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Huihsin Chang - One of the best experts on this subject based on the ideXlab platform.
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utilizing a PTPN22 gene signature to predict response to targeted therapies in rheumatoid arthritis
Journal of Autoimmunity, 2019Co-Authors: Huihsin Chang, Beverly Tomita, Andrea Silva, Jeffrey A Sparks, Elizabeth W KarlsonAbstract:Abstract Despite the development of several targeted therapies for rheumatoid arthritis (RA), there is still no reliable drug-specific predictor to assist rheumatologists in selecting the most effective targeted therapy for each patient. Recently, a gene signature caused by impaired induction of PTPN22 in anti-CD3 stimulated peripheral blood mononuclear cells (PBMC) was observed in healthy at-risk individuals. However, the downstream target genes of PTPN22 and the molecular mechanisms regulating its expression are still poorly understood. Here we report that the PTPN22 gene signature is also present in PBMC from patients with active RA and can be reversed after effective treatment. The expression of PTPN22 correlates with that of more than 1000 genes in Th cells of anti-CD3 stimulated PBMC of healthy donors and is inhibited by TNFα or CD28 signals, but not IL-6, through distinct mechanisms. In addition, the impaired induction of PTPN22 in PBMC of patients with active RA can be normalized in vitro by several targeted therapies. More importantly, the in vitro normalization of PTPN22 expression correlates with clinical response to the targeted therapies in a longitudinal RA cohort. Thus, in vitro normalization of PTPN22 expression by targeted therapies can potentially be used to predict clinical response.
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utilizing a PTPN22 gene signature to predict response to targeted therapies in rheumatoid arthritis
bioRxiv, 2019Co-Authors: Huihsin Chang, Beverly Tomita, Andrea Silva, Jeffrey A Sparks, Elizabeth W KarlsonAbstract:Abstract Despite the development of several targeted therapies for rheumatoid arthritis (RA), there is still no reliable drug-specific predictor to assist rheumatologists in selecting the most effective targeted therapy for each patient. Recently, a gene signature caused by impaired induction of PTPN22 in anti-CD3 stimulated peripheral blood mononuclear cells (PBMC) was observed in healthy at-risk individuals. However, the downstream target genes of PTPN22 and the molecular mechanisms regulating its expression are still poorly understood. Here we report that the PTPN22 gene signature is also present in PBMC from patients with active RA and can be reversed after effective treatment. The expression of PTPN22 correlates with that of more than 1000 genes in Th cells of anti-CD3 stimulated PBMC of healthy donors and is inhibited by TNFα or CD28 signals, but not IL-6, through distinct mechanisms. In addition, the impaired induction of PTPN22 in PBMC of patients with active RA can be normalized in vitro by several targeted therapies. More importantly, the in vitro normalization of PTPN22 expression correlates with clinical response to the targeted therapies in a longitudinal RA cohort. Thus, in vitro normalization of PTPN22 expression by targeted therapies can potentially be used to predict clinical response in a drug-specific manner.
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a molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22
JCI insight, 2016Co-Authors: Huihsin Chang, Nishant Dwivedi, Guangyaw Liu, Bo Sun, Yuko Okamoto, Jennifer D Kinslow, Kevin D DeaneAbstract:A unique feature of rheumatoid arthritis (RA) is the presence of anti-citrullinated protein antibodies (ACPA). Several risk factors for RA are known to increase the expression or activity of peptidyl arginine deiminases (PADs), which catalyze citrullination and, when dysregulated, can result in hypercitrullination. However, the consequence of hypercitrullination is unknown and the function of each PAD has yet to be defined. Th cells of RA patients are hypoglycolytic and hyperproliferative due to impaired expression of PFKFB3 and ATM, respectively. Here, we report that these features are also observed in peripheral blood mononuclear cells (PBMCs) from healthy at-risk individuals (ARIs). PBMCs of ARIs are also hypercitrullinated and produce more IL-2 and Th17 cytokines but fewer Th2 cytokines. These abnormal features are due to impaired induction of PTPN22, a phosphatase that also suppresses citrullination independently of its phosphatase activity. Attenuated phosphatase activity of PTPN22 results in aberrant expression of IL-2, ATM, and PFKFB3, whereas diminished nonphosphatase activity of PTPN22 leads to hypercitrullination mediated by PADs. PAD2- or PAD4-mediated hypercitrullination reduces the expression of Th2 cytokines. By contrast, only PAD2-mediated hypercitrullination can increase the expression of Th17 cytokines. Taken together, our data depict a molecular signature of preclinical RA that is triggered by impaired induction of PTPN22.
