Abstract
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.
Highlights
Most inflammatory diseases including Rheumatoid Arthritis (RA) have always been classified as autoimmune diseases due to genetic disorders and association with environmental triggers
The odds ratio (OR) value was determined to be 5.74, where the presence of Mycobacterium avium subspecies paratuberculosis (MAP) DNA is most likely to occur in RA patients
It is imperative that the pathogenesis of RA is deciphered in order to develop protocols for accurate and early detection and treatment of the disease
Summary
Most inflammatory diseases including Rheumatoid Arthritis (RA) have always been classified as autoimmune diseases due to genetic disorders and association with environmental triggers. SNPs in these genes alter or stimulate the activation and regulation of major components of the immune system (T-cells, B-cells, macrophages, etc.) and osteoclasts which could lead to immune-dysregulation (Brennan and McInnes, 2008; McInnes and Schett, 2011; Smolen et al, 2016) This leads to accumulation of immune cells in and around synovial joints and excessive production of anti-CCP, rheumatoid factor autoantibodies (RF) and various pro-inflammatory cytokines such as TNF-α, IFN-γ, IL-1, and IL-6 (Brennan and McInnes, 2008; McInnes and Schett, 2011; Smolen et al, 2016). PTPN2/22 encode proteins that act as phosphatases that negatively regulate the immune response and some regulatory cellular functions (Gurzov et al, 2015; Sharp et al, 2015). T-cells remain constantly active, leading to hypersecretion of pro-inflammatory cytokines and inflammation along with tissue damage (Gurzov et al, 2015; Sharp et al, 2015)
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