Variations within the gene locus encoding protein tyrosine phosphatase non-receptor type 22 (PTPN22) are associated with the risk to develop inflammatory bowel disease (IBD). PTPN22 is involved in the regulation of T- and B-cell receptor signaling, but although it is highly expressed in innate immune cells, its function in other signaling pathways is less clear. Here, we study whether loss of PTPN22 controls muramyl-dipeptide (MDP)-induced signaling and effects in immune cells.

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.

BACKGROUND Ankylosing spondylitis (AS) is a chronic autoimmune disease that involves the imbalance of peripheral tolerance possibly caused by the negative signal of activated T cells. The polymorphisms in the human protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene have been pointed out to be related to the pathogenesis of AS, but conclusions over this issue remain contradictory. We attempted to give a more precise conclusion about the effects of PTPN22 polymorphisms on AS risk by means of a meta-analysis. MATERIAL AND METHODS PubMed, Embase, Wanfang, and Chinese National Knowledge Infrastructure (CNKI) were searched for relevant studies published in the English or Chinese language. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated with a fixed- or random-effects model to evaluate the correlation between PTPN22 rs2488457, rs1217414, and rs2476601 polymorphisms and AS susceptibility. Sensitivity analysis was also carried out to detect the stability of the results. RESULTS The present meta-analysis showed a positive correlation of both PTPN22 rs2488457 and rs1217414 polymorphisms with AS risk under CC vs. GG, CC + GC vs. GG, CC vs. GC + GG, allele C vs. allele G (OR=1.39, 95% CI=1.04-1.85, P=0.646; OR=1.29, 95% CI=1.03-1.62, P=0.426; OR=1.26, 95% CI=1.02-1.56, P=0.971; OR=1.20, 95% CI=1.05-1.38, P=0.571), and TT vs. CC and TT vs. CT + CC models (OR=3.83, 95% CI=1.11-13.24, P=0.196; OR=3.83, 95% CI=1.09-13.42, P=0.244), respectively. CONCLUSIONS PTPN22 rs2488457 and rs1217414 polymorphisms may be risk factors for AS occurrence.

Endogenous uveitis is a major cause of visual loss mediated by the immune system. The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene encodes a lymphoid-specific phosphatase that plays a key role in T-cell receptor (TCR) signaling. Two independent functional missense single nucleotide polymorphisms (SNPs) located within the PTPN22 gene (R263Q and R620W) have been associated with different autoimmune disorders. We aimed to analyze for the first time the influence of these PTPN22 genetic variants on endogenous non-anterior uveitis susceptibility.

BACKGROUND The aim of the current study was to explore the anti-arthritic effect of pinitol via assessing its effect on various inflammatory mediators and its possible mechanism of action. MATERIAL AND METHODS We assessed the anti-arthritic effect of pinitol in a formaldehyde- and CFA-induced arthritic model in Wistar Swiss albino strain rats divided into 6 groups. The rats received different doses of pinitol and indomethacin for 28 days. The arthritic index and body weight were determined at regular intervals, together with hepatic, hematological, and antioxidant parameters. The expression of proinflammatory cytokines (e.g., IL-6, TNF-α, and IL-1β) and inflammatory mediators (e.g., COX-2 and VEGF) were also estimated with histopathological evaluation of the joint tissue of rats. A docking study of pinitol with PTPN22 was also carried out. RESULTS The CFA-induced model rats developed redness and nodules in the tail and front paws, and the arthritic control (AC) group rats showed similar symptoms, which were decreased by pinitol administration. The body weight of AC group rats was decreased, while pinitol-treated rats showed considerably increased body weight. Hematological, hepatic, and antioxidant parameters were altered by pinitol in a dose-dependent manner. Pinitol significantly decreased the elevated concentration of proinflammatory cytokines and inflammatory mediators, with improvement in histopathological condition. The docking study suggested that pinitol efficiently interacted with PTPN22 via Arg59, Tyr60, Leu106, and Lys138 by creating close interatomic hydrogen bonds and hydrophobic contacts. CONCLUSIONS Pinitol showed anti-arthritic effects via reduction of proinflammatory cytokines and inflammatory mediators via inhibition of PTPN22.

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 132 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.

