MedicalResearch.com Interview with:
Robert B. Lochhead PhD
Clinical Fellow in Medicine
Division of Rheumatology, Allergy & Immunology
Massachusetts General Hospital
Harvard Medical School, Boston, MA
Medical Research: What is the background for this study? What are the main findings?
Dr. Lochhead: Lyme arthritis (LA), caused by the tick-borne spirochete Borrelia burgdorferi, usually resolves appropriately with antibiotic treatment, called antibiotic-responsive Lyme arthritis. However, in some patients, arthritis persists for months or years after spirochetal killing with oral and IV antibiotic therapy, called antibiotic-refractory Lyme arthritis. Synovial lesions in these patients show marked synovial proliferation, inflammation, and vascularization, accompanied by autoimmune T and B cell responses. MicroRNAs (miRNAs) regulate many biological processes including inflammation, immune responses, and cell proliferation, and are effective biomarkers that may reveal molecular mechanisms of disease. Our objective here was to identify extracellular miRNAs (ex-miRNAs) in synovial fluid (SF) that distinguish regulated (responsive) from dysregulated (refractory) immune responses in Lyme arthritis, thereby providing insights into underlying biological processes and potential diagnostic biomarkers to distinguish between these disease courses.
Medical Research: What is the background for this study? What are the key findings?
Dr. Lochhead: In synovial fluid from patients with responsive or refractory Lyme arthritis or Rheumatoid Arthritis, miRNAs reflective of an inflammatory signature (e.g., miR-146a, miR-155) were significantly up-regulated compared with that of OA patients. Furthermore, up-regulation of the inflammatory ex-miRNA signature was most pronounced in patients whose symptoms persisted after IV antibiotic therapy (refractory LA), compared to patients with active infection (before IV antibiotic therapy). This pattern was also observed in synovial tissue, and expression correlated with disease duration and cytokine expression. However, the most novel finding in refractory Lyme arthritis was marked up-regulation of a cell proliferation signature, which included miR-223, miR-142, and miR-17-92 family members, miRNAs associated with oncogenesis. For miR-17 and miR-142, the levels were ~3-to-6-fold greater in SF from refractory Lyme arthritis and RA, compared with the earlier infectious stage of LA, or OA. In synovial tissue, these miRNAs were highest in LA, compared with other patient groups. Preliminary cell culture experiments suggest that some of these ex-miRNAs are transferred to fibroblast-like synoviocytes where they may alter target gene expression
Medical Research: What should clinicians and patients take away from your report?
Dr. Lochhead: Analyzing microRNA expression in the synovial environment provides important insight into pathogenic genetic feedback loops. For example, elevated miR-155/miR146a ratio in synovial tissue is a biomarker for a dysregulated pro-inflammatory immune response. Also, higher levels of proliferative miRNAs, such as miR-223, miR-142, and miR-17-92 family members further indicate a failure to properly control repair of damaged tissue, may be a specific prognostic biomarker for a more refractory Lyme Arthritis course, and could lead to important insights into how proliferative synovitis persists in antibiotic-refractory Lyme arthritis patients.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Lochhead: The role of miRNAs in providing robustness to clinically relevant biological processes is quite firmly established. Moving forward in the field of miRNA research, I think there are two major questions that need to be addressed:
- First, what is the relevant cellular and regulatory context associated with individual miRNA function?
- Second, how can we exploit the function of these miRNAs to therapeutically target specific pathogenic feedback loops?
Lochhead RB, Kim ND, Arvikar S, Strle K, Steere AC. Extracellular MicroRNAs in Synovial Fluid Reveal a Marked Proliferative Signature in Patients with Antibiotic-Refractory Lyme Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10).
microRNAs in Joint Fluid As Biomarker For Antibiotic Resistant Lyme Arthritis (2015).