image: Analysis of joint tissue reveals reactive and thickened synovium covering the tendon sheath. view more
Credit: Sarah Whiteside
Every year, more than 300,000 Americans contract Lyme disease, an infection caused by Borrelia burgdorferi, a bacterium transferred during a tick bite. In a small percentage of patients, infection symptoms, including arthritis, persist despite antibiotic treatment.
Scientists at University of Utah Health believe they identified a mechanism that activates T cells, a key component of the immune system, which could explain the elusive link between a tick bite and persistent Lyme arthritis. The results are published online in the February 5th issue of the Journal of Immunology.
"We believe that in this model persistent Lyme arthritis is a result of [overactive] immune response," said the study's first author Sarah Whiteside, a graduate student in Janis Weis's lab at U of U Health.
The researchers identified a receptor on T cells that interacts with molecules on the surface of B. burgdorferi. Like a key fitting into a lock, the receptors join in a process resulting in bystander activation. This activation mechanism triggers the T cell to produce inflammatory molecules that accumulate around the joints and contribute to inflammation and arthritis.
Some of the newly 'turned-on' T cells can interact with residual bacteria that persists long after the initial tick bite, producing a cascading cycle of inflammation that could lead to infection-induced autoimmunity.
"Through bystander activation, a whole repertoire of T cells may be activated, independent of their specificity for infecting pathogens," said Weis, Ph.D., professor of Pathology at U of U Health.
Whiteside cautions the exact mechanism of T cell activation needs clarification, but the results from this study suggest new therapeutic approaches, such as focusing on anti-inflammatory mechanisms, might be more effective for patients with persistent Lyme arthritis.
"If you can suppress T cell activation for the short-term, we might help re-establish the control mechanism [for the immune response] in the body," said Weis.
In addition to new therapies, future studies may focus on the broader implications of bystander activation for other pathogen-induced and autoimmune diseases.
These inquiries will benefit from the mouse model developed for this study by Whiteside. The mice, which lack an anti-inflammatory molecule (IL-10), mimic the symptoms of sustained arthritis in human patients. In the absence of the anti-inflammatory molecule, the mice reveal the disease-causing potential of T cells during infection.
Mice in the study were followed for 18 weeks following infection. Within two weeks, the concentration of T cells and inflammation markers in the joint fluid of the mice increased, despite the extremely low or often undetectable amounts of B. burgdorferi in the joint tissue. Microscopic examination of joint tissue of mice in the study revealed thickened tissue covering the tendon sheath, resulting from infiltration of cells producing inflammatory molecules. Neutralization of the inflammatory molecules resulted in reduced ankle swelling and arthritis severity in the mice.
"Growing up in Vermont, I know several people with Lyme disease," said Whiteside. "It is rewarding to develop a model that mimics arthritis so we can study what is happening in these patients."
Most patients diagnosed with a Lyme infection receive a 2- to 3-week course of antibiotics and recover without long-term complications.
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This research was funded by the National Institutes of Health, National Institutes of Allergy and Infectious Disease Research Training Grant, the American Association of Immunologists Careers in Immunology Fellowship Program, Edward Mallinckrodt Jr. Foundation, Pew Scholars Program, NSF Career Award and Packard Fellowship in Science and Engineering.
In this study, Weis and Whiteside were joined by co-authors Jeremy Snook, Ying Ma, F. Lynn Sonderegger, Colleen Fisher, Charisse Petersen, June Round and Matthew Williams at U of U Health and James Zachary at the University of Illinois at Urbana-Champaign.
University of Utah Health is the state's only academic health care system, providing leading-edge and compassionate medicine for a referral area that encompasses 10% of the U.S., including Idaho, Wyoming, Montana and much of Nevada. A hub for health sciences research and education in the region, U of U Health touts a $291 million research enterprise and trains the majority of Utah's health care professionals at its Schools of Medicine and Dentistry and Colleges of Nursing, Pharmacy and Health. Staffed by more than 20,000 employees, the system includes 12 community clinics and four hospitals - University Hospital; University Neuropsychiatric Institute; Huntsman Cancer Hospital; and the University Orthopaedic Center. For eight straight years, U of U Health has ranked among the top 10 U.S. academic medical centers in the rigorous Vizient Quality and Accountability Study, including reaching No. 1 in 2010 and 2016.
Journal
The Journal of Immunology