A mesiodens is a supernumerary tooth located in the midline of the premaxilla. To investigate the genetic cause of mesiodens, clinical and radiographic examination were performed on 23 family members of a two-generation Hmong family. Whole exome sequencing (WES) or Sanger sequencing were performed in 22 family members and two unrelated Thai patients with mesiodens. WES in the Hmong family revealed a missense mutation (c.1807G>A;p.Glu603Lys) in PTPN23 in seven affected members and six unaffected members. The mode of inheritance was autosomal dominance with incomplete penetrance (53.84%). Two additional mutations in PTPN23, c.2248C>G;p.Pro750Ala and c.3298C>T;p.Arg1100Cys were identified in two unrelated patients with mesiodens. PTPN23 is a regulator of endosomal trafficking functioning to move activated membrane receptors, such as EGFR, from the endosomal sorting complex towards the ESCRT-III complex for multivesicular body biogenesis, lysosomal degradation, and subsequent downregulation of receptor signaling. Immunohistochemical study and RNAscope on developing mouse embryos showed broad expression of PTPN23 in oral tissues, while immunofluorescence showed that EGFR was specifically concentrated in the midline epithelium. Importantly, PTPN23 mutant protein was shown to have reduced phosphatase activity. In conclusion, mesiodens were associated with genetic variants in PTPN23, suggesting that mesiodens may form due to defects in endosomal trafficking, leading to disrupted midline signaling.

Macrophages are a heterogeneous population of innate immune cells that are often divided into two major subsets: classically activated, typically pro-inflammatory (M1) macrophages that mediate host defense, and alternatively activated, tolerance-inducing (M2) macrophages that exert homeostatic and tissue-regenerative functions. Disturbed macrophage function/differentiation results either in inadequate, excessive immune activation or in a failure to induce efficient protective immune responses against pathogens. Loss-of-function variants in protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with chronic inflammatory disorders, but the effect of macrophage-intrinsic PTPN2 loss is still poorly understood. Here we report that PTPN2-deficient macrophages fail to acquire an alternatively activated/M2 phenotype. This was the consequence of reduced IL-6 receptor expression and a failure to induce IL-4 receptor in response to IL-6, resulting in an inability to respond to the key M2-inducing cytokine IL-4. Ultimately, failure to adequately respond to IL-6 and IL-4 resulted in increased levels of M1 macrophage marker expression in vitro and exacerbated lung inflammation upon infection with Nippostrongylus brasiliensis in vivo. These results demonstrate that PTPN2 loss interferes with the ability of macrophages to adequately respond to inflammatory stimuli and might explain the increased susceptibility of PTPN2 loss-of-function carriers to developing inflammatory diseases.

Protein tyrosine phosphatase non-receptor type 2 (PTPN2) plays a pivotal role in immune homeostasis and has been associated with human autoimmune and chronic inflammatory diseases. Though PTPN2 is well-characterized in lymphocytes, little is known about its function in innate immune cells. Our findings demonstrate that dendritic cell (DC)-intrinsic PTPN2 might be the key to explain the central role for PTPN2 in the immune system to maintain immune tolerance. Partial genetic PTPN2 ablation in DCs resulted in spontaneous inflammation, particularly in skin, liver, lung and kidney 22 weeks post-birth. DC-specific PTPN2 controls steady-state immune cell composition and even incomplete PTPN2 deficiency in DCs resulted in enhanced organ infiltration of conventional type 2 DCs, accompanied by expansion of IFNγ-producing effector T-cells. Consequently, the phenotypic effects of DC-specific PTPN2 deficiency were abolished in T-cell deficient Rag knock-out mice. Our data add substantial knowledge about the molecular mechanisms to prevent inflammation and maintain tissue tolerance.

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) plays an important role in immune cell function and intestinal homeostasis. The single nucleotide polymorphism (SNP) rs2476601 within the PTPN22 gene locus results in aberrant function of PTPN22 protein and protects from Crohn's disease (CD). Here, we investigated associations of PTPN22 SNP rs2476601 in inflammatory bowel disease (IBD) patients in the Swiss IBD Cohort Study (SIBDCS).