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the w620 polymorphism in PTPN22 disrupts its interaction with peptidylarginine deiminase type 4 and enhances citrullination and netosis
Arthritis & Rheumatism, 2015Co-Authors: Huihsin Chang, Nishant Dwivedi, Anthony P NicholasAbstract:Objective A C-to-T single-nucleotide polymorphism (SNP) located at position 1858 of human protein tyrosine phosphatase PTPN22 complementary DNA carries the highest risk of rheumatoid arthritis (RA) among all non-HLA genetic variants. This C1858T SNP converts an arginine (R620) to a tryptophan (W620), but it is unclear why it has such a strong impact on RA, a disease characterized by anti–citrullinated protein antibodies. The aim of this study was to test the hypothesis that PTPN22 regulates protein citrullination. Methods The level of citrullinated proteins in immune cells was quantified by Western blotting. The physical interaction between PTPN22 and peptidyl arginine deiminase type 4 (PAD-4), which is one of the enzymes that catalyzes protein citrullination, was examined by coimmunoprecipitation. Neutrophils were collected from healthy donors carrying the C1858T SNP and healthy donors not carrying this SNP. The formation of neutrophil extracellular traps (NETs) was examined by immunocytochemistry. Results PTPN22 physically interacted with PAD-4, and a deficiency in PTPN22 enhanced protein citrullination. This abnormality was reversed by exogenous wild-type PTPN22 or catalytically dead mutant PTPN22. The R-to-W conversion rendered PTPN22 unable to interact with PAD-4 and suppress citrullination. The C1858T SNP was associated with hypercitrullination in peripheral blood mononuclear cells and a heightened propensity for spontaneous formation of NETs, which is a PAD-4–dependent process. Conclusion PTPN22 is an inhibitor of PAD-4 and protein citrullination. This function of PTPN22 is independent of its phosphatase activity but requires R620. Our data not only establish a molecular link between PTPN22 and PAD-4, but also suggest that the C1858T SNP increases the risk of RA by enhancing protein citrullination and spontaneous formation of NETs.
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altered expression of protein tyrosine phosphatase non receptor type 22 isoforms in systemic lupus erythematosus
Arthritis Research & Therapy, 2014Co-Authors: Huihsin Chang, William Tseng, Jing Cui, Karen H CostenbaderAbstract:Introduction: A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human protein tyrosine phosphatase, non-receptor type 22 (PTPN22) complementary DNA (cDNA) is associated with an increased risk of systemic lupus erythematosus (SLE). How the overall activity of PTPN22 is regulated and how the expression of PTPN22 differs between healthy individuals and patients with lupus are poorly understood. Our objectives were to identify novel alternatively spliced forms of PTPN22 and to examine the expression of PTPN22 isoforms in healthy donors and patients with lupus. Methods: Various human PTPN22 isoforms were identified from the GenBank database or amplified directly from human T cells. The expression of these isoforms in primary T cells and macrophages was examined with real-time polymerase chain reaction. The function of the isoforms was determined with luciferase assays. Blood samples were collected from 49 subjects with SLE and 15 healthy controls. Correlation between the level of PTPN22 isoforms in peripheral blood and clinical features of SLE was examined with statistical analyses.
Rose Zamoyska - One of the best experts on this subject based on the ideXlab platform.
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crispr cas mediated deletion of PTPN22 in jurkat t cells enhances tcr signaling and production of il 2
Frontiers in Immunology, 2018Co-Authors: Cara Bray, David L Wright, Sonja Haupt, Sharyn Thomas, Hans J Stauss, Rose ZamoyskaAbstract:A single nucleotide polymorphism, C1858T, in the gene encoding the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) results in one of the strongest genetic traits associated with autoimmune disease outside of the Major Histocompatibility Complex (MHC) genes. However, the consequences of this polymorphism, which introduces an arginine to tryptophan substitution at amino acid 620, for the function of PTPN22 protein is unclear and conflicting results have been obtained in human compared to mouse cells expressing this variant phosphatase. In mouse the variant appears to be a loss-of-function allele resembling a milder form of the null allele, while studies in human cells have reported it to be a gain-of-function mutation. To address whether the phosphatase has distinct functions in mouse vs. human T cells, we used CRISPR gene-editing to generate the first example of human PTPN22-KnockOut (KO) T cells. By comparing isogenic human T cells which express or lack PTPN22, we showed that PTPN22 KO T cells displayed enhanced expression of IL-2 and CD69 upon stimulation with cognate antigen. PTPN22 KO cells also showed increased Erk phosphorylation upon stimulation with weak antigen, but the difference was diminished in response to strong antigen, indicating that PTPN22 plays a more critical role in regulating weak-antigen responses. These data are in keeping with a role for PTPN22 in determining the threshold of stimulation required to activate T cells, a critical function of autoimmune pathogenesis. Our data indicate that PTPN22 has comparable functions in mouse and human T cells, and that the conflicting results in the literature regarding the impact of the point mutation are not due to differences in the activity of PTPN22 itself, but may be related to interactions with other proteins or splice variation.
