PTPN2 is Associated with Crohn’s Disease and Its Expression Is Regulated by NKX2-3

PTPN2 is a risk gene for Crohn's disease (CD). We investigated whether PTPN2 genetic variants (rs2542151 and rs2542152) were associated with CD in a familial IBD registry. Both rs2542151 and rs2542152 are associated with CD, but not ulcerative colitis (UC). mRNA expression levels of PTPN2 were significantly increased in intestinal tissues (p=0.0493), and nearly significantly increased in B cells (p=0.0889) from CD patients, but not significantly altered in UC. cDNA microarray results found that PTPN2 was down-regulated by NKX2-3 knockdown in human cells. We confirmed this observation by RT-PCR analyses in NKX2-3 knockdown in B cells from IBD patients and human intestinal microvascular endothelial cells (HIMEC). In addition, we found that mRNA expression of another IBD-associated gene, NKX2-3, was increased in intestinal tissues and B cells from CD patients, but not significantly increased in UC patients. A positive correlation was observed between mRNA expression of PTPN2 and NKX2-3 in B cells and in intestinal tissues from both CD and UC patients. These results suggest that PTPN2 may have an important role in CD pathogenesis and may represent a potential diagnostic and therapeutic target for IBD.

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Distinct patterns of naive, activated and memory T and B cells in blood of patients with ulcerative colitis or Crohn’s disease

Clinical & Experimental Immunology ◽

10.1111/cei.13294 ◽

2019 ◽

Cited By ~ 1

Author(s):

H. Rabe ◽

M. Malmquist ◽

C. Barkman ◽

S. Östman ◽

I. Gjertsson ◽

...

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

B Cells ◽

Crohn's Disease ◽

T And B Cells

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While IL-6 mRNA detected by in situ hybridization is more abundant in the inflamed mucosa of Crohn's disease, IL-8 mRNA expression is alternatively pronounced in ulcerative colitis

Gastroenterology ◽

10.1016/0016-5085(95)27400-6 ◽

1995 ◽

Vol 108 (4) ◽

pp. A773

Author(s):

F. Arai ◽

T. Takahashi ◽

K. Furukawa ◽

H. Asakura

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

In Situ Hybridization ◽

Crohn's Disease ◽

Mrna Expression

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Prevalence of IGR2198a_1 and IGR2096a_1 genetic variants in Hungarian patients with Crohn's disease and ulcerative colitis

Zeitschrift für Gastroenterologie ◽

10.1055/s-2008-1079657 ◽

2008 ◽

Vol 46 (05) ◽

Author(s):

L Lakner ◽

V Csöngei ◽

L Magyari ◽

L Járomi ◽

E Sáfrány ◽

...

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Genetic Variants

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P017 C86/CD16 macrophages accumulate in the mucosa of B3 patients and could mediate EMT in Crohn’s disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.146 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S138-S138

Author(s):

A Boronat-Muñoz ◽

A Cejudo-Garces ◽

P Lledo-Gil ◽

J Cosín-Roger ◽

S Coll ◽

...

Keyword(s):

Crohn’S Disease ◽

Statistical Analysis ◽

Crohn's Disease ◽

Mrna Expression ◽

U937 Cells ◽

Macrophage Phenotype ◽

Rt Pcr ◽

Intestinal Tissue ◽

Healthy Donors ◽

Emt Markers

Abstract Background Macrophages contribute to fibrosis through the release of different mediators and the pattern of secretion may vary according to their phenotype. Methods The aim of the present study is to analyse the pattern of expression of macrophages, of EMT-related genes and cytokines in surgical resections from Crohn’s disease (CD, n = 43) patients which were categorised according to Montreal classification (B2 or B3); unaffected mucosa of patients with ileocecal cancer was used as control (n = 20). mRNA was isolated from intestinal samples and the expression of macrophage, EMT markers and cytokines were analysed by RT-PCR. PBMCS were isolated from healthy donors and treated during 5 days with secretomes, from control, B2 or B3 surgical resections; the mRNA expression of macrophage markers was determined by RT-PCR. U937 cells were differentiated to macrophages and then treated with IFNγ (20 ng/ml) for 4 days, the mRNA expression of macrophages markers were determined by RT-PCR. Results are expressed as mean ± SEM (n ≥ 5). Statistical analysis was performed by ANOVA + Newman–Keuls or t-test. Correlations between data were analysed using Pearson’s correlation coefficient (*p < 0.05). Results The expression of CD16 and CD86 was significantly higher in intestinal samples from B3 CD patients (7.2 ± 1.1 and 7.7 ± 1.3, respectively) than in controls (1.4 ± 0.2 and 2.5 ± 0.4, respectively) or B2 CD patients (4.8 ± 0.9 and 4.5 ± 0.6, respectively). The mRNA expression of CD16 and CD86 were significantly higher in PBMCS treated with B3-secretomes than in those treated with B2- or control secretomes. The expression of CD16 and CD86 significantly correlated with FSP1 (r = 0.74, p = 0.002* and r = 0.66, p = 0.003*, respectively), VIMENTIN (r = 0.60, p = 0.02* and r = 0.82, p = 0.001*, respectively), SNAIL1 (r = 0.61, p < 0.01* r = 0.52, p = 0.04*, respectively), IL4 (r = 0.63, p = 0.01* and r = 0.60, p = 0.02*, respectively) and IFNγ (r = 0.56, p = 0.001* and r = 0.58, p = 0.01*, respectively) in intestinal tissue from the fistulising CD group. U937 cells treated with IFNγ increased significantly the mRNA expression of CD16 (1.94 ± 0.24* vs. vehicle) and CD86 (1.60 ± 0.17* vs. vehicle). Conclusion A macrophage phenotype expressing CD86/CD16 may act as a source of EMT mediators in intestinal tissue from CD patients with a penetrating (B3) behaviour. IFNγ could be responsible for the increase in the number of CD86/CD16 macrophages in the B3 behaviour.

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Defective generation of tetanus-specific antibody-producing B cells after in vivo immunization of Crohn's disease and ulcerative colitis patients

Gastroenterology ◽

10.1016/0016-5085(85)90011-3 ◽

1985 ◽

Vol 88 (6) ◽

pp. 1860-1866 ◽

Cited By ~ 26

Author(s):

Ronald Stevens ◽

Michael Oliver ◽

Michael Brogan ◽

John Heiserodt ◽

Stephan Targan

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

B Cells ◽

Crohn's Disease ◽

Specific Antibody

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Association of genetic variants of mannan-binding (MBL) lectin-2 gene, MBL levels and function in ulcerative colitis and Crohn’s disease

Innate Immunity ◽

10.1177/1753425910384531 ◽

2010 ◽

Vol 17 (6) ◽

pp. 526-531 ◽

Cited By ~ 7

Author(s):

G Sivaram ◽

Santosh K Tiwari ◽

Avinash Bardia ◽

G Manoj ◽

B Santhosh ◽

...

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Genetic Variants ◽

And Function

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Identification of Disease-Associated DNA Methylation in B Cells from Crohn’s Disease and Ulcerative Colitis Patients

Digestive Diseases and Sciences ◽

10.1007/s10620-012-2288-z ◽

2012 ◽

Vol 57 (12) ◽

pp. 3145-3153 ◽

Cited By ~ 36

Author(s):

Zhenwu Lin ◽

John P. Hegarty ◽

Wei Yu ◽

Jon A. Cappel ◽

Xi Chen ◽

...

Keyword(s):

Ulcerative Colitis ◽

Dna Methylation ◽

Crohn’S Disease ◽

B Cells ◽

Crohn's Disease

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Overexpression of the Receptor for Hyaluronan-Mediated Motility (RHAMM) Characterizes the Malignant Clone in Multiple Myeloma: Identification of Three Distinct RHAMM Variants

Blood ◽

10.1182/blood.v93.5.1684.405k22_1684_1696 ◽

1999 ◽

Vol 93 (5) ◽

pp. 1684-1696 ◽

Cited By ~ 1

Author(s):

Mary Crainie ◽

Andrew R. Belch ◽

Michael J. Mant ◽

Linda M. Pilarski

Keyword(s):

Multiple Myeloma ◽

Crohn’S Disease ◽

B Cells ◽

Crohn's Disease ◽

Plasma Cells ◽

Lymphocytic Leukemia ◽

Pcr Analysis ◽

Rt Pcr ◽

Activated B Cells

The receptor for hyaluronan (HA)-mediated motility (RHAMM) controls motility by malignant cells in myeloma and is abnormally expressed on the surface of most malignant B and plasma cells in blood or bone marrow (BM) of patients with multiple myeloma (MM). RHAMM cDNA was cloned and sequenced from the malignant B and plasma cells comprising the myeloma B lineage hierarchy. Three distinct RHAMM gene products, RHAMMFL, RHAMM−48, and RHAMM−147, were cloned from MM B and plasma cells. RHAMMFL was 99% homologous to the published sequence of RHAMM. RHAMM−48 and RHAMM−147 variants align with RHAMMFL, but are characterized by sequence deletions of 48 bp (16 amino acids [aa]) and 147 bp (49 aa), respectively. The relative frequency of these RHAMM transcripts in MM plasma cells was determined by cloning of reverse-transcriptase polymerase chain reaction (RT-PCR) products amplified from MM plasma cells. Of 115 randomly picked clones, 49% were RHAMMFL, 47% were RHAMM−48, and 4% were RHAMM−147. All of the detected RHAMM variants contain exon 4, which is alternatively spliced in murine RHAMM, and had only a single copy of the exon 8 repeat sequence detected in murine RHAMM. RT-PCR analysis of sorted blood or BM cells from 22 MM patients showed that overexpression of RHAMM variants is characteristic of MM B cells and BM plasma cells in all patients tested. RHAMM also appeared to be overexpressed in B lymphoma and B-chronic lymphocytic leukemia (CLL) cells. In B cells from normal donors, RHAMMFL was only weakly detectable in resting B cells from five of eight normal donors or in chronically activated B cells from three patients with Crohn’s disease. RHAMM−48 was detectable in B cells from one of eight normal donors, but was undetectable in B cells of three donors with Crohn’s disease. RHAMM−147 was undetectable in normal and Crohn’s disease B cells. In situ RT-PCR was used to determine the number of individual cells with aggregate RHAMM transcripts. For six patients, 29% of BM plasma cells and 12% of MM B cells had detectable RHAMM transcripts, while for five normal donors, only 1.2% of B cells expressed RHAMM transcripts. This work suggests that RHAMMFL, RHAMM−48, and RHAMM−147 splice variants are overexpressed in MM and other B lymphocyte malignancies relative to resting or in vivo–activated B cells, raising the possibility that RHAMM and its variants may contribute to the malignant process in B-cell malignancies such as lymphoma, CLL, and MM.

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