We elucidate in this study that up-regulation of miR-574-5p in gastric cancer cells under hypoxic conditions contributed to angiogenesis. We found that miR-574-5p and HIF-1α were up-regulated in gastric cancer cells cultured under 2% O2 or in medium containing CoCl2, and in muscle tissues of mice injected with NaNO2, indicating up-regulation of miR-574-5p in vitro or in vivo in response to hypoxic conditions. We hypothesized that up-regulation of miR-574-5p could promote angiogenesis. Transfection of gastric cancer cells with miR-574-5p mimics or inhibitor resulted in increase or decrease in the expression of VEGFA. Viability, migration, invasion and tube formation of HUVECs cultured with conditioned medium from SGC/574 cells transfected with miR-574-5p inhibitor were reduced. Tube formation of HUVECs cultured with conditioned medium from SGC-7901 cells transfected with miR-574-5p mimics was increased. An in vivo study demonstrated that inhibition of miR-574-5p in the tumor xenografts of mice reduced the expression of CD31 one of the endothelial cell markers. We identified PTPN3 a tyrosine phosphatase as a target of miR-574-5p that bound to the 3'UTR of PTPN3 mRNA to inhibit the expression of PTPN3. Furthermore, the data in this study demonstrated that inhibition of PTPN3 in gastric cancer cells enhanced phosphorylation of p44/42 MAPKs and promoted angiogenesis. We conclude that miR-574-5p in gastric cancer cells promoted angiogenesis via enhancing phosphorylation of p44/42 MAPKs by miR-574-5p inhibition of PTPN3 expression.

Crohn's disease (CD) is one of the sub-entities of Inflammatory Bowel Disease which causes chronic inflammation in the gastrointestinal tract. The development of CD has shown to have a strong genetic association. Therefore, the present study aimed to investigate the association between genetic polymorphisms in a susceptible locus of CD, the protein tyrosine phosphatase, non-receptor type 2 (PTPN2) gene and the development of CD in Malaysian patients. A total of 137 CD patients and 274 matched healthy controls were recruited in the present study. Genomic DNA was extracted from the venous blood of participants and five targeted single nucleotide polymorphisms (SNPs) in the PTPN2 gene were genotyped using polymerase chain reaction. Associations between the SNPs and CD were determined using Fisher's exact test and odds ratio. Findings showed that all five selected SNPs were not significantly associated with the development of CD in Malaysian patients, which was in contrast to studies among the European populations. Malaysian Chinese with rs487273 heterozygous G/T genotype was found to have a lower occurrence of CD (P-value = 0.0253; OR = 0.4396). Patients with rs2542152 homozygous T genotype were associated with stricturing behaviour (P-value = 0.0302, OR = 2.9944). The rs16939895 A/G genotype was associated with inflammation at the ileum site (P-value = 0.0387, OR = 2.2105)while homozygous G genotype was associated with colonic CD (P-value = 0.0164, OR = 2.3917). Functional studies of these SNPs are needed to evaluate their potential use as a biomarker for disease phenotypes among Asian patients.

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease which involves the loss of self-tolerance with hyperactivation of autoreactive T- and B-cells. Protein tyrosine phosphatase non-receptor type 22 (PTPN22) encodes for lymphoid specific phosphatase (LYP) which is a key negative regulator of T lymphocyte activation. The aim of this study was to investigate the association between PTPN22 gene functional variant R620W and systemic lupus erythematosus (SLE) by comparing its prevalence in Kuwaiti SLE patients and controls.

Interactions between the hepatitis B virus core protein (HBc) and host cell proteins are poorly understood, although they may be essential for the propagation of the virus and its pathogenicity. HBc has a C-terminal PDZ (PSD-95, Dlg1, ZO-1)-binding motif (PBM) that is responsible for interactions with host PDZ domain-containing proteins. In this work, we focused on the human protein tyrosine phosphatase non-receptor type 3 (PTPN3) and its interaction with HBc. We solved the crystal structure of the PDZ domain of PTPN3 in complex with the PBM of HBc, revealing a network of interactions specific to class I PDZ domains despite the presence of a C-terminal cysteine in this atypical PBM. We further showed that PTPN3 binds the HBc protein within capsids or as a homodimer. We demonstrate that overexpression of PTPN3 significantly affects HBV infection in HepG2 NTCP cells. Finally, we performed proteomics studies on both sides by pull-down assays and screening of a human PDZ domain library. We identified a pool of human PBM-containing proteins that might interact with PTPN3 in cells and that could be in competition with the HBc PBM during infection, and we also identified potential cellular partners of HBc through PDZ-PBM interactions. This study opens up many avenues of future investigations into the pathophysiology of HBV.

