Protein Tyrosine Phosphatases: Regulators of CD4 T Cells in Inflammatory Bowel Disease

Pike, Kelly A.; Tremblay, Michel L.

doi:10.3389/fimmu.2018.02504

Cited by 29 publications

(27 citation statements)

References 178 publications

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“…Recently, the CD susceptibility genes PTPN2 (protein tyrosine phosphatase non-receptor type 2) and PTPN22 have been implicated in the regulation of autophagy and inflammasome activities [64,65]. It has been reported that a loss-of-function variant in PTPN2 gene is a risk factor for CD, while a gain-of-function variant in PTPN22 gene is associated with reduced risk of CD [66]. PTPN22 dephosphorylates NLRP3 inflammasome to limit the sequestration of NLRP3 into autophagosomes to be degraded in autolysosomes [64] ( Figure 1J).…”

Section: Autophagy and Inflammasome Activationmentioning

confidence: 99%

New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD

2019

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One of the most significant challenges of inflammatory bowel disease (IBD) research is to understand how alterations in the symbiotic relationship between the genetic composition of the host and the intestinal microbiota, under impact of specific environmental factors, lead to chronic intestinal inflammation. Genome-wide association studies, followed by functional studies, have identified a role for numerous autophagy genes in IBD, especially in Crohn disease. Studies using in vitro and in vivo models, in addition to human clinical studies have revealed that autophagy is pivotal for intestinal homeostasis maintenance, gut ecology regulation, appropriate intestinal immune responses and anti-microbial protection. This review describes the latest researches on the mechanisms by which dysfunctional autophagy leads to disrupted intestinal epithelial function, gut dysbiosis, defect in anti-microbial peptide secretion by Paneth cells, endoplasmic reticulum stress response and aberrant immune responses to pathogenic bacteria. A better understanding of the role of autophagy in IBD pathogenesis may provide better sub-classification of IBD phenotypes and novel approaches for disease management.

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Section: Autophagy and Inflammasome Activationmentioning

confidence: 99%

New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD

2019

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“…By screening a cohort of VEO-IBD patients, we identified a de novo mutation resulting in PTPN2 haplo-insufficiency in a child with intestinal autoimmunity of very early onset. The missense mutation replaced the highly conserved cysteine of the ‘PTP signature motif’ that is indispensable for the catalytic activity of Class I-III phosphatases 36,48 by a glycine residue. Accordingly, the C216G PTPN2 mutant allele was totally deprived of phosphatase activity.…”

Section: Discussionmentioning

confidence: 99%

Network Analysis of Inflammatory Bowel Disease Reveals PTPN2 As New Monogenic Cause of Intestinal Inflammation

Parlato

Pázmándi

Nian

et al. 2019

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54BACKGROUND & AIMS: Genome-wide association studies (GWAS) have uncovered multiple 55 loci associated with inflammatory bowel disease (IBD), yet delineating functional consequences 56 is complex. We used a network-based approach to uncover traits common to monogenic and 57 polygenic forms of IBD in order to reconstruct disease relevant pathways and prioritize causal 58 genes. 59 METHODS:We have used an iterative random walk with restart to explore network 60 neighborhood around the core monogenic IBD cluster and disease-module cohesion to identify 61 functionally relevant GWAS genes. Whole exome sequencing was used to screen a cohort of 62 monogenic IBD for germline mutations in top GWAS genes. One mutation was identified and 63 validated by a combination of biochemical approaches. 64 RESULTS: Monogenic IBD genes clustered siginificantly on the molecular networks and had 65 central roles in network topology. Iterative random walk from these genes allowed to rank the 66 GWAS genes, among which 14 had high disease-module cohesion and were selected as putative 67 causal genes. As a proof of concept, a germline loss of function mutation was identified in PTPN2, 68 one of the top candidates, as a novel genetic etiology of early-onset intestinal autoimmunity. The 69 mutation abolished the catalytic activity of the enzyme, resulting in haploinsufficiency and hyper-70 activation of the JAK/STAT pathway in lymphocytes. 71 CONCLUSIONS: Our network-based approach bridges the gap between large-scale network 72 medicine prediction and single-gene defects and underscores the crucial need of fine tuning the 73 JAK/STAT pathway to preserve intestinal immune homeostasis. Our data provide genetic-based 74 rationale for using drugs targeting the JAK/STAT pathway in IBD.75

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“…Importantly, several lines of evidence suggest that a loss-of-function single-nucleotide polymorphism (C1858T substitution; “R620W variant”; “rs2476601”) of PTPN22 (a phosphatase involved in synthesizing AEA [ 48 ], which normally suppresses T-cell proliferation), which leads to its rapid degradation, is coupled to several autoimmune diseases (for details, see [ 31 ]), including alopecia areata (AA) [ 146 , 147 , 148 , 149 , 150 , 151 , 152 ]. Although PTPN22 has several other functions besides AEA synthesis [ 153 ], and eCB levels were not measured yet in lesional skin of AA patients, one might hypothesize based on the above correlation that a decrease in the anti-inflammatory eCB-tone induced by PTPN22 dysfunction might contribute to the onset of the disease. Thus, elevation of the eCB-tone as well as direct CB 1 agonism might be promising tools to prevent the onset/relapse of AA.…”

Section: Translational Potential Of the Cutaneous Cannabinoid Signmentioning

confidence: 99%

Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System

et al. 2019

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The endocannabinoid system (ECS) has lately been proven to be an important, multifaceted homeostatic regulator, which influences a wide-variety of physiological processes all over the body. Its members, the endocannabinoids (eCBs; e.g., anandamide), the eCB-responsive receptors (e.g., CB1, CB2), as well as the complex enzyme and transporter apparatus involved in the metabolism of the ligands were shown to be expressed in several tissues, including the skin. Although the best studied functions over the ECS are related to the central nervous system and to immune processes, experimental efforts over the last two decades have unambiguously confirmed that cutaneous cannabinoid (“c[ut]annabinoid”) signaling is deeply involved in the maintenance of skin homeostasis, barrier formation and regeneration, and its dysregulation was implicated to contribute to several highly prevalent diseases and disorders, e.g., atopic dermatitis, psoriasis, scleroderma, acne, hair growth and pigmentation disorders, keratin diseases, various tumors, and itch. The current review aims to give an overview of the available skin-relevant endo- and phytocannabinoid literature with a special emphasis on the putative translational potential, and to highlight promising future research directions as well as existing challenges.

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Protein Tyrosine Phosphatases: Regulators of CD4 T Cells in Inflammatory Bowel Disease

Cited by 29 publications

References 178 publications

New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD

New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD

Network Analysis of Inflammatory Bowel Disease Reveals PTPN2 As New Monogenic Cause of Intestinal Inflammation

Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System

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