Rheumatoid arthritis (RA) is a chronic autoimmune disease in which the immune system mistakenly attacks the lining of the joints (the synovium), causing pain, swelling, and progressive damage. Approximately 18 million people worldwide live with RA. Early diagnosis and treatment can relieve symptoms, slow disease progression, and help prevent disability.

Current therapies focus on reducing inflammation and preserving joint function, but up to 30% of patients do not respond well. This underscores the pressing need to better understand its pathology for early diagnosis and the development of more effective therapies.

Helper T cells are a type of white blood cell that act as the “commanders” of the immune system. They play a crucial role by recognizing threats and coordinating immune responses. However, in autoimmune diseases like RA, these commanders become dysregulated and cause the immune system to attack the body’s own tissues.

Although helper T cells are known to be major players in RA, the precise molecular mechanisms driving inflammation are still unclear.

Now, researchers at Kyoto University have discovered a primate-specific cytokine called IGFL2, produced by a subset of helper T cells known as peripheral helper T (Tph) cells in the joints of patients with RA.

Their findings, published in Science Immunology, suggest that IGFL2 helps regulate inflammation in the synovial tissue of affected joints and could serve as both a marker of disease activity and a promising target for new therapies.

This research is led by Assistant Professor Akinori Murakami of the Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University; Associate Professor Hiroyuki Yoshitomi of the Department of Immunology (also Associate Investigator at WPI-ASHBi), and others.

Key findings

Using gene expression data from single-cell analysis and clinical information, researchers analyzed individual helper T cells from the joint tissue of patients with RA. They identified a distinct subgroup known as Tph cells, which are closely linked to more severe disease.

Notably, these cells produce IGFL2 (Insulin-like Growth Factor-Like Family Member 2), a cytokine found only in primates. IGFL2 was exclusively expressed in helper T cells within synovial tissue, with the highest levels seen in Tph cells.

The researchers then explored how IGFL2 drives inflammation in RA. They found that IGFL2 boosts the production of a protein called CXCL13, which promotes the production of autoantibodies. Additionally, IGFL2 activates immune cells known as monocytes and macrophages, further amplifying inflammation and joint damage. This is supported by the fact that blocking IGFL2 reduces the activation of these cells.

To assess its clinical relevance, the team measured IGFL2 levels in blood samples from patients with RA. IGFL2 levels were much higher in patients compared to healthy individuals, and even higher in those with more severe symptoms. Its ability to distinguish patients with RA from healthy individuals was similar to commonly used diagnostic markers.

Taken together, these findings suggest that IGFL2 is not just a marker of disease activity but may also actively drive inflammation in RA, making it a promising target for new treatments.

“We performed single-cell analysis on human samples and successfully identified a cytokine produced specifically by helper T cells that plays a key role in human rheumatoid arthritis pathology,” said Yoshitomi, lead author of the paper.

“Because this gene is unique to primates, this discovery wouldn’t have been possible using conventional animal models like mice or rats.”

Moving forward, the researchers aim to clarify how IGFL2 expression is regulated and its functions within the immune system. This work will deepen the understanding of RA pathology and could lead to more precise diagnostics, innovative targeted therapies, and ultimately, better outcomes and quality of life for people affected by RA and other autoimmune diseases.