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protein tyrosine phosphatase PTPN22 regulates lfa 1 dependent th1 responses
Journal of Autoimmunity, 2018Co-Authors: Cristina Sanchezblanco, Rose Zamoyska, Georgina H Cornish, Fiona Clarke, David Depoil, S J Thompson, Xuezhi Dai, David J Rawlings, Michael L Dustin, Andrew P CopeAbstract:A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in PTPN22-/- T-cells and in T-cells from mice expressing PTPN22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in PTPN22-/- T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of PTPN22-/- T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed PTPN22-/- bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response.
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regulation of autoimmune and anti tumour t cell responses by PTPN22
Immunology, 2018Co-Authors: Rebecca J Brownlie, Rose Zamoyska, Robert J SalmondAbstract: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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protein tyrosine phosphatase PTPN22 regulates il 1β dependent th17 responses by modulating dectin 1 signaling in mice
European Journal of Immunology, 2018Co-Authors: Harriet A Purvis, Rose Zamoyska, Georgina H Cornish, Fiona Clarke, Xuezhi Dai, David J Rawlings, Christine K Jordan, Cristina Sanchez Blanco, Andrew P CopeAbstract:A single nucleotide polymorphism within the PTPN22 gene is a strong genetic risk factor predisposing to the development of multiple autoimmune diseases. PTPN22 regulates Syk and Src family kinases downstream of immuno-receptors. Fungal β-glucan receptor dectin-1 signals via Syk, and dectin-1 stimulation induces arthritis in mouse models. We investigated whether PTPN22 regulates dectin-1 dependent immune responses. Bone marrow derived dendritic cells (BMDCs) generated from C57BL/6 wild type (WT) and PTPN22−/− mutant mice, were pulsed with OVA323-339 and the dectin-1 agonist curdlan and co-cultured in vitro with OT-II T-cells or adoptively transferred into OT-II mice, and T-cell responses were determined by immunoassay. Dectin-1 activated PTPN22−/− BMDCs enhanced T-cell secretion of IL-17 in vitro and in vivo in an IL-1β dependent manner. Immunoblotting revealed that compared to WT, dectin-1 activated PTPN22−/− BMDCs displayed enhanced Syk and Erk phosphorylation. Dectin-1 activation of BMDCs expressing PTPN22R619W (the mouse orthologue of human PTPN22R620W) also resulted in increased IL-1β secretion and T-cell dependent IL-17 responses, indicating that in the context of dectin-1 PTPN22R619W operates as a loss-of-function variant. These findings highlight PTPN22 as a novel regulator of dectin-1 signals, providing a link between genetically conferred perturbations of innate receptor signaling and the risk of autoimmune disease. This article is protected by copyright. All rights reserved
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protein tyrosine phosphatase PTPN22 is dispensable for dendritic cell antigen processing and promotion of t cell activation by dendritic cells
PLOS ONE, 2017Co-Authors: Fiona Clarke, Rose Zamoyska, Georgina H Cornish, Cristina Sanchezblanco, Xuezhi Dai, David J Rawlings, Christine K Jordan, Enrique Gutierrezmartinez, Jack A Bibby, Pierre GuermonprezAbstract:The PTPN22R620W single nucleotide polymorphism increases the risk of developing multiple autoimmune diseases including type 1 diabetes, rheumatoid arthritis and lupus. PTPN22 is highly expressed in antigen presenting cells (APCs) where the expression of the murine disease associated variant orthologue (PTPN22R619W) is reported to dysregulate pattern recognition receptor signalling in dendritic cells (DCs) and promote T-cell proliferation. Because T-cell activation is dependent on DC antigen uptake, degradation and presentation, we analysed the efficiency of these functions in splenic and GM-CSF bone marrow derived DC from wild type (WT), PTPN22-/- or PTPN22R619W mutant mice. Results indicated no differential ability of DCs to uptake antigen via macropinocytosis or receptor-mediated endocytosis. Antigen degradation and presentation was also equal as was WT T-cell conjugate formation and subsequent T-cell proliferation. Despite the likely presence of multiple phosphatase-regulated pathways in the antigen uptake, processing and presentation pathways that we investigated, we observed that PTPN22 and the R619W autoimmune associated variant were dispensable. These important findings indicate that under non-inflammatory conditions there is no requirement for PTPN22 in DC dependent antigen uptake and T-cell activation. Our findings reveal that perturbations in antigen uptake and processing, a fundamental pathway determining adaptive immune responses, are unlikely to provide a mechanism for the risk associated with the PTPN22 autoimmune associated polymorphism.
