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When immune commanders misfire: new insights into rheumatoid arthritis inflammation

2025-08-01
(Press-News.org)

Researchers at Kyoto University have 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 patients with RA and acts like fuel on a fire: it activates more immune cells, further amplifying inflammation and worsening 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 IGFL2’s potential as a diagnostic marker, a tool for monitoring disease progression, and a target for new therapies, paving the way for earlier detection, more effective treatments, and better quality of life for people with RA worldwide.

 

KYOTO, Japan – August 1st 2025

 

Overview

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 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), Graduate School of Medicine; Professor Hideki Ueno, Vice Director and Principal Investigator at WPI-ASHBi (also Professor at the Department of Immunology, Graduate School of Medicine, and Director of the Kyoto University Immunological Monitoring Center, KIC); and Professor Shuichi Matsuda of the Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University. The findings will be published in Science Immunology on August 1, 2025.

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.

Future Perspectives

“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 Hiroyuki 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 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.

 

Glossary

Helper T Cells: A type of white blood cell that acts as the "commander" of the immune system. They play a key role in directing immune responses by helping B cells produce antibodies and by supporting the activation of other immune cells in response to infections or foreign substances. Single-cell analysis: A technique that isolates RNA from individual cells and analyzes which genes are being expressed and to what extent at the single-cell level. Unlike traditional bulk analysis, which provides only averaged data from a group of cells, single-cell analysis allows researchers to observe differences between individual cells, identify rare cell types, and trace processes like immune cell activation and cellular differentiation. Peripheral Helper T Cells (Tph cells): A subset of helper T cells in inflamed tissues and assist in forming structures for sustained immune activation. Cytokine: A small protein released by cells that affects the behavior of other cells, particularly in immune responses. Monocytes/Macrophages: Immune cells involved in detecting, engulfing, and destroying pathogens and cellular debris. Monocytes circulate in the bloodstream and migrate into tissues, where they differentiate into macrophages.

 

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About Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University

What key biological traits make us ‘human’, and how can knowing these lead us to better cures for disease? ASHBi investigates the core concepts of human biology with a particular focus on genome regulation and disease modeling, creating a foundation of knowledge for developing innovative and unique human-centric therapies.

About the World Premier International Research Center Initiative (WPI)

The WPI program was launched in 2007 by Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster globally visible research centers boasting the highest standards and outstanding research environments. Numbering more than a dozen and operating at institutions throughout the country, these centers are given a high degree of autonomy, allowing them to engage in innovative modes of management and research. The program is administered by the Japan Society for the Promotion of Science (JSPS).  

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[Press-News.org] When immune commanders misfire: new insights into rheumatoid arthritis inflammation