CRISPR-Cas9–Mediated Modification of the NOD Mouse Genome With <i>Ptpn22R619W</i> Mutation Increases Autoimmune Diabetes

Lin, Xiaotian; Pelletier, S. William; Gingras, Sébastien; Rigaud, Stéphanie; Maine, Christian J.; Marquardt, Kristi; Dai, Yang; Sauer, Karsten; Rodríguez, Alberto Rodríguez; Martin, Greg S.; Kupriyanov, Sergey; Jiang, Ling; Yu, Liping; Green, Douglas R.; Sherman, Linda A.

doi:10.2337/db16-0061

Cited by 41 publications

(42 citation statements)

References 25 publications

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“…The results of these studies paint a complicated picture of the role of PTPN22 in the regulation of autoimmunity. Under some circumstances, the absence of PTPN22 confers a protective effect whilst, in others, PTPN22‐deficiency or PTPN22 R619W expression enhances the severity of autoimmunity . These apparently contradictory results are likely explained, at least in part, by the fact that PTPN22 regulates both inflammatory and anti‐inflammatory T‐cell responses.…”

Section: Mouse Models Of Ptpn22 Function In Autoimmunitymentioning

confidence: 99%

“…Under some circumstances, the absence of PTPN22 confers a protective effect 6,43,45,46 whilst, in others, PTPN22-deficiency or PTPN22 R619W expression enhances the severity of autoimmunity. 17,32,[40][41][42]47 These apparently contradictory results are likely explained, at least in part, by the fact that PTPN22 regulates both inflammatory and anti-inflammatory T-cell responses. For example, PTPN22-deficient mice have increased numbers of peripheral regulatory T-cells (Tregs), 17,46,48 and these Tregs are more suppressive.…”

Section: Mouse Models Of Ptpn22 Function In Autoimmunitymentioning

confidence: 99%

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Regulation of autoimmune and anti‐tumour T‐cell responses by PTPN22

2018

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A number of polymorphisms in immune-regulatory genes have been identified as risk factors for the development of autoimmune disease. PTPN22 (that encodes a tyrosine phosphatase) has been associated with the development of several autoimmune diseases, including type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus. PTPN22 regulates the activity and effector functions of multiple important immune cell types, including lymphocytes, granulocytes and myeloid cells. In this review, we describe the role of PTPN22 in regulating T-cell activation and effector responses. We discuss progress in our understanding of the impact of PTPN22 in autoimmune disease in humans and mouse models, as well as recent evidence suggesting that genetic manipulation of PTPN22 expression might enhance the efficacy of anti-tumour T-cell responses.

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Section: Mouse Models Of Ptpn22 Function In Autoimmunitymentioning

confidence: 99%

Section: Mouse Models Of Ptpn22 Function In Autoimmunitymentioning

confidence: 99%

Regulation of autoimmune and anti‐tumour T‐cell responses by PTPN22

2018

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“…Specific mutations can be introduced in any genetic background. For example, in NOD mouse, a model of spontaneous type 1 diabetes (T1D), a R619W mutation in the protein tyrosine phosphatase non-receptor type 22 ( Ptpn22 ) gene was introduced by CRISPR/Cas9 and homology-directed repair (Lin et al 2016 ). This mutation corresponds to the human allelic variant of PTPN22 (R620W), an allele strongly associated with type 1 diabetes (T1D) which increases the risk of T1D by two- to fourfold.…”

Section: Crispr/cas9 Polygenic Disorders and Personalized Medicinementioning

confidence: 99%

Modeling human disease in rodents by CRISPR/Cas9 genome editing

Birling¹,

Hérault²,

Pavlovic³

2017

Mamm Genome

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Modeling human disease has proven to be a challenge for the scientific community. For years, generating an animal model was complicated and restricted to very few species. With the rise of CRISPR/Cas9, it is now possible to generate more or less any animal model. In this review, we will show how this technology is and will change our way to obtain relevant disease animal models and how it should impact human health.

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“…PTPN22 is expressed in hematopoietic cells, but through GWAS a minor allelic form of this gene PTPN22 R620W was found to be associated with an increased risk of diabetes in humans. The introduction of this gene in the NOD mouse model using CRISPR/Cas9 technology showed increased insulin autoantibodies concomitantly with an earlier onset and higher penetrance of T1D [99]. The knowledge from GWAS in combination with hESC-derived beta-cells is an invaluable tool to define the specific mechanistic role of genes associated with human diabetes.…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

The Nexus of Stem Cell-Derived Beta-Cells and Genome Engineering

2017

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Diabetes, type 1 and type 2 (T1D and T2D), are diseases of epidemic proportions, which are complicated and defined by genetics, epigenetics, environment, and lifestyle choices. Current therapies consist of whole pancreas or islet transplantation. However, these approaches require life-time immunosuppression, and are compounded by the paucity of available donors. Pluripotent stem cells have advanced research in the fields of stem cell biology, drug development, disease modeling, and regenerative medicine, and importantly allows for the interrogation of therapeutic interventions. Recent developments in beta-cell differentiation and genomic modifications are now propelling investigations into the mechanisms behind beta-cell failure and autoimmunity, and offer new strategies for reducing the propensity for immunogenicity. This review discusses the derivation of endocrine lineage cells from human pluripotent stem cells for the treatment of diabetes, and how the editing or manipulation of their genomes can transcend many of the remaining challenges of stem cell technologies, leading to superior transplantation and diabetes drug discovery platforms.

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CRISPR-Cas9–Mediated Modification of the NOD Mouse Genome With Ptpn22R619W Mutation Increases Autoimmune Diabetes

Cited by 41 publications

References 25 publications

Regulation of autoimmune and anti‐tumour T‐cell responses by PTPN22

Regulation of autoimmune and anti‐tumour T‐cell responses by PTPN22

Modeling human disease in rodents by CRISPR/Cas9 genome editing

The Nexus of Stem Cell-Derived Beta-Cells and Genome Engineering

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