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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.

frontiers in cellular and infection microbiology

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