Bacteria in milk and beef could trigger rheumatoid arthritis

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A strain of bacteria commonly found in milk and beef may be a trigger for developing rheumatoid arthritis in people who are genetically at risk, according to a new study from the University of Central Florida. A team of UCF College of Medicine researchers has discovered a link between rheumatoid arthritis and Mycobacterium avium subspecies paratuberculosis, known as MAP, a bacteria found in about half the cows in the US. The bacteria can be spread to humans through the consumption of infected milk, beef and produce fertilised by cow manure.

The UCF researchers are the first to report this connection between MAP and rheumatoid arthritis. The study, funded in part by a $500,000 grant from the Florida Legislative, was a collaboration between Saleh Naser, UCF infectious disease specialist, Dr Shazia Bég, rheumatologist at UCF’s physician practice, and Robert Sharp, a biomedical sciences doctoral candidate at the medical school.

Naser had previously discovered a connection between MAP and Crohn’s disease and is involved in the first ever phase III-FDA approved clinical trial to treat Crohn’s patients with antibiotics. Crohn’s and rheumatoid arthritis share the same genetic predispositions and both are often treated using the same types of immuno-suppressive drugs. Those similarities led the team to investigate whether MAP could also be linked to rheumatoid arthritis.

“Here you have two inflammatory diseases, one affects the intestine and the other affects the joints, and both share the same genetic defect and treated with the same drugs. Do they have a common trigger? That was the question we raised and set out to investigate,” Naser said.

For the study, Bég recruited 100 of her patients who volunteered clinical samples for testing – 78% of the patients with rheumatoid arthritis were found to have a mutation in the PTPN2/22 gene, the same genetic mutation found in Crohn’s patients, and 40% of that number tested positive for MAP.

“We believe that individuals born with this genetic mutation and who are later exposed to MAP through consuming contaminated milk or meat from infected cattle are at a higher risk of developing rheumatoid arthritis,” Naser said.

About 1.3m adults in the US have rheumatoid arthritis – an autoimmune and inflammatory disease that causes the immune system to attack a person’s joints, muscles, bones and organs. Patients suffer from pain and deformities mostly in the hands and feet. It can occur at any age but the most common onset is between 40 and 60 years old and is three times more prevalent in women.

Although case studies have reported that some RA patients suffer from Crohn’s disease and vice versa, the researchers say a national study needs to investigate the incidence of the two diseases in the same patients.

“We don’t know the cause of rheumatoid arthritis, so we’re excited that we have found this association,” Bég said. “But there is still a long way to go. We need to find out why MAP is more predominant in these patients – whether it’s present because they have RA, or whether it caused RA in these patients. If we find that out, then we can target treatment toward the MAP bacteria.”

The team is conducting further studies to confirm findings and plan to study patients from different geographical and ethnic backgrounds.

“Understanding the role of MAP in rheumatoid arthritis means the disease could be treated more effectively,” Naser said. “Ultimately, we may be able to administer a combined treatment to target both inflammation and bacterial infection.”

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.

Authors
Robert C Sharp, Shazia A Beg, Saleh A Naser

University of Central Florida material
Frontiers in Cellular and Infection Microbiology abstract


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