Saleh A Naser - One of the best experts on this subject based on the ideXlab platform.
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pathophysiology of rheumatoid arthritis is associated with polymorphisms in protein tyrosine phosphatase non receptor type 2 and 22 ptpn2 22 and susceptibility to mycobacteria
Journal of Immunology, 2018Co-Authors: Robert C Sharp, Shazia Beg, Saleh A NaserAbstract:Single nucleotide polymorphisms (SNPs) in T-cell regulator genes such as Protein Tyrosine Phosphatase Non-receptor type 2 and 22 ( PTPN2/22 ) have been associated with many inflammatory autoimmune disorders including rheumatoid arthritis (RA). Along with these SNPs and an environmental trigger of a mycobacterial infection from Mycobacterium avium subspecies paratuberculosis (MAP), we hypothesis that this will lead to chronic inflammation of the synovial joints of RA. We gathered 132 consented subjects blood samples, where genotyping was done for nine SNPs found in PTPN2/22 using TaqMan™ genotyping. Quantification of the effect of the SNPs on gene expression of PTPN2/22 and IFN-γ expression was determined through real time PCR. T-cell proliferation assays were done to examine the response of phytohematoagglutonin (PHA) and mycobacterial antigens in subject samples by the use of BrdU proliferation assays. Detection of MAP bacterial IS900 DNA was done by nested PCR. Out of the nine SNPs examined, PTPN2:rs478582/PTPN22:rs2476601 were found significant in RA compared to the healthy controls (p-values PTPN2/22 was downregulated in RA overall compared to healthy controls. IFN-γ expression was upregulated in samples with significant SNPs. T-cell proliferation increased when T-cells tested had significant SNPs (p-values IS900 MAP DNA was detected more significantly in RA than in healthy controls, where samples with either significant SNPs had higher presence of MAP (p-values PTPN2/22 dysregulates T-cell regulation and increases susceptibility to Mycobacteria , leading to increased proliferation of T-cells and higher amounts of IFN-γ expression in RA.
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role of ptpn2 22 polymorphisms in pathophysiology of crohn s disease
World Journal of Gastroenterology, 2018Co-Authors: Robert C Sharp, Shazia Beg, Saleh A NaserAbstract:AIM To establish the relationship of protein tyrosine phosphatase non-receptor type 2 and 22 (PTPN2/22) polymorphisms and mycobacterial infections in Crohn's disease (CD). METHODS All 133 subjects' blood samples were genotyped for nine single nucleotide polymorphisms (SNPs) in PTPN2/22 using TaqMan™ genotyping, while the effect of the SNPs on PTPN2/22 and IFN-γ gene expression was determined using RT-PCR. Detection of Mycobacterium avium subspecies paratuberculosis (MAP) IS900 gene was done by nPCR after DNA extraction from the isolated leukocytes of each subjects' blood samples. T-cells isolated from the patient samples were tested for response to phytohematoagglutonin (PHA) mitogen or mycobacterial antigens by BrdU proliferation assays for T-cell activity. RESULTS Out of the nine SNPs examined, subjects with either heterozygous (TC)/minor (CC) alleles in PTPN2:rs478582 occurred in 83% of CD subjects compared to 61% healthy controls (P-values < 0.05; OR = 3.03). Subjects with either heterozygous (GA)/minor (AA) alleles in PTPN22:rs2476601 occurred in 16% of CD compared to 6% healthy controls (OR = 2.7). Gene expression in PTPN2/22 in CD subjects was significantly decreased by 2 folds compared to healthy controls (P-values < 0.05). IFN-γ expression levels were found to be significantly increased by approxiately 2 folds in subjects when either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 were found (P-values < 0.05). MAP DNA was detected in 61% of CD compared to only 8% of healthy controls (P-values < 0.05, OR = 17.52), where subjects with either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 had more MAPbacteremia presence than subjects without SNPs did. The average T-cell proliferation in CD treated with PHA or mycobacteria antigens was, respectively, 1.3 folds and 1.5 folds higher than healthy controls without any significant SNP. CONCLUSION The data suggests that SNPs in PTPN2/22 affect the negative regulation of the immune response in CD patients, thus leading to an increase in inflammation/apoptosis and susceptibility of mycobacteria.
