Autoimmunity associated allele of tyrosine phosphatase gene PTPN22 enhances anti-viral immunity
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PROVIDER: PRJNA1075774 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we examine gene expression and function of immune cell subsets to demonstrate how a common allelic variant of PTPN22, which strongly increases the risk of autoimmune disease, promotes successful clearance of an otherwise chronic viral infection.
2024-03-14 | GSE255614 | GEO
Project description:Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene segregates with most autoimmune diseases; its risk allele encodes overactive PTPN22 phosphatases that alter B cell receptor (BCR) signaling potentially involved in the regulation of central B cell tolerance. To assess whether PTPN22 risk allele affects the removal of developing autoreactive B cells, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from asymptomatic healthy individuals carrying one or two PTPN22 risk allele(s). We found that new emigrant/transitional and mature naive B cells from PTPN22 risk allele carriers contained high frequencies of autoreactive clones compared to non-carrier control donors. Hence, a single PTPN22 risk allele has a dominant effect on altering autoreactive B cell counterselection, suggesting that early B cell tolerance checkpoint defects precede the onset of autoimmunity. In addition, gene array experiments comparing mature naïve B cells from healthy individuals carrying or not PTPN22 risk allele(s) revealed that the strength of association of PTPN22 for autoimmunity, second in importance only to the MHC, may not only be due to BCR signaling alteration but also to the regulation of other genes, which themselves have also been identified as involved in the development of autoimmune diseases. The PTPN22 risk allele is a single nucleotide change (cytidine to thymidine) at residue 1858, which results in a single amino acid substitution from arginine to tryptophan at position 620 of the PTPN22/Lyp protein.
2010-10-16 | GSE24736 | GEO
Project description:Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene segregates with most autoimmune diseases; its risk allele encodes overactive PTPN22 phosphatases that alter B cell receptor (BCR) signaling potentially involved in the regulation of central B cell tolerance. To assess whether PTPN22 risk allele affects the removal of developing autoreactive B cells, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from asymptomatic healthy individuals carrying one or two PTPN22 risk allele(s). We found that new emigrant/transitional and mature naive B cells from PTPN22 risk allele carriers contained high frequencies of autoreactive clones compared to non-carrier control donors. Hence, a single PTPN22 risk allele has a dominant effect on altering autoreactive B cell counterselection, suggesting that early B cell tolerance checkpoint defects precede the onset of autoimmunity. In addition, gene array experiments comparing mature naïve B cells from healthy individuals carrying or not PTPN22 risk allele(s) revealed that the strength of association of PTPN22 for autoimmunity, second in importance only to the MHC, may not only be due to BCR signaling alteration but also to the regulation of other genes, which themselves have also been identified as involved in the development of autoimmune diseases. The PTPN22 risk allele is a single nucleotide change (cytidine to thymidine) at residue 1858, which results in a single amino acid substitution from arginine to tryptophan at position 620 of the PTPN22/Lyp protein. Data from mature naïve B cell populations from patients carrying 1 or 2 PTPN22 T alleles and non-carrier patients were compared in order to characterize the impact of PTPN22 polymorphism on B cell physiology. RNA was extracted from batch-sorted CD19+CD10-CD21+CD27- conventional mature naive B cells using the Absolutely RNA microprep kit (Stratagene). 100-200 ng of RNA was obtained per sample, and the quality of the purified RNA was assessed by the Bioanalyzer from Agilent. Using the Ovation biotin system kit from Nugen, 30-50ng of RNA was amplified and labeled to produce cDNA. Labeled cDNA was hybridized on chips containing the whole human genome (Human Genome U133 Plus 2.0 from Affymetrix).
