Tissue- and age-specific changes in gene expression during disease induction and progression in NOD mice

Kodama, Keiichi; Butte, Atul J.; Creusot, Rémi J.; Su, Leon; Sheng, Deqiao; Hartnett, Mark; Iwai, Hideyuki; Soares, Luis; Fathman, C. Garrison

doi:10.1016/j.clim.2008.07.028

Cited by 55 publications

(58 citation statements)

References 18 publications

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“…Although several studies have been performed to characterise diabetes predisposing genes and proteins, most of them have focused on the role of the immune system in this process instead of the islets themselves [8][9][10][11][12]26] or expression levels of only mRNA [9] or proteins [27] were investigated.…”

Section: Discussionmentioning

confidence: 99%

“…The NOD mouse has been used worldwide to investigate the genes, proteins or pathways implicated in type 1 diabetes susceptibility, with a main focus on the role of the immune system [8][9][10][11][12]. However, increasing evidence points towards a role for the beta cells themselves in the initiation of the autoimmune process and attraction/activation of immune cells; however, the exact mechanisms involved remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Early differences in islets from prediabetic NOD mice: combined microarray and proteomic analysis

et al. 2017

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Aims/hypothesis Type 1 diabetes is an endocrine disease where a long preclinical phase, characterised by immune cell infiltration in the islets of Langerhans, precedes elevated blood glucose levels and disease onset. Although several studies have investigated the role of the immune system in this process of insulitis, the importance of the beta cells themselves in the initiation of type 1 diabetes is less well understood. The aim of this study was to investigate intrinsic differences present in the islets from diabetes-prone NOD mice before the onset of insulitis. Methods The islet transcriptome and proteome of 2-3-week-old mice was investigated by microarray and 2-dimensional difference gel electrophoresis (2D-DIGE), respectively. Subsequent analyses using sophisticated pathway analysis and ranking of differentially expressed genes and proteins based on their relevance in type 1 diabetes were performed. Results In the preinsulitic period, alterations in general pathways related to metabolism and cell communication were already present. Additionally, our analyses pointed to an important role for post-translational modifications (PTMs), especially citrullination by PAD2 and protein misfolding due to low expression levels of protein disulphide isomerases (PDIA3, 4 and 6), as causative mechanisms that induce beta cell stress and potential auto-antigen generation. Conclusions/interpretation We conclude that the pancreatic islets, irrespective of immune differences, may contribute to the initiation of the autoimmune process. Data availability All microarray data are available in the ArrayExpress database (www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-5264.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Early differences in islets from prediabetic NOD mice: combined microarray and proteomic analysis

et al. 2017

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“…At the same period, islet-specific antigen presentation and activation of autoreactive lymphocytes occur in the pLN and early insulitis appears. Accordingly, the gene expression profile of NOD pLNs at early insulitis shows an upregulation of various islet peripheral tissue antigens (PTAs) [28], correlating with the presence of insulin autoantibodies [29]. Undoubtedly, the transcriptome analysis from pancreaticdraining lymph nodes, spleen and pancreas from T1D patients would provide some relevant clues of the autoreactive process, but these samples are extremely difficult to obtain.…”

Section: Gene Expression Profiles In Lymphoid Organsmentioning

confidence: 99%

Global gene expression changes in type 1 diabetes: Insights into autoimmune response in the target organ and in the periphery

Planas¹,

Pujol-Borrell²,

Vives-Pi³

2010

Immunology Letters

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“…These paradoxical results suggest that Pep regulates effector T cells and T regs simultaneously but causes different effects on the maintenance of immune homeostasis and/ or induction of autoimmunity. A recent report (22) indicated that NOD mice exhibit lower Ptpn22 transcription in PLNs compared with nondiabetic NOD. B10 mice in the early stage of autoimmune diabetes, implying an association between a lower Pep expression level and the diabetic process in NOD mice.…”

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confidence: 99%

Different Modulation of Ptpn22 in Effector and Regulatory T Cells Leads to Attenuation of Autoimmune Diabetes in Transgenic Nonobese Diabetic Mice

Yeh

Miaw

Lin

et al. 2013

The Journal of Immunology

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Ptpn22 encodes PEST domain–enriched tyrosine phosphatase (Pep), which negatively regulates TCR proximal signaling and is strongly associated with a variety of autoimmune diseases in humans. The net effect of Pep on the balance of immunity and tolerance is uncertain because of the simultaneous inhibition of TCR-mediated signaling of effector and regulatory T cells (Tregs). In this study, we generated transgenic NOD mice that overexpressed Pep in T cells. The transgenic mice had a significantly lower incidence of spontaneous autoimmune diabetes, which was accompanied by fewer IFN-γ–producing T cells, and an increased ratio of CD4+Foxp3+ Tregs to CD4+IFN-γ+ or to CD8+IFN-γ+ T cells, respectively, in pancreatic islets. Transgenic T cells showed markedly decreased TCR-mediated effector cell responses such as proliferation and Th1 differentiation. By contrast, the inhibitory effect of transgenic Pep on TCR signaling did not affect the differentiation of Tregs or their suppressive activity. Adoptive transfer experiments showed that transgenic splenocytes exhibited attenuated diabetogenic ability. To examine further the pathogenic features of transgenic T cells, we generated Ptpn22/BDC2.5 doubly transgenic mice and found reduced proliferation and Th1 differentiation in CD4+ T lymphocytes with additional Pep in pancreatic lymph nodes but not in inguinal lymph nodes of NOD/SCID recipients. This finding indicates that transgenic Pep attenuates T cell functions in an islet Ag–driven manner. Taken together, our results demonstrate that Pep overexpression in T cells attenuates autoimmune diabetes in NOD mice by preferentially modulating TCR signaling–mediated functions in diabetogenic T cells but not in Tregs.

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Tissue- and age-specific changes in gene expression during disease induction and progression in NOD mice

Cited by 55 publications

References 18 publications

Early differences in islets from prediabetic NOD mice: combined microarray and proteomic analysis

Early differences in islets from prediabetic NOD mice: combined microarray and proteomic analysis

Global gene expression changes in type 1 diabetes: Insights into autoimmune response in the target organ and in the periphery

Different Modulation of Ptpn22 in Effector and Regulatory T Cells Leads to Attenuation of Autoimmune Diabetes in Transgenic Nonobese Diabetic Mice

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