Exploring the Genetic Influence of Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) on Inflammatory Biomarkers in Endometriosis Progression.

The single-nucleotoide polymorphisms (SNP) rs1893217, located in the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2), is associated with inflammatory disorders, including inflammatory bowel disease (IBD), rheumatic arthritis, and type 1 diabetes. We have demonstrated that PTPN2 plays a crucial role in maintaining intestinal homeostasis. The polyamine spermidine, which is a potent activator of PTPN2 enzymatic activity, limits IFNg-induced pro-inflammatory signalling events via activation of PTPN2. Of note, spermidine treatment promotes intestinal barrier function and reduces intestinal inflammation in a mouse model of colitis in vivo. However, it is unclear how spermidine modulates inflammatory signalling cascades in primary immune cells from IBD patients. The aim of this study was to investigate whether spermidine treatment is effective in reducing IFNg-induced signalling in peripheral blood mononuclear cells (PBMC) from IBD patients and to investigate how the presence of the PTPN2 risk allele (SNP rs1893217) affects the outcome of spermidine treatment. PBMC were isolated from IBD patients heterozygous for SNP rs1893217 (CT; n = 4) or homozygous for the major allele (TT; n = 4), as well as from healthy controls (all TT; n = 5) and treated with INFg (100 ng/ml) and/or spermidine (10 nM). mRNA expression of INFg, PTPN2, intercellular adhesion molecule-1 (ICAM1) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) was analysed by quantitative PCR. As expected, IFNg-treatment resulted in increased mRNA expression of the IFN-g response genes ICAM1, PTPN2, and NOD2. In PBMC from patients with the CT genotype, basal mRNA expression of those genes was already elevated, and their mRNA expression level following IFNg treatment was clearly higher than those observed in PTPN2 wild-type cells. Activation of PTPN2 by spermidine clearly ameliorated IFN-g-induced up-regulation of ICAM1, IFNG and NOD2 mRNA expression in all patients (p < 0.05). Of particular interest and despite elevated IFN-g responses, spermidine treatment was more effective in patients with the CT genotype (p < 0.05). Our results demonstrate that spermidine treatment is effective in reducing inflammatory signalling in PBMC from IBD patients. The presence of the C allele in PTPN2 SNP rs1893217 promotes inflammatory responses, but concurrently renders the cells more susceptible to the anti-inflammatory effects of spermidine. This indicates that spermidine treatment might be a promising novel therapeutic approach in IBD patients and that the C allele might serve as a good predictor for treatment response. This might be a step towards personalised medicine in the management of IBD.

Background: Autoimmune thyroid diseases are multifactorial diseases with a genetic susceptibility and environmental factors. A potential role of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, the interferon-induced helicase domain 1 (IFIH1) gene, the thyroid-stimulating hormone receptor (TSHR) gene polymorphisms on autoimmune thyroid diseases (AITDs) in adults has been established unequivocally, but there is still lack of research articles including group of children.Objective and hypotheses: To estimate the association of polymorphisms of PTPN22, IFIH1 and TSH-R genes with the pre-disposition to Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) in children.Methods: The study was performed in 142 patients with GD, 57 with HT and 160 healthy volunteers. The three single-nucleotide polymorphisms (SNPs): rs2476601 – PTPN22, rs1990760 – IFIH1 and rs179247 – TSHR were genotyped by TaqMan SNP genotyping assay using the real-time PCR.Results: Rs2476601 A alleles were more frequent in patients with GD in comparison to healthy subjects (p = .009 with odds ratio [OR] = 2.13). Rs2476601 A alleles were more frequent in patients with HT in comparison to healthy subjects (p = .008, OR = 2.48). Rs1990760 T alleles were more frequent in male patients with GD in comparison to healthy males (p = .003, OR = 3.00). In case of HT patients, rs1990760 T alleles were also more frequent in males compared to healthy subjects (p = .086, OR =2.47). Rs179247 A alleles were more frequent in patients with GD in comparison to healthy subjects (p = 0.039, OR = 1.51).Conclusions: Rs2476601 A/G, Rs1990760 C/T and Rs179247 A/G polymorphisms could contribute to the development of AITDs in children. The main risk factor for rs2476601 and rs179247 is allele A. In case of rs1990760, the main risk factor is allele T.