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polymorphisms in protein tyrosine phosphatase non receptor type 2 and 22 ptpn2 22 are linked to hyper proliferative t cells and susceptibility to mycobacteria in rheumatoid arthritis
Frontiers in Cellular and Infection Microbiology, 2018Co-Authors: Robert C Sharp, Shazia A Beg, Saleh A NaserAbstract:A shared genetic pre-disposition, chronic inflammation and treatment with similar biologics between Rheumatoid arthritis (RA) and Crohn’s disease (CD) have intrigued us to investigate whether the two disorders share trigger association or possible causation. We hypothesized earlier that Single Nucleotide Polymorphisms (SNPs) in the negative regulators Protein Tyrosine Phosphatase Non-receptor type 2 and 22 (PTPN2/22) lead to a dysregulated immune response, susceptibility to environmental triggers, and continued apoptosis as seen in chronic inflammation in RA and CD. To test the hypothesis, peripheral leukocytes samples from 131 consented subjects were genotyped for 9 SNPs in PTPN2/22 using TaqMan™ genotyping. The effect of the SNPs on PTPN2/22 and IFN-γ expression was determined using real time PCR. T-cell proliferation and response to phytohematoagglutonin (PHA) mitogen and mycobacterial antigens were determined by BrdU proliferation assay. Blood samples were also analyzed for the Mycobacterium avium subspecies paratuberculosis (MAP) IS900 gene by nPCR. Out of 9 SNPs examined, heterozygous (TC) or minor (CC) alleles of PTPN2:rs478582 occurred in 79% RA compared to 60% healthy controls (p-values ≤ 0.05; OR= 2.28). Similarly, heterozygous (GA) or minor (AA) alleles of PTPN22:rs2476601 occurred in 29% RA compared to 6% healthy controls (p-values ≤ 0.05; OR= 5.90). PTPN2/22 expression in RA was decreased by 1.2 fold compared to healthy controls. PTPN2:rs478582 upregulated IFN-γ in RA by 1.5 fold. Combined PTPN2:rs478582 and PTPN22:rs2476601 increased T-cell proliferation by 2.7 fold when treated with PHA. Surprisingly, MAP DNA was detected in 34% of RA samples compared to 8% healthy controls, (p-values ≤ 0.05, OR= 5.74). RA samples with PTPN2:rs478582 and/or PTPN22:rs2476601 were more positive for MAP than samples without polymorphisms. Combined occurrence of PTPN2:rs478582 and PTPN22:rs2476601 in association with the presence of MAP has significantly increased T-cell response and elevated IFN-γ expression in RA samples. The data suggest that genetic polymorphisms may play vital role in T-cell regulation, susceptibility to mycobacteria and ultimately response to treatment. This is the first study to report the detection of MAP DNA in the blood of RA patients; further studies are needed using larger number of samples.
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genetic variations of ptpn2 and PTPN22 role in the pathogenesis of type 1 diabetes and crohn s disease
Frontiers in Cellular and Infection Microbiology, 2015Co-Authors: Robert C Sharp, Muna Abdulrahim, Ebraheem S Naser, Saleh A NaserAbstract:Genome wide association studies have identified several genes that might be associated with increase susceptibility to Type 1 Diabetes (T1D) and Crohn's disease. Both Crohn's disease and T1D have a profound impact on the lives of patients and it is pivotal to investigate the genetic role in patients acquiring these diseases. Understanding the effect of single nucleotide polymorphisms (SNP's) in key genes in patients suffering from T1D and Crohn's disease is crucial to finding an effective treatment and generating novel therapeutic drugs. This review article is focused on the impact of SNP's in PTPN2 (protein tyrosine phosphatase, non-receptor type 2) and PTPN22 (protein tyrosine phosphatase non-receptor type 22) on the development of Crohn's disease and T1D. The PTPN2 gene mutation in T1D patients play a direct role in the destruction of beta cells while in Crohn's disease patients, it modulates the innate immune responses. The PTPN22 gene mutations also play a role in both diseases by modulating intracellular signaling. Examining the mechanism through which these genes increase the susceptibility to both diseases and gaining a better understanding of their structure and function is of vital importance to understand the etiology and pathogenesis of Type 1 Diabetes and Crohn's disease.
