of β cells. It is known that β cell regeneration in nonautoimmune diabetic mice can come from differentiation of progenitors and/or transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune nonobese diabetic (NOD) mice remains unclear. Here, we show that, after reversal of autoimmunity by induction of haploidentical mixed chimerism, administration of gastrin plus epidermal growth factor augments β cell regeneration and normalizes blood glucose in the firmly established diabetic NOD mice. Using transgenic NOD mice with inducible lineage-tracing markers for insulin-producing β cells, Sox9+ductal progenitors, Nestin+mesenchymal stem cells, and glucagon-producing α cells, we have found that both reactivation of dysfunctional low-level insulin expression (insulinlo) β cells and neogenesis contribute to the regeneration, with the latter predominantly coming from transdifferentiation of α cells. These results indicate that, after reversal of autoimmunity, reactivation of β cells and transdifferentiation of α cells can provide sufficient new functional β cells to reach euglycemia in firmly established T1D.

scholarly journals Effects of hyperglycemia and aging on nuclear sirtuins and DNA damage of mouse hepatocytes

2013 ◽  
Vol 24 (15) ◽  
pp. 2467-2476 ◽  
Author(s):  
Flávia Gerelli Ghiraldini ◽  
Ana Carolina Vitolo Crispim ◽  
Maria Luiza Silveira Mello
Keyword(s):  
Dna Damage ◽  
Cell Metabolism ◽  
Nod Mice ◽  
Mouse Strains ◽  
Compensatory Mechanism ◽  
New Therapeutic Approaches ◽  
Nonobese Diabetic ◽  
Damage Repair ◽  
Younger Age ◽  
Mouse Hepatocytes

Hyperglycemia, like aging, induces chromatin remodeling in mouse hepatocytes in comparison to normoglycemia and younger age, respectively. Changes in glucose metabolism also affect the action and expression of sirtuins, promoting changes in chromatin conformation and dynamics. Here we investigate the abundance and activity of the nuclear sirtuins Sirt1, Sirt6, and Sirt7 in mouse hepatocytes in association with specific histone acetylation, DNA damage, and the activation of nucleolar organizing regions (NORs) in hyperglycemic nonobese diabetic (NOD) and old normoglycemic BALB/c mouse strains. Higher levels of Sirt1 and PGC-1α and increased expression of gluconeogenesis pathway genes are found in the hyperglycemic NOD mice. Increased Sirt6 abundance is found in the hyperglycemic NOD mice, which might increase DNA damage repair. With aging, lower Sirt1 abundance and activity, increased acetylated histone modifications and Sirt7 levels, and NOR methylation are found. Thus, whereas in normal aging cell metabolism is reduced, in the diabetic mice a compensatory mechanism may elevate Sirt1 and Sirt6 levels, increasing gluconeogenesis and DNA repair from the oxidative damage caused by hyperglycemia. Therefore understanding the regulation of epigenetic factors in diabetes and aging is crucial for the development of new therapeutic approaches that could prevent diseases and improve quality of life.

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