Genetic susceptibility of increased intestinal permeability is associated with progressive liver disease and diabetes in patients with non-alcoholic fatty liver disease

Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) with the onset of inflammatory bowel disease (IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.

Objectives: The protein tyrosine phosphatase non-receptor type 22 (PTPN22) is generally accepted as a key factor in maintaining immune cellular homeostasis. So far, no association has been reported between the polymorphisms of PTPN22 and ankylosing spondylitis (AS) in Chinese populations. We attempted to explore the association between the PTPN22 gene and AS in a central south Chinese Han population.Method: Our study involved 180 HLA-B27+ unrelated patients and 360 HLA-B27– healthy individuals. Seven single nucleotide polymorphisms (SNPs: rs2476601, rs1217414, rs1217418, rs1746853, rs1970559, rs3765598, and rs3811021) were detected. Genotyping was conducted using the polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) method.Results: rs2476601 was not polymorphic enough in both patients and controls. The SNP rs1217414 was found to be associated with AS but the other five of the seven selected SNPs (rs1217418, rs1746853, rs1970559, rs3765598 and rs3811021) were not.Conclusions: The PTPN22 gene might be associated with AS in a central south Chinese Han population.

Objectives The association between interleukin-10 (IL-10) and protein tyrosine phosphatase non-receptor type 22 (PTPN22) has been implicated in immune regulation and autoimmune risk. This meta-analysis aimed to evaluate the association between specific gene variants rs1800896, rs1800871, and rs1800872 in interleukin-10 and rs2476601 in protein tyrosine phosphatase non-receptor type 22 (PTPN22) with rheumatoid arthritis susceptibility. Methods The studies included in this article were obtained by using online databases. We searched databases such as Scopus, PubMed, Embase, and Web of Science for case–control articles related to focusing on studies published from 2019 to 2025. Results A total of fifteen case–control studies were included. The rs1800896 variant in interleukin-10 was significantly associated with increased rheumatoid arthritis risk under the allele contrast model (G vs. A: OR 1.15, 95% CI 1.01 to 1.32, p = 0.03) and the dominant model (GG + GA vs. AA: OR 1.28, 95% CI 1.06 to 1.54, p = 0.01). No significant associations were found for rs1800871 or rs1800872 under any genetic model. For the PTPN22 gene, the rs2476601 variant was significantly protective under the dominant model (CC + CT vs. TT: OR 0.39, 95% CI 0.21 to 0.72, p = 0.002). Subgroup analyses were feasible for IL-10 (rs1800896, rs1800871, rs1800872) and PTPN22 (rs2476601), but no significant associations were identified, and power analysis confirmed the robustness of our results. Conclusions This meta-analysis identified a significant association between the interleukin-10 rs1800896 variant and increased risk of rheumatoid arthritis, and a protective role for the rs2476601 variant in PTPN22. Variants rs1800871 and rs1800872 did not show any association. These findings emphasize the importance of genetic screening in understanding disease susceptibility and the need for further studies across diverse populations to refine the genetic risk profile of rheumatoid arthritis.