2010-10-16 | E-GEOD-24736 | biostudies-arrayexpress
Project description:Protein Tyrosine Phosphatase Non-receptor type 22 (PTPN22) is encoded by a major autoimmunity gene and is a known inhibitor of T cell receptor (TCR) signaling and drug target for cancer immunotherapy. However, little is known about PTPN22 post-translational regulation. Here we characterize a phosphorylation site at Ser325 situated C-terminal to the catalytic domain of PTPN22, and its roles in altering protein function. Signaling through the major TCR-dependent pathway under PTPN22 control was enhanced by CRISPR/Cas9 mediated suppression of Ser325 phosphorylation and inhibited by mimicking it via glutamic acid substitution. Next-generation sequencing (NGS) revealed it differentially regulates the expression of chemokines and T cell activation pathways. In conclusion, this study explores the function of a novel phosphorylation site of PTPN22 that is involved in complex regulation of TCR signaling .
2024-07-17 | GSE264373 | GEO
Project description:Major autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis, rheumatoid arthritis and Graves’ disease display a striking female bias, with a female-to-male incidence ratio ranging up to 9:1 in SLE. Sex hormones contribute to protection of males from autoimmunity, but precise molecular mechanisms of such protection are poorly understood. Here, we find that Androgen Receptor (AR), a nuclear receptor regulating a plethora of genes, is active in T cells during development and regulates directly genes involved in T cell activation or indirectly through regulation of other transcription factors. A gene encoding a phosphatase Ptpn22, a negative regulator of T cell receptor signaling, was found to be dependent of the presence of androgen receptor (AR) in males. Castration or deletion of AR reduced expression of Ptpn22. In a mouse model of Systemic Lupus Erythematosus (SLE), Ptpn22 deletion led to the loss of sexual dimorphism. Moreover, analysis of the regulatory regions of Ptpn22 gene revealed a highly conserved sequence that was necessary for upregulation of the gene’s expression by androgens. Mutation of this sequence in Non-Obese Diabetic (NOD) mice led to enhanced ability of T cells to cause Type 1 diabetes. Thus, PTPN22 is likely to participate in disease pathogenesis making it and other AR-regulated genes fair targets for therapeutic interventions in major autoimmune diseases.
2024-07-30 | GSE271153 | GEO
Project description:Major autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis, rheumatoid arthritis and Graves’ disease display a striking female bias, with a female-to-male incidence ratio ranging up to 9:1 in SLE. Sex hormones contribute to protection of males from autoimmunity, but precise molecular mechanisms of such protection are poorly understood. Here, we find that Androgen Receptor (AR), a nuclear receptor regulating a plethora of genes, is active in T cells during development and regulates directly genes involved in T cell activation or indirectly through regulation of other transcription factors. A gene encoding a phosphatase Ptpn22, a negative regulator of T cell receptor signaling, was found to be dependent of the presence of androgen receptor (AR) in males. Castration or deletion of AR reduced expression of Ptpn22. In a mouse model of Systemic Lupus Erythematosus (SLE), Ptpn22 deletion led to the loss of sexual dimorphism. Moreover, analysis of the regulatory regions of Ptpn22 gene revealed a highly conserved sequence that was necessary for upregulation of the gene’s expression by androgens. Mutation of this sequence in Non-Obese Diabetic (NOD) mice led to enhanced ability of T cells to cause Type 1 diabetes. Thus, PTPN22 is likely to participate in disease pathogenesis making it and other AR-regulated genes fair targets for therapeutic interventions in major autoimmune diseases.
2023-06-07 | GSE234134 | GEO
Project description:The presence of the PTPN22 risk variant (1858T) is associated to several autoimmune diseases including rheumatoid arthritis (RA). Despite a number of studies exploring the function of PTPN22 in T cells, the exact impact of the PTPN22 risk variant on T cell function in humans is still unclear. In this study, using RNA sequencing, we show that, upon TCR-activation, naïve CD4+ T cells carrying two PTPN22 risk alleles overexpress a limited number of genes including CFLAR and 4-1BB important for cytotoxic T cell differentiation. Moreover, an increased number of cytotoxic EOMES+ CD4+ T cells were observed in PTPN22 risk allele carriers, which negatively correlated with a decreased number of naïve T cells in older individuals. No difference in the frequency of other CD4+ T cell subsets (Th1, Th17, Tfh, Treg) was observed in PTPN22 risk allele carriers and Treg suppressive capacity was not altered. Finally, in synovial fluids of RA patients, an accumulation of EOMES+ CD4+ T cells was observed with a more pronounced production of Perforin-1 in PTPN22 risk allele carriers. Altogether, our data provide a novel mechanism of action of PTPN22 risk variant on CD4+ T-cell differentiation and identify EOMES+ CD4+ T cell as a relevant T cell subset in RA.
