The immune molecule was found to play a key role in regulating inflammation in rheumatoid arthritis

Researchers at the University of Kyoto discovered that an immune molecule found only in primates, called IGFL2, plays a key role in regulating inflammation in rheumatoid arthritis (RA). IGFL2 is produced by a subset of immune cells in the joints of RA patients and acts like fire fuel: activates more immune cells, further enhancing inflammation and deterioration of joint damage. They also found that IGFL2 levels were much higher in the blood of patients with RA, especially in those with more severe symptoms. These findings support the potential of IGFL2 as a diagnostic index, a tool for monitoring the progression of the disease and the goal of new therapies, paving the way for previous detection, more effective therapies and better quality of life for people with RA worldwide.

Overview

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which the immune system incorrectly attacks the joints of the joints (the articular), causing pain, swelling and progressive damage. About 18 million people worldwide live with RA. Early diagnosis and treatment can relieve symptoms, slow down the disease and help prevent disability. Current treatments focus on reducing inflammation and maintaining joint function, but up to 30% of patients do not respond well. This emphasizes the pressing need for a better understanding of her pathology for early diagnosis and developing more effective therapies.

Auxiliary T cells are a type of white blood cells that act as “commanders” of the immune system. They play a decisive role by recognizing threats and coordinating immunoocials. However, in autoimmune diseases such as RA, these commanders become regulated and cause the immune system to attack the tissues of the body. Although auxiliary T cells are known to be important players in RA, the exact molecular mechanisms that lead to inflammation are still unclear. Now, researchers at the University of Kyoto have discovered a special cytokin called IGFL2, produced by a subset of auxiliary cells known as regional TPH cells in the joints of patients with RA. Their findings indicate that IGFL2 helps regulate inflammation in the articular tissue of the affected joints and could serve both as an indicator of the activity of the disease and as a promising goal for new therapies.

This research is guided by Assistant Professor Akinori Murakami of the Institute for the advanced study of the University of Kyoto’s human biology (WPI-ASHBI). Associate Professor Hiryuki Yoshitomi of the Department of Immunology (also a researcher at WPI-ASHBI), Postgraduate School of Medicine. Professor Hideki Ueno, Vice President and Major Researcher at WPI-ASHBI (also a professor in the Department of Immunology, Postgraduate School of Medicine and Director of the Kyoto University Immunology Center, Kic). And Professor Shuichi Matsuda of the Department of Orthopedic Surgery, Postgraduate School of Medicine, University of Kyoto. Findings will be published in Science immunology On August 1, 2025.

Basic findings

Using gene expression data from one cell analysis and clinical information, the researchers analyzed individual auxiliary T cells from the articulated tissue of patients with RA. They identified a separate subgroup known as TPH cells, which are closely linked to a more serious illness. Specifically, these cells produce IGFL2 (a member of the growth -like family -like family), a cytokin found in primary only. IGFL2 was expressed exclusively in auxiliary T cells in articular tissue, with the highest levels observed in Tria cells.

The researchers then investigated how IGFL2 drives inflammation in RA. They found that IGFL2 enhances the production of a protein called CXCL13, which promotes the production of autoantibodies. In addition, IGFL2 activates immune cells known as monocytes and macrophages, further enhancing inflammation and joint damage. This is supported by the fact that impeding IGFL2 reduces the activation of these cells.

To evaluate its clinical significance, the group measured IGFL2 levels in blood samples from patients with RA. IGFL2 levels were much higher in patients than healthy people and even higher in those with more severe symptoms. His ability to distinguish patients with RA from healthy people was similar to the commonly used diagnostic markers.

Overall, these findings indicate that IGFL2 is not just an index of disease activity, but can also actively lead to inflammation in RA, making it a promising goal for new therapies.

Future perspectives

“We have analyzed a cell in human samples and successfully identified a cytokine produced specifically by auxiliary T cells that play a key role in the pathology of human rheumatoid arthritis.” said Hiryuki Yoshitomi, chief author of the document. “Because this gene is unique to primates, this discovery would not be possible using conventional animal models such as mice or rats.”

Going forward, the researchers aim to clarify how IGFL2 expression and its functions in the immune system are regulated. This project will deepen the understanding of RA’s pathology and could lead to more accurate diagnostic, innovative targeted therapies and ultimately better results and quality of life for people affected by RA and other autoimmune diseases.

Glossary

• Assistants T Cells: A type of white blood cell that acts as a “commander” of the immune system. They play a key role in the guidance of immunocommiles by helping B cells produce antibodies and support the activation of other immune cells in response to infections or foreign substances.
• Analysis of a Cell: A technique that isolates RNA from individual cells and analyzes expressed by genes and to what extent at the level of a cell. Unlike traditional bulk analysis, which provides only average data from a group of cells, the analysis of a cell allows researchers to observe differences between individual cells, recognize rare cellular types and trace elements such as immunocytic activation and cellular activation.
• Peripheral auxiliary T cells (TPH cells): A subset of auxiliary T cells in inflammatory tissues and helps to form structures for prolonged immune activation.
• Cytokine: A small protein released by cells that affect the behavior of other cells, especially in immunocompromises.
• Single cells/macrophages: The cells of the immune system involved in the detection, collapse and destruction of pathogens and cell debris. The monocytes are circulated in the bloodstream and migrate to tissues where they differentiate into macrophages.