Joint Space Immunology Lab

Long term goal: preserve human pain-free mobility through prevention and mitigation of arthritis and synovitis.

Projects:

Evaluation of Synovium Immune Privilege
Articulating joints such as the hip and knee are surrounded by a fleshy capsule known as synovium. The synovium has a specific architecture and function. First, it has 2 major layers: the innermost layer composed mostly of epithelial-like resident synovial macrophages (RSMs) bound together by tight junctions; and second, the sub-lining layer, made of fibroblast-like synoviocytes and RSM precursors, among other cells such as mast cells and endothelial cells. When the RSM layer is intact, the synovial fluid within the joint capsule seems protected from the peripheral immune system. When the layer breaks down, the peripheral immune system can enter the joint. This coincides with symptoms such as joint pain and swelling. Joint pain and swelling (synovitis), coincides with damage to cartilage (arthritis). We are evaluating the potential for immune privilege of the joint space through RSM barrier function. We do this using our Joint Space Analysis System (JSAS) and ex vivo human tissue.

Lyme Arthritis and Modulation of Resident Synovial Macrophage Functions

Lyme arthritis (LA) occurs when B. burgdorferi, the bacteria that cause Lyme disease, spreads to the joints, causing infection and inflammation. In some cases, even after treatment, LA can develop into a more serious condition called Antibiotic-Refractory Lyme Arthritis (ARLA), which can lead to long-term pain and disability. The exact cause of this transition is not well understood, but studying how Lyme arthritis changes into ARLA is important for better treatment and prevention. 

This study focuses on understanding how immune cells in the joint called resident synovial macrophages (RSMs) change from being anti-inflammatory to inflammatory in ARLA. We think that this process is similar to what happens in rheumatoid arthritis (RA), where immune cells break down the protective barriers in the joint. When the barrier breaks down, other inflammatory cells from circulation may gain entry and cause more damage. The goal of this research is to explore how these changes happen in ARLA, using three approaches: 1) observing how synovial immune cell layers break down during infection, 2) studying the immune response of synovial tissue when exposed to B. burgdorferi and 3) investigating how the loss of the protective RSM layer leads to bone and cartilage damage. 

Our long-term goal is to stop the transition from Lyme arthritis to ARLA and prevent other types of infectious arthritis from becoming chronic. This research could also lead to new treatments for Lyme arthritis and similar diseases. By using human joint tissue in our experiments, we hope to gain new insights that can be applied to other inflammatory arthritis conditions. The results may lead to better therapies and help improve the lives of people with arthritis caused by infections.

The importance of the fibroblast-macrophage signaling axis in inflammatory joint disease
Inflammatory arthritis is characterized by pathogenic fibroblast like synoviocyte (pFLS) overgrowth in the synovium. pFLS can directly degrade cartilage through pannus formation. pFLS also secrete cytokines including IL-6 and CCL2/MCP-1, which in turn are likely to promote M1 or inflammatory macrophage/monocytes. Resident synovial macrophages (RSMs) likewise secrete IL-1B and TNF-a, which promote FLS secretion of IL-6 and CCL2. Understanding how these two major cell types of the synovium communicate to create pro-inflammatory or anti-inflammatory environments is key to preventing or attenuating inflammatory arthritis. This project aims to individually and sequentially block RSM or FLS signaling in an inflammatory environment to uncover the initiation and perpetuation mechanisms of arthritis.

Anti-histamines as arthritis and/or synovitis preventatives 
Epidemiologic studies have identified that those who take anti-histamines may experience less arthritis or joint pain. The mechanism behind this possible protection is unknown. We are evaluating the effect of anti-histamines on human ex vivo synovium and osteochondral cores. We are testing anti-histamines in our Joint Space Analysis System before adding inflammatory stimulus (simulating prevention) vs, after inflammation (simulating care in an acute care setting, such as urgent care or emergency department). We want to know if anti-histamines prevent synovium from becoming inflammatory and secreting enzymes that may damage cartilage.