Functional Dysregulation of PBMC and PMN in Crohn's Disease

Naser, Saleh A.; Romero, Claudia; Elwasila, Sammer; Ghonaim, Mohamed; Naser, Najih; Valentine, John F.

doi:10.2174/1875041900902010024

Cited by 3 publications

(10 citation statements)

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“…The prevalence of MAP in CD patients was 40 % compared to 7.4 % MAP in healthy relatives (P < 0.01), indicating that the CD patients were more susceptible to MAP infection. This is consistent with published reports [ 7 , 30 – 32 , 34 – 36 ]. This study is the first to investigate the association of MAP and CD did using healthy relatives as controls.…”

Section: Discussionsupporting

confidence: 94%

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Oxidative stress due to Mycobacterium avium subspecies paratuberculosis (MAP) infection upregulates selenium-dependent GPx activity

et al. 2016

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ObjectiveThis study was designed to determine the relationship between Mycobacterium avium subspecies paratuberculosis (MAP) infection and selenium-dependent glutathione peroxidase (GPx) activity, in the blood of humans and cattle infected with MAP.DesignMAP infection status and GPx activity were determined in sera from 42 cattle, a group of 27 patients with Crohn’s disease and 27 of their healthy biological relatives, and a group of 66 subjects with various diseases other than Crohn’s disease and 34 non-related healthy subjects.ResultsGPx activity was significantly higher overall in the case of MAP infection in both humans and cattle. The mean value for GPx activity was 1.59 ± 0.65 units/ml in MAP positive cattle compared to 0.46907 ± 0.28 units/ml in healthy cattle sera, where a unit was defined as one mmol/minute (P < 0.01). The mean value of the GPx activity in MAP negative humans clinical sera was 0.42367 ± 0.229 units/ml compared to 0.80941 ± 0.521 in MAP positive sera in a study comparing Crohn’s disease patients to their healthy relatives. The mean activity in MAP negative humans was 0.4702 ± 0.1299 compared to 0.6510 ± 00.1665 units/ml in positive samples in a randomized field study of 100 subjects.ConclusionThis study demonstrated a strong correlation between MAP and the elevation of GPx activity. This was especially evident in Crohn’s patients, which further supports the association of MAP and Crohn’s disease. GPx activity may also be used to predict MAP infection status and to show that Crohn’s disease patients who are infected with MAP have higher tendency to develop oxidative stress than Crohn’s disease patients who are negative for the bacteria.

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Section: Discussionsupporting

confidence: 94%

“…Our findings strengthen the growing body of literature supporting the correlation between MAP and CD. Of course the role of MAP in CD etiology remains debated but genetic susceptibility especially single nucleotide polymorphism in key genes in patients with CD may promote MAP infection [ 7 , 34 – 36 ].…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress due to Mycobacterium avium subspecies paratuberculosis (MAP) infection upregulates selenium-dependent GPx activity

et al. 2016

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“…Isolation of peripheral lymphocytes was performed using Lymphoprep™ reagent (Axis-Shield®) as described previously (Naser et al, 2009b ). A stock of 2X freezing media containing 10.0 mL of 25% human serum albumin (Gemini®), 10.0 mL of sterile RPMI-1640 (Sigma-Aldrich®), and 5.0 mL DMSO was made for the use of preserving lymphocytes for storage at −80°C.…”

Section: Methodsmentioning

confidence: 99%

“…T-cell proliferation assay was done using bromodeoxyuridine (BrdU) labeling proliferation ELISA kit (Roche Molecular Biochemicals®) as described previously (Naser et al, 2009b ). Phytohematoagglutunin (PHA) was used to evaluate T-cell response.…”

Section: Methodsmentioning

confidence: 99%

“…T-cells were then labeled with BrdU and incubated for 24 h at 37°C and 5% CO 2 . Cell proliferation was measured through Roche BrdU proliferation ELISA kit as described previously (Naser et al, 2009b ). Relative T-cell proliferation levels of samples were compared to blanks (RPMI only) and controls (isolated T-cells in RPMI only) by examining fold change in absorbance reading of each well at 450 nm.…”

Section: Methodsmentioning

confidence: 99%

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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

Sharp

Bég

Naser

2018

Front. Cell. Infect. Microbiol.

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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.

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Role ofPTPN2/22polymorphisms in pathophysiology of Crohn’s disease

Sharp

Bég

Naser

2018

WJG

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AIMTo establish the relationship of protein tyrosine phosphatase non-receptor type 2 and 22 (PTPN2/22) polymorphisms and mycobacterial infections in Crohn’s disease (CD).METHODSAll 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.RESULTSOut 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.CONCLUSIONThe 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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Functional Dysregulation of PBMC and PMN in Crohn's Disease

Cited by 3 publications

References 40 publications

Oxidative stress due to Mycobacterium avium subspecies paratuberculosis (MAP) infection upregulates selenium-dependent GPx activity

Oxidative stress due to Mycobacterium avium subspecies paratuberculosis (MAP) infection upregulates selenium-dependent GPx activity

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

Role ofPTPN2/22polymorphisms in pathophysiology of Crohn’s disease

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