Andrew P Cope - One of the best experts on this subject based on the ideXlab platform.
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protein tyrosine phosphatase PTPN22 regulates lfa 1 dependent th1 responses
Journal of Autoimmunity, 2018Co-Authors: Cristina Sanchezblanco, Rose Zamoyska, Georgina H Cornish, Fiona Clarke, David Depoil, S J Thompson, Xuezhi Dai, David J Rawlings, Michael L Dustin, Andrew P CopeAbstract:A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in PTPN22-/- T-cells and in T-cells from mice expressing PTPN22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in PTPN22-/- T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of PTPN22-/- T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed PTPN22-/- bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response.
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protein tyrosine phosphatase PTPN22 regulates il 1β dependent th17 responses by modulating dectin 1 signaling in mice
European Journal of Immunology, 2018Co-Authors: Harriet A Purvis, Rose Zamoyska, Georgina H Cornish, Fiona Clarke, Xuezhi Dai, David J Rawlings, Christine K Jordan, Cristina Sanchez Blanco, Andrew P CopeAbstract:A single nucleotide polymorphism within the PTPN22 gene is a strong genetic risk factor predisposing to the development of multiple autoimmune diseases. PTPN22 regulates Syk and Src family kinases downstream of immuno-receptors. Fungal β-glucan receptor dectin-1 signals via Syk, and dectin-1 stimulation induces arthritis in mouse models. We investigated whether PTPN22 regulates dectin-1 dependent immune responses. Bone marrow derived dendritic cells (BMDCs) generated from C57BL/6 wild type (WT) and PTPN22−/− mutant mice, were pulsed with OVA323-339 and the dectin-1 agonist curdlan and co-cultured in vitro with OT-II T-cells or adoptively transferred into OT-II mice, and T-cell responses were determined by immunoassay. Dectin-1 activated PTPN22−/− BMDCs enhanced T-cell secretion of IL-17 in vitro and in vivo in an IL-1β dependent manner. Immunoblotting revealed that compared to WT, dectin-1 activated PTPN22−/− BMDCs displayed enhanced Syk and Erk phosphorylation. Dectin-1 activation of BMDCs expressing PTPN22R619W (the mouse orthologue of human PTPN22R620W) also resulted in increased IL-1β secretion and T-cell dependent IL-17 responses, indicating that in the context of dectin-1 PTPN22R619W operates as a loss-of-function variant. These findings highlight PTPN22 as a novel regulator of dectin-1 signals, providing a link between genetically conferred perturbations of innate receptor signaling and the risk of autoimmune disease. This article is protected by copyright. All rights reserved
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op0296 autoimmune associated gene PTPN22 negatively regulates dectin 1 signalling in dendritic cells
Annals of the Rheumatic Diseases, 2017Co-Authors: Harriet A Purvis, Rose Zamoyska, Georgina H Cornish, Cristina Sanchezblanco, Fiona Clarke, David J Rawlings, Christine K Jordan, Andrew P CopeAbstract:Background A single nucleotide polymorphism within the phosphatase PTPN22 increases the risk of developing multiple autoimmune and connective tissue diseases.1 PTPN22 is a negative regulator of Syk and Src family kinases downstream of immuno-receptor signalling cascades.2 Fungal β-glucan receptor dectin-1, signals via Syk kinase, and induces dendritic cells to secrete pro-inflammatory cytokines IL-1β, IL-6, IL-12/23p40 and TNFα, in turn allowing the induction of IL-17 secreting T-cell responses, which are critical to the clearance of fungal infections.3 IL-17 has been implicated as a key cytokine in inflammatory responses associated with RA, JIA, and psoriasis.4 Objectives To investigate if PTPN22 regulates dectin-1 signalling and controls the capability of dectin-1 matured BMDC to promote adaptive immune responses. Methods GM-CSF bone marrow derived dendritic cells (BMDC) were generated from C57BL/6 WT, PTPN22-/- or PTPN22R619W (human PTPN22R620W orthologue) mice, and pulsed with OVA323–339 in the presence or absence of the dectin-1 agonist curdlan. Activated BMDC were co-cultured in vitro with OT-II T-cells or adoptively transferred into OT-II mice and the resulting T-cell response assessed. Cytokine secretion from curdlan activated PTPN22 variant mouse BMDC was determined by immunoassay and the kinetics of Syk and Erk phosphorylation were determined by immunoblot. Results We observed that Dectin-1 activated PTPN22-/- BMDC had an enhanced capability to induce T-cell IL-17 secretion both in vitro and in vivo compared to WT BMDC. Following dectin-1 priming PTPN22-/- BMDC secreted increased IL-1β compared to WT BMDC, and the increase