The aim of this study was to determine the association between 13 single nucleotide polymorphisms (SNPs) in the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes with scleritis in a Chinese Han population. We recruited 432 scleritis patients and 710 healthy controls. Four tag SNPs of CTLA4 and nine tag SNPs of PTPN22 were selected using Haploview. Genotyping was performed with the Sequenom MassArray® iPLEX GOLD Assay. Genotype and allele frequency differences were analyzed by χ2 test and Bonferroni correction. Haplotype analysis was performed to further evaluate the association of these two genes with scleritis. In this study, CTLA4/rs3087243 G allele frequency and GG genotype frequency were significantly increased in scleritis patients compared to healthy controls [corrected P-value (Pc)=0·02, odds ratio (OR)=1·475, 95% confidence interval (CI)=1·175-1·851; Pc=0·04, OR=1·546, 95% CI=1·190-2·008, respectively]. None of the tested SNPs in the PTPN22 gene showed an association with scleritis. Haplotype analysis revealed a lower frequency of a CTLA4 TCAA haplotype (order of SNPs: rs733618, rs5742909, rs231775, rs3087243) (Pc=4·26×10-3 , OR=0·618, 95% CI=0·540-0·858) and a higher frequency of a PTPN22 TTATACGCG haplotype (order of SNPs: rs3789604, rs150426536, rs1746853, rs1217403, rs1217406, rs3789609, rs1217414, rs3789612, rs2488457) (Pc=2·83×10-4 , OR=1·457, 95% CI=1·210-1·754) in scleritis patients when compared to healthy controls. In conclusion, our findings indicate that CTLA4 and PTPN22 might confer genetic susceptibility to scleritis in a Chinese Han population.

Genetic factors appear to be important in the development of restenosis after percutaneous coronary intervention, as well as in the process of inflammation, a pivotal factor in restenosis. Caspase-1, interleukin-1-receptor and protein tyrosine phosphatase nonreceptor type 22 are important mediators in the inflammatory response and caspase-1 also in apoptosis. Therefore, we examined whether polymorphisms in these candidate genes are related to the risk of developing restenosis after percutaneous coronary intervention. The GENetic DEterminants of Restenosis-project is a multicenter prospective follow-up study. The 5352G/A (L235L) caspase-1-polymorphism, the 7464C/G (A124G) interleukin-1r-polymorphism and the 1858C/T (R620W) protein tyrosine phosphatase nonreceptor type 22-polymorphism were genotyped. To examine the functional effect of the caspase-1 polymorphism, mature plasma interleukin-1beta levels were measured by enzyme-linked immunosorbent assay in lipopolysaccharide-stimulated whole blood from a subpopulation of patients. A total of 3104 patients, age 62.1+/-10.7 years, were included after successful percutaneous coronary intervention. A significant association between the 5352AA genotype of the caspase-1 gene and target vessel revascularization (relative risk 2.2, 95% confidence interval 1.32-3.76) was observed after correcting for clinical variables. Angiographic analysis of a subgroup of patients (N=478) also showed an increased risk for developing restenosis for patients having the 5352GA/AA genotype (P=0.001). The results were corroborated, although they were not statistically significant, by somewhat higher mature interleukin-1beta levels in patients with the 5352AA genotype. The present study shows that patients with the 5352AA genotype in the caspase-1 gene are at increased risk of developing restenosis. If confirmed by other studies, screening patients for this genotype can lead to better risk stratification and provide indications for improving individual treatment; for instance, by providing a new target for drug-eluting stents.

IntroductionBody composition including percentage of fat, fat mass and fat‐free mass (FFM) is an important consideration for athletes. An evaluation of FFM in racehorses concluded that racing performance is positively correlated with FFM both pre‐ and post‐training. Athletic performance is influenced by interactions among the environment and genes that influence anatomical, metabolic and physiological traits relevant to exercise. The aim of this study was to determine the effects of genetic variation in six candidate genes with functions in growth and metabolism (IL1RA, PTPN1, MC3R, IGF1, LEPR and MSTN) on FFM in Thoroughbreds.MethodsFFM was calculated from rump fat thickness measured ultrasonographically in 110 two‐year‐old Thoroughbred horses‐in‐training in the same yard after two (T2) and eight (T8) months of training. Twenty‐one SNPs in six genes were selected from the EquCab2.0 SNP database and were genotyped for all horses using custom Sequenom SNP genotyping assays. Quantitative tests of association were performed between SNPs and FFM at T2 and T8, and the FFM ratio between the two time points (T2 : T8) using PLINK software.ResultsTwo SNPs in both the IGF1 (Insulin‐Like Growth Factor 1) and PTPN1 (Protein Tyrosine Phosphatase, Non‐Receptor Type 1) genes were significantly associated with FFM (T2) (P&lt;0.05). The two IGF1 SNPs and two LEPR (Leptin Receptor) gene SNPs were significantly associated with FFM (T8) (P&lt;0.05). One LEPR SNP was significantly (P&lt;0.005) associated with changes in FFM (T2 : T8).ConclusionsThese results suggest a genetic contribution to FFM variation in Thoroughbreds. Further validation will determine whether these SNPs may be used to predict the effects of training on FFM.Ethical Animal ResearchInstitutional Animal Research Ethics Committee approval was obtained. Explicit owner informed consent for participation in this study is not stated. Sources of funding: The study was funded by a Science Foundation Ireland, President of Ireland Young Researcher Award (04‐YI1‐ B539). Competing interests: Dr Hill is a co‐founder and Chairman of Equinome Ltd.

