Some joints may be primed for rheumatoid arthritis before birth

Researchers at the Kennedy Institute in Oxford have discovered that certain joints may be predisposed to rheumatoid arthritis even before a person is born. This finding could shed light on the puzzling pattern of the disease targeting specific joints while others remain unaffected. The study, titled "The embryonic origins of site-specific arthritis," was published in the journal Nature Immunology.

It proposes that the answer to this conundrum may lie not only in the immune system but also in the inherent biological differences of individual joints during their development.

Rheumatoid arthritis is an autoimmune condition where the immune system mistakenly attacks the synovium, the tissue that lines the joints. This leads to pain, swelling, and stiffness, and over time, can damage cartilage, bone, and surrounding tissues. To understand why rheumatoid arthritis tends to affect particular joints, the researchers compared two types of finger joints with contrasting susceptibility to the disease: proximal interphalangeal (PIP) joints, which are frequently affected by the condition, and distal interphalangeal (DIP) joints, which are generally spared.

The PIP joints exhibited larger synovial tissue volumes and contained a higher concentration of PI16+ fibroblasts, a specialized type of connective tissue cell. Crucially, these differences were already present before the infants were born, suggesting that the local tissue environment of a joint might influence the likelihood of inflammation developing later in life.

Professor Christopher Buckley, Kennedy Professor of Translational Rheumatology at the University of Oxford, commented that while it has long been known that rheumatoid arthritis favors certain joints, the reasons behind this selective targeting have remained unclear. The study suggests that the cellular and structural characteristics formed during joint development may play a crucial role in determining where inflammation takes hold later in life.

The research team utilized advanced techniques such as single-cell sequencing, high-resolution 3D X-ray scanning, and detailed mapping of human finger joints during their development. They discovered that developing joints primarily consist of structural cells, including fibroblasts and cartilage-forming cells. Further examination revealed that the synovial lining, which produces substances to lubricate joints, may originate from two sources: cartilage and surrounding joint fibroblasts. Local factors, such as areas with low oxygen levels, also seem to impact this development process.

Differences between PIP and DIP joints were also identified. Using specialized image analysis tools, the researchers observed that PI16+ fibroblasts were more abundant in PIP joints and tended to cluster around blood vessels and where tendons and ligaments connect to nearby tissue. These cells also reacted differently to inflammatory signals compared to other fibroblast populations.

While PI16+ and PI16- fibroblasts shared a general pro-inflammatory response, the PI16+ cells exhibited unique changes in biological pathways related to immune regulation and tissue organization.

High-resolution 3D imaging conducted at the Diamond Light Source facility at the Harwell Science and Innovation Campus revealed that PIP joints contained more synovial tissue, which was organized differently from the synovium in joints typically spared by rheumatoid arthritis. These differences in both cell populations and tissue structure could provide insights into why inflammation develops more readily in some joints than others.

Lead author Dr. Sarah Davidson, a Postdoctoral Researcher at the Kennedy Institute, noted that joints commonly affected by rheumatoid arthritis already contain distinct cellular populations before birth. The PI16+ fibroblasts were overrepresented in these vulnerable joints and demonstrated altered responses to inflammatory signals.

Their location and behavior suggest they might contribute to shaping where the disease develops. The findings imply that rheumatoid arthritis's selective impact on certain joints may not be solely determined by immune activity later in life but could also depend on the cellular and structural features established during joint formation.

The research was conducted by scientists from the Kennedy Institute of Rheumatology at the University of Oxford, in collaboration with colleagues from the Universities of Birmingham, London, and Diamond Light Source. The study was supported by the Medical Research Council (MRC).