in IL-1β was found to be sufficient to cause the enhanced IL-17 response induced by PTPN22-/- BMDC. Dectin-1 induced IL-1β secretion was found to be Syk and Erk dependent and assessment of Syk and Erk kinetics of phosphorylation revealed that dectin-1 activated PTPN22-/- BMDC displayed enhanced Syk and Erk phosphorylation compared to WT BMDC. Furthermore, PTPN22R619W BMDC (orthologue of human PTPN22R620W) exhibited a similar enhancement in IL-1β secretion and induced enhanced T-cell dependent IL-17 responses in vivo, indicating that the PTPN22 polymorphism behaves as a loss-of-function allele in the context of dectin-1 signals. Conclusions Data highlight PTPN22 as a novel regulator of dectin-1 signals and provide a link between genetically conferred perturbation to innate receptor signalling pathways and autoimmunity. References Burn, G. L., Svensson, L., Sanchez-Blanco, C., Saini, M. & Cope, A. P. Why is PTPN22 a good candidate susceptibility gene for autoimmune disease? FEBS Lett. 585, 3689–98 (2011). Cloutier, J. F. & Veillette, A. Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J. Exp. Med. 189, 111–21 (1999). Dambuza, I. M. & Brown, G. D. C-type lectins in immunity: recent developments. Curr. Opin. Immunol. 32, 21–27 (2015). Tabarkiewicz, J., Pogoda, K., Karczmarczyk, A., Pozarowski, P. & Giannopoulos, K. The Role of IL-17 and Th17 Lymphocytes in Autoimmune Diseases. Arch. Immunol. Ther. Exp. (Warsz). 63, 435–49 (2015). Disclosure of Interest None declared
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lack of the phosphatase PTPN22 increases adhesion of murine regulatory t cells to improve their immunosuppressive function
Science Signaling, 2012Co-Authors: Rebecca J Brownlie, Lisa A Miosge, Demetrios Vassilakos, Lena Svensson, Andrew P Cope, Rose ZamoyskaAbstract:The cytoplasmic phosphatase PTPN22 (protein tyrosine phosphatase nonreceptor type 22) plays a key role in regulating lymphocyte homeostasis, which ensures that the total number of lymphocytes in the periphery remains relatively constant. Mutations in PTPN22 confer an increased risk of developing autoimmune diseases; however, the precise function of PTPN22 and how mutations contribute to autoimmunity remain controversial. Loss-of-function mutations in PTPN22 are associated with increased numbers of effector T cells and autoreactive B cells in humans and mice; however, the complete absence of PTPN22 in mice does not result in spontaneous autoimmunity. We found that PTPN22 was a key regulator of regulatory T cell (T reg ) function that fine-tuned the signaling of the T cell receptor and integrins. PTPN22 −/− T regs were more effective at immunosuppression than were wild-type T regs , and they suppressed the activity of PTPN22 −/− effector T cells, preventing autoimmunity. Compared to wild-type T regs , PTPN22 −/− T regs produced increased amounts of the immunosuppressive cytokine interleukin-10 and had enhanced adhesive properties mediated by the integrin lymphocyte function–associated antigen-1, processes that are critical for T reg function. This previously undiscovered role of PTPN22 in regulating integrin signaling and T reg function suggests that PTPN22 may be a useful therapeutic target for manipulating T reg function in human disease.
Nunzio Bottini - One of the best experts on this subject based on the ideXlab platform.
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the contribution of PTPN22 to rheumatic disease
Arthritis & Rheumatism, 2019Co-Authors: Tomas Mustelin, Nunzio Bottini, Stephanie M StanfordAbstract:One of the unresolved questions in modern medicine is why certain individuals develop a disorder such as rheumatoid arthritis (RA) or lupus, while others do not. Contemporary science indicates that genetics is partly responsible for disease development, while environmental and stochastic factors also play a role. Among the many genes that increase the risk of autoimmune conditions, the risk allele encoding the W620 variant of protein tyrosine phosphatase N22 (PTPN22) is shared between multiple rheumatic diseases, suggesting that it plays a fundamental role in the development of immune dysfunction. Herein, we discuss how the presence of the PTPN22 risk allele may shape the signs and symptoms of these diseases. Besides the emerging clarity regarding how PTPN22 tunes T and B cell antigen receptor signaling, we discuss recent discoveries of important functions of PTPN22 in myeloid cell lineages. Taken together, these new insights reveal important clues to the molecular mechanisms of prevalent diseases like RA and lupus and may open new avenues for the development of personalized therapies that spare the normal function of the immune system.
