Rheumatoid arthritis does not affect all joints equally. Some joints are affected particularly frequently, while others remain largely unaffected despite the same autoimmune disease. Researchers have been studying why this is the case for many years. A new study by researchers at the Kennedy Institute now offers a possible explanation: the varying susceptibility of certain joints may already arise during fetal development. The study, published in *Nature Immunology* and titled “The embryonic origins of site-specific arthritis,” suggests that it is not solely the immune system that determines where rheumatoid arthritis develops. The characteristics of the respective joint tissue may also play an important role.
Some Joints are Different from the Very Beginning
In rheumatoid arthritis, the immune system attacks the synovial membrane, which lines the inside of the joint. This can result in pain, swelling, and limited mobility. As the disease progresses, cartilage, bone, and surrounding structures can be damaged. But why does the disease affect certain joints particularly frequently? To investigate this question, the scientists compared two types of finger joints: the proximal interphalangeal joints (PIP), which are frequently affected by rheumatoid arthritis, and the distal interphalangeal joints (DIP), which are typically less susceptible.
In doing so, they discovered significant biological differences. Among other things, the PIP joints had more synovial tissue and a greater number of certain fibroblasts known as PI16-positive fibroblasts. Of particular interest: These differences were already detectable before birth. This could mean that a joint’s later susceptibility does not arise only when an autoimmune reaction begins. Instead, the foundation for this could already be laid during development.
The Tissue itself Could Play an Important Role
“Why rheumatoid arthritis targets certain joints may not be explained solely by a malfunction of the immune system. The new research findings suggest that the properties of the joint tissue could also play an important role. It appears to depend on which cell types are present in a joint, how they are arranged, and how they respond to inflammatory signals. Differences that arise as early as the developmental stage could thus influence whether inflammation later spreads more easily in a particular joint and becomes permanently established.
This shifts the focus of research more squarely onto the joint itself. Scientists aim to better understand how the different cell types and tissue structures develop and why some joints become more susceptible to rheumatoid arthritis than others as a result.
Researchers Create Detailed Map of Joint Development
For their studies, the scientists combined various modern methods. These included single-cell sequencing, computer-aided image analysis, and high-resolution three-dimensional X-ray imaging. This enabled them to examine the development of human finger joints at the cellular and tissue levels.
In the early stages of development, the joints consisted primarily of structure-forming cells. These included fibroblasts as well as cells involved in cartilage formation. Immune cells, on the other hand, played a significantly smaller role in these early stages of development. The researchers then investigated which signals are responsible for the original cells developing into different specialized cell types.
Of particular interest were the fibroblasts, which later form the synovial lining of the joint. Under normal conditions, these cells perform important protective functions. Among other things, they help lubricate the joint and enable movement with as little friction as possible. In rheumatoid arthritis, however, synovial fibroblasts can undergo changes and contribute to the maintenance of inflammation. The study suggests that the synovial lining can arise from different cellular sources during development. Both cartilage cells and fibroblasts from the surrounding joint tissue play a role in this process.
Local conditions within the tissue also appear to influence this developmental process. These include, for example, areas with particularly low oxygen levels. These findings could help us understand in the future how synovial fibroblasts develop their different properties—and why some of them undergo pathological changes in arthritis.
PI16+ Fibroblasts are More Common in Susceptible Joints
A particularly interesting finding concerned the so-called PI16+ fibroblasts. These specialized connective tissue cells were significantly more common in the PIP joints than in the less susceptible DIP joints. Their exact location was also striking: they were concentrated primarily near blood vessels and in areas where tendons and ligaments merge into the surrounding tissue.
Their behavior also differs from that of other fibroblasts. When exposed to inflammatory signals, PI16+ fibroblasts respond in a distinctive way. The researchers observed changes in biological signaling pathways involved, among other things, in the regulation of immune responses and tissue organization.
These characteristics could contribute to inflammation developing more easily or persisting longer in certain joints. The findings thus provide further evidence that the local composition of joint tissue may play an important role in a joint’s susceptibility to rheumatoid arthritis.
The Structure of the Joint also Appears to Make a Difference
The differences between the joints involved not only individual cell types but also their spatial arrangement. Using high-resolution 3D imaging, the researchers examined the structure of the joints and found that the PIP joints contained more synovial tissue. Furthermore, this tissue was organized differently than in the less susceptible DIP joints. These differences could play an important role in how a joint responds to inflammatory signals. The synovial membrane is in close contact with blood vessels and various connective tissue cells and can therefore play a significant role in the development and maintenance of inflammation.
The researchers found a particularly high number of PI16-positive fibroblasts near blood vessels as well as at the junctions between tendons, ligaments, and joint tissue. Local conditions, such as oxygen supply, may also influence the properties these cells will later possess during development. This paints a more comprehensive picture: Not only the immune system, but also the cellular composition and structure of the respective joint could determine how susceptible it is to inflammation later in life. The researchers
New Perspectives for Arthritis Research
The findings could expand our understanding of rheumatoid arthritis in the long term. In addition to the immune system, the joint itself is increasingly taking center stage. Cell types and tissue structures that form during development could help determine how a joint reacts to inflammatory processes decades later. These findings could also be relevant for future treatment. If certain characteristics of joint tissue promote the onset or persistence of inflammation, they could potentially be targeted. The role of synovial fibroblasts, in particular, could be significant in this regard.
A better understanding of these cells could potentially help develop new strategies that not only suppress the immune response but also specifically modify the processes within the affected joint. In the long term, it might be possible to strengthen the natural protective functions of the joint tissue, thereby hindering the spread of inflammation. The study also raises new questions for research. If certain characteristics of a joint are already determined before birth, this raises the question, for example, of whether similar differences can also be found in other joints of the body. It is also still unclear which other factors throughout life contribute to a congenital tissue characteristic actually developing into chronic inflammation.
It is therefore not yet conclusively clear what direct influence the differences that arise before birth actually have on the development of rheumatoid arthritis. However, the study provides an important new approach to better understanding one of the great mysteries of the disease: Why are some joints particularly susceptible, while others remain largely unaffected? Above all, these new findings demonstrate one thing: Rheumatoid arthritis may not be exclusively a disease of the immune system. The individual development and structure of a joint may also play a role in determining where the disease takes hold later in life.