A research group led by Assistant Professor Akinori Murakami