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PTPN22 the archetypal non hla autoimmunity gene
Nature Reviews Rheumatology, 2014Co-Authors: Stephanie M Stanford, Nunzio BottiniAbstract:SNPs ofPTPN22, a 'shared autoimmunity gene', are important risk factors for rheumatoid arthritis, juvenile idiopathic arthritis and other autoimmune diseases. In this article, Stanford and Bottini review the function of mouse and human PTPN22 in Toll-like receptor and lymphocyte antigen-receptor signalling pathways, and suggest functional models for the involvement of PTPN22 variants in the pathogenesis of autoimmune diseases. PTPN22 encodes a tyrosine phosphatase that is expressed by haematopoietic cells and functions as a key regulator of immune homeostasis by inhibiting T-cell receptor signalling and by selectively promoting type I interferon responses after activation of myeloid-cell pattern-recognition receptors. A single nucleotide polymorphism of PTPN22, 1858C>T (rs2476601), disrupts an interaction motif in the protein, and is the most important non-HLA genetic risk factor for rheumatoid arthritis and the second most important for juvenile idiopathic arthritis. PTPN22 exemplifies a shared autoimmunity gene, affecting the pathogenesis of systemic lupus erythematosus, vasculitis and other autoimmune diseases. In this Review, we explore the role of PTPN22 in autoimmune connective tissue disease, with particular emphasis on candidate-gene and genome-wide association studies and clinical variability of disease. We also propose a number of PTPN22-dependent functional models of the pathogenesis of autoimmune diseases.
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Tyrosine Phosphatase PTPN22: Multifunctional Regulator of Immune Signaling, Development, and Disease
Annual Review of Immunology, 2013Co-Authors: Nunzio Bottini, Erik J. PetersonAbstract:Inheritance of a coding variant of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is associated with increased susceptibility to autoimmunity and infection. Efforts to elucidate the mechanisms by which the PTPN22-C1858T variant modulates disease risk revealed that PTPN22 performs a signaling function in multiple biochemical pathways and cell types. Capable of both enzymatic activity and adaptor functions, PTPN22 modulates signaling through antigen and innate immune receptors. PTPN22 plays roles in lymphocyte development and activation, establishment of tolerance, and innate immune cell–mediated host defense and immunoregulation. The disease-associated PTPN22-R620W variant protein is likely involved in multiple stages of the pathogenesis of autoimmunity. Establishment of a tolerant B cell repertoire is disrupted by PTPN22-R620W action during immature B cell selection, and PTPN22-R620W alters mature T cell responsiveness. However, after autoimmune attack has initiated tissue injury, PTPN...
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PTPN22 alters the development of regulatory t cells in the thymus
Journal of Immunology, 2012Co-Authors: Christian J Maine, Nunzio Bottini, Stephanie M Stanford, Jocelyn Cheung, Emma E Hamiltonwilliams, Linda S Wicker, Linda A ShermanAbstract:PTPN22 encodes a tyrosine phosphatase that inhibits Src-family kinases responsible for Ag receptor signaling in lymphocytes and is strongly linked with susceptibility to a number of autoimmune diseases. As strength of TCR signal is critical to the thymic selection of regulatory T cells (Tregs), we examined the effect of murine PTPN22 deficiency on Treg development and function. In the thymus, numbers of pre-Tregs and Tregs increased inversely with the level of PTPN22. This increase in Tregs persisted in the periphery and could play a key part in the reduced severity observed in the PTPN22-deficient mice of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. This could explain the lack of association of certain autoimmune conditions with PTPN22 risk alleles.
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association between PTPN22 and endometriosis
Fertility and Sterility, 2008Co-Authors: Maria Ammendola, Nunzio Bottini, Adalgisa Pietropolli, Patrizia Saccucci, F GloriabottiniAbstract:PTPN22 is currently one of the few known shared-autoimmunity genes and is therefore a candidate marker for endometriosis. Our data show that female carriers of the PTPN22( *)T variant are significantly more susceptible to endometriosis than controls.