2018-02-27 | GSE94859 | GEO
Project description:PEST-domain-enriched tyrosine phosphatase (PEP) is a cytoplasmic protein tyrosine phosphatase that regulates immune cell functions, including mast cell functions. Using bone marrow derived mast cells (BMMCs) from PEP+/+ and PEP-/- mice, RNA-seq data showed that dinitrophenol (DNP) - activated PEP-/- BMMCs have misregulated gene expression, with some cytokine/chemokine genes (eg.TNFα, IL13, CSF2) showing reduced gene expression in the dinitrophenol (DNP) - activated PEP-/- BMMCs compared to (DNP)-activated PEP+/+ BMMCs. Also, the ability of the glucocorticoid dexamethasone (Dex) to negatively regulate DNP - induced COX-2 gene expression in PEP-/- BMMCs was inhibited compared to the PEP+/+ BMMCs.
2018-01-31 | GSE108972 | GEO
Project description:The 1858C>T allele of the tyrosine phosphatase PTPN22 (causing amino acid substitution R620W in encoded protein lymphoid tyrosine phosphatase) is present in 5-10% of the North American population and is strongly associated with numerous autoimmune diseases. Although much research has been done to define how this allele potentiates autoimmunity, the influence PTPN22 and its proautoimmune allele have in tumor immunity is poorly defined. To interrogate the role this allele may have in the antitumor immune response, we used CRISPR/Cas9 to generate mice in which the ortholog of lymphoid tyrosine phosphatase, PEST domain-enriched protein (PEP), is mutated at position 619 to produce the relevant proautoimmune mutation (R619W). Results of this study show that mice homozygous for this alteration (PEP-619WW) resist tumor growth as compared with wild-type mice. Consistent with these results, tumors from PEP-619WW mice have more CD45 infiltrates containing more activated CD8 T cells and CD4 T cells. In addition, there are more conventional dendritic cell type 1 (cDC1) cells and fewer myeloid-derived suppressor cells in tumors from PEP-619WW mice. Interestingly, the tumor-infiltrating PEP-619WW cDC1 cells have decreased PD-L1 expression compared with cDC1 cells from PEP-wild-type mice. Taken together, our data show that the proautoimmune allele of Ptpn22 drives a strong antitumor response in innate and adaptive immune cells resulting in superior control of tumors.
| S-EPMC8428750 | biostudies-literature
Project description:Efforts to improve the clinical outcome of highly aggressive triplenegative breast cancer (TNBC) have been hindered by the lack of effective targeted therapies. Hence, it is important to identify the specific gene targets/pathways driving the invasive phenotype to develop more effective therapeutics. Here we show that UBASH3B (ubiquitin associated and SH3 domain containing B), a protein tyrosine phosphatase, is overexpressed in TNBC, where it supports malignant growth, invasion and metastasis in large through modulating EGFR. We also show that UBASH3B is a functional target of anti-invasive miR-200a that is downregulated in TNBC. Importantly, the oncogenic potential of UBASH3B is dependent on its tyrosine phosphatase activity, which targets CBL ubiquitin ligase for dephosphorylation and inactivation, leading to EGFR upregulation. Thus, UBASH3B may function as a crucial node in bridging multiple invasion-promoting pathways, thus providing a potential new therapeutic target for TNBC. Breast cancer tissues and breast cancer cell lines
2013-06-01 | E-GEOD-36693 | biostudies-arrayexpress