Scientists at the University of Oxford have uncovered evidence suggesting that a person's vulnerability to rheumatoid arthritis—a chronic autoimmune disease that causes joint inflammation—may be established before birth. The study, titled "The embryonic origins of site-specific arthritis," was published in the journal Nature Immunology. Researchers focused on two types of finger joints with differing susceptibility to the disease: the proximal interphalangeal (PIP) joints, which are commonly affected, and the distal interphalangeal (DIP) joints, which are usually spared. They found that PIP joints had more synovial tissue and a higher number of PI16-positive (PI16+) fibroblasts, a type of connective tissue cell. These differences were already present in the developing fetus, indicating that the local environment of a joint may influence its susceptibility to inflammation later in life. To explore this, the researchers used advanced techniques such as single-cell sequencing, high-resolution 3D X-ray scanning, and image analysis to map the development of human finger joints. They discovered that developing joints were mainly composed of structural cells, such as fibroblasts and cartilage-forming cells, rather than immune cells. The team then examined how signals guide these cells to develop into specialized types, particularly those that form the synovial lining—the tissue that lines joints and helps them move smoothly. In arthritis, these cells can behave abnormally, contributing to inflammation and joint damage. Further analysis revealed that the synovial lining in joints may originate from two sources: cartilage and surrounding fibroblasts. Local conditions, such as low oxygen levels, also appeared to influence this development. The researchers found that PI16+ fibroblasts, which were more abundant in PIP joints, were concentrated around blood vessels and where tendons and ligaments connect to surrounding tissue. These cells responded differently to inflammatory signals compared to other fibroblast types. While both PI16+ and PI16- fibroblasts showed a general pro-inflammatory response, the PI16+ cells exhibited unique changes in biological pathways related to immune regulation and tissue structure. Using high-resolution 3D imaging at the Diamond Light Source facility in Harwell, the team found that PIP joints had more synovial tissue, which was organized differently from the synovium in DIP joints. These structural and cellular differences may explain why inflammation develops more readily in some joints than in others. The findings suggest that the tendency for rheumatoid arthritis to target specific joints may not be determined solely by immune activity later in life, but also by cellular and structural features established during fetal development. Each joint’s local biological environment may influence how susceptible it becomes to the disease years or even decades later. The research was led by scientists at the Kennedy Institute of Rheumatology at the University of Oxford, with collaboration from institutions including the University of Birmingham, University College London, and Diamond Light Source, and was supported by the Medical Research Council (MRC).