Adoptive cell therapy (ACT) is a promising strategy for treating cancer, yet it faces several challenges such as lack of long-term protection due to T cell exhaustion induced by chronic TCR stimulation in the tumor microenvironment. One benefit of ACT, however, is that it allows for cellular manipulations, such as deletion of the phosphotyrosine phosphatase non-receptor type 22 (PTPN22), which improves CD8+ T cell antitumor efficacy in ACT. We tested whether Ptpn22KO cytolytic T cells (CTLs) were also more effective than Ptpn22WT CTL in controlling tumors in scenarios that favor T cell exhaustion.

The AKT/PKB kinase is a key signaling component of one of the most frequently activated pathways in cancer and is a major target of cancer drug development. Most studies have focused on its activation by Receptor Tyrosine Kinase (RTK) mediated Phosphatidylinositol-3-OH kinase (PI3K) activation or loss of Phosphatase and Tensin homolog (PTEN). We have uncovered that growth factors binding to RTKs lead to activation of a non-receptor tyrosine kinase, Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation. Mice expressing activated Ack1 specifically in the prostate exhibit AKT Tyr176-phosphorylation and develop murine prostatic intraepithelial neoplasia (mPINs). Further, expression levels of Tyr176-phosphorylated-AKT and Tyr284-phosphorylated-Ack1 were positively correlated with the severity of disease progression, and inversely correlated with the survival of breast cancer patients. Thus, RTK/Ack1/AKT pathway provides a novel target for drug discovery.

Type 1 diabetes mellitus (T1DM) is disease caused by the destruction of β pancreatic cells. The activation of T-lymphocyte and proliferation inhibitor are induced by protein tyrosine phosphatase non-receptor type 22 (PTPN22). However, the link between PTPN22 C1858T gene polymorphism and T1DM is still controversy. This study aimed to analyse the C1858T gene polymorphism in Indonesian children with T1DM.

The coordination mechanism of neural innate immune responses for axon regeneration is not well understood. Here, we showed that neuronal deletion of protein tyrosine phosphatase non-receptor type 2 sustains the IFNγ-STAT1 activity in retinal ganglion cells (RGCs) to promote axon regeneration after injury, independent of mTOR or STAT3. DNA-damage-induced cGAMP synthase (cGAS)-stimulator of interferon genes (STINGs) activation is the functional downstream signaling. Directly activating neuronal STING by cGAMP promotes axon regeneration. In contrast to the central axons, IFNγ is locally translated in the injured peripheral axons and upregulates cGAS expression in Schwann cells and infiltrating blood cells to produce cGAMP, which promotes spontaneous axon regeneration as an immunotransmitter. Our study demonstrates that injured peripheral nervous system (PNS) axons can direct the environmental innate immune response for self-repair and that the neural antiviral mechanism can be harnessed to promote axon regeneration in the central nervous system (CNS).

Elucidating the mechanisms that controlled T cell activation requires visualization of the spatial organization of multiple proteins on the submicron scale. Here, we use stoichiometrically accurate, multiplexed, single-molecule super-resolution microscopy (DNA-PAINT) to image the nanoscale spatial architecture of the primary inhibitor of the T cell signaling pathway, Csk, and two binding partners implicated in its membrane association, PAG and TRAF3. Combined with a newly developed co-clustering analysis framework, we find that Csk forms nanoscale clusters proximal to the plasma membrane that are lost post-stimulation and are re-recruited at later time points. Unexpectedly, these clusters do not co-localize with PAG at the membrane but instead provide a ready pool of monomers to downregulate signaling. By generating CRISPR-Cas9 knockout T cells, our data also identify that a major risk factor for autoimmune diseases, the protein tyrosine phosphatase non-receptor type 22 (PTPN22) locus, is essential for Csk nanocluster re-recruitment and for maintenance of the synaptic PAG population.

Vogt-Koyanagi-Harada (VKH) disease is an autoimmune disorder against melanocytes. Polymorphisms of the protein tyrosine phosphatase non-receptor 22 gene (PTPN22) have recently been reported to be associated with susceptibility to several autoimmune diseases. In this study, genetic susceptibility to VKH disease was investigated by screening for single nucleotide polymorphisms (SNPs) of PTPN22.