Loss of Protein Tyrosine Phosphatase Nonreceptor Type 22 Regulates Interferon-γ–Induced Signaling in Human Monocytes

Background: Rheumatoid Arthritis (RA) is a chronic disorder characterized by an inflammation of synovial tissue in joints resulting in pain, deformities and affects the quality of life. The gene for protein tyrosine phosphatase non-receptor type 22 (PTPN22) encodes a lymphoid specific phosphatase (LYP), which serves as a negative regulator of T lymphocyte activation and is associated with a number of autoimmune/chronic diseases in various ethnic groups. Objective: This study was undertaken to investigate an association between PTPN22 gene functional polymorphism (C1858T; rs2476601) and rheumatoid arthritis (RA) in Kuwaiti Arabs. The frequency of this candidate locus was compared between Kuwaiti RA patients and the controls and with that reported from other populations. Methods: The study was carried out in 191 Kuwaiti RA patients and 214 healthy controls. The diagnosis of RA was carried out according to the guidelines of the American College of Rheumatology (ACR). The genotypes of PTPN22 gene (C1858T) polymorphism were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and confirmed by DNA sequence analysis in RA patients and controls. Results: The TT genotype of PTPN22 gene functional polymorphism C1858T was found in 2/191 (1%) in RA patients compared to 2/214 (1%) in the controls (P = 1.0). In contrast, heterozygous CT genotype was detected in 3/191 (1.57%) RA patients compared to 32/214 (14.9%) in the controls. The CC genotype was detected in 186/191 (97.38%), RA patients while it was detected in 180/214 (84.1%) of the controls. The two RA patients who carried the homozygous variant (TT) genotype were both positive for rheumatoid factor (RF) and did not have any extra-articular manifestations. Amongst the Kuwaiti RA patients, 27% had a family history of RA. No correlation was found between the activity/severity of the disease and PTPN22 gene polymorphism genotypes. Conclusion: This study did not find an association between the PTPN22 gene functional polymorphism (C1858T) and clinical manifestation and activity/severity of RA in Kuwaiti Arabs. This is in sharp contrast to previous reports from Caucasian and some other populations in which a positive association of PTPN22 gene (C1858T) polymorphism with genetic susceptibility to RA has been reported.

Among the ~200 susceptibility loci associated with Inflammatory Bowel Disease (IBD), are loss‐of‐function single nucleotide polymorphisms (SNPs) in the locus (18p11) containing the Protein Tyrosine Phosphatase non‐receptor Type 2 (PTPN2) gene. PTPN2 encodes the T Cell Protein Tyrosine Phosphatase (TCPTP) that functions as a negative regulator of diverse intracellular pathways repressing inflammatory signals. In Ptpn2‐deficient mice, we observed altered intestinal homeostasis in the form of intestinal epithelial barrier defects and altered intestinal microbiome composition. Intestinal epithelial homeostasis is maintained by active‐cycling and slow cycling stem cells confined within the crypt‐based niche and subsequent differentiation into secretory and absorptive epithelial lineages as cells migrate up the crypt‐villus axis. The goal of this study was to determine whether Ptpn2‐loss affects intestinal epithelial cell populations and function that could contribute to altered host‐bacterial interactions.MethodsIntestinal tissues (ileum, cecum, proximal and distal colon) from 21 day old wild type (WT), heterozygous (HET) and constitutive Ptpn2 knockout (KO) Balb/C mice were harvested and processed for imaging to detect proliferation (Ki‐67), apoptosis (TUNEL), Paneth cell (lysozyme), and goblet cell (periodic‐acid Shiff) numbers via staining of specific markers. cDNA was generated by reverse transcriptase, and mRNA expression of key genes associated with Paneth and goblet cells function were measured by PCR.ResultsProximal and distal colon of Ptpn2‐KO mice showed clusters of apoptotic cells at the crypt base in comparison to wildtype. In addition, the number of proliferative cells was higher in the crypts of proximal and distal colon of Ptpn2‐KO mice compared to WT (p=0.0032 and p=0.0005 respectively; n=3). Lysozyme‐positive Paneth cells were significantly reduced in HET mice (p=0.0452 vs. WT; n=2–5) and further reduced in KO mice (p=0.0040; n=4). Moreover, KO mice were almost completely devoid of both lysozyme positive and negative Paneth cells, the latter characterized by large cytosolic granules at the crypt base. mRNA expression of the Paneth cell antimicrobial peptide, Lyz1, was reduced in Ptpn2‐KO mice compared to WT (p=0.017; n=2), whereas expression of antimicrobial peptides Defa5 and Defa6 were not altered. Goblet cell number was slightly reduced in the ileum and distal colon of KO mice (n=2). There was also a preliminary trend towards reduced expression of goblet cell secreted mucin proteins, Muc2, a major mucus layer constituent, and Muc3, a mucin protein homologous to MUC17 in humans shown to be protective against enteroinvasive E. coli, in the cecum of Ptpn2‐KO mice compared to wildtype (n=2).ConclusionPtpn2‐deficiency compromises intestinal epithelial cell differentiation leading to altered numbers and function of Paneth and goblet cells consistent with increased susceptibility to bacterial infection.Support or Funding InformationSupported by NIH 2R01DK091281 (DFM), the Crohn's and Colitis Foundation (DFM), and Science Without Borders Fellowship (VC)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by the inflammation of synovial fluid. The incidence of cardiovascular diseases (CVDs) is increasing in RA patients. This research is the first report to investigate the anti-arthritic effect of avocado peel nutraceutical (APN) and its potential in mitigating the cardiovascular risk associated with RA. The antioxidant activity and phytochemical composition of APN were assessed. The potential interaction of APN's active compounds with protein tyrosine phosphatase non-receptor type 22 (PTPN22) was studied using molecular docking. The impact of APN on the plasma lipid profile, oxidative and inflammatory markers, and the indices of coronary risk and atherogenicity as CVD markers were evaluated. The gene expression of COX-2, IL-6, IL-1β, IL-10, and TNF-α in liver and spleen tissues were measured. The rat gut microbiota profile was investigated using 16S rRNA amplicon sequencing. APN exhibited high antioxidant activity, low atherogenicity and thrombogenicity indices, and a high ratio of hypocholesterolemic to hypercholesterolemic fatty acids indicating its cardioprotective potential. The administration of APN led to a reduction in oxidative stress markers, inflammatory markers, dyslipidemia, and CVD markers. APN administration downregulated the expression of COX-2, IL-6, IL-1β, and TNF-α genes, while the IL-10 gene was significantly upregulated in the liver and spleen. Treatment with APN was favorable in restoring eubiosis in the gut by modulating RA-associated bacterial taxa linked to impaired immune function and cardiometabolic diseases. In molecular docking, β-amyrin and ellagic acid showed the highest binding affinity for PTPN22. APN may represent a promising approach to ameliorating the cardiovascular risk of RA. The present results will be offering a foundation for future in-depth research in nutraceuticals from agriculture by-products. Additionally, they will be supporting the public health policies aimed at preventing and controlling rheumatoid arthritis.

Prediction of future rheumatoid arthritis.

Pathogenesis of primary adrenal insufficiency