Published online Feb 14, 2018. doi: 10.3748/wjg.v24.i6.657
Peer-review started: December 21, 2017
First decision: December 27, 2017
Revised: January 3, 2018
Accepted: January 18, 2018
Article in press: January 18, 2018
Published online: February 14, 2018
To establish the relationship of protein tyrosine phosphatase non-receptor type 2 and 22 (PTPN2/22) polymorphisms and mycobacterial infections in Crohn’s disease (CD).
All 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.
Out 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.
The 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.
Core tip: Knowledge of the pathophysiology of Crohn’s disease (CD) is vital in the development of new diagnosis techniques and treatments for the disease. Our study involves the investigation of single nucleotide polymorphisms (SNPs) in protein tyrosine phosphatase non-receptor type 2 and 22 (PTPN2/22) and their effects on susceptibility to mycobacteria species and the elevation of pro-inflammatory cytokines. Our data demonstrates that SNPs in PTPN2/22 lead to less negative regulation in T-cells and increase susceptibility to mycobacteria, thus increasing inflammation and apoptosis in intestinal tissues. Personalized treatment could be accomplished by genetic testing and antibiotic treatment for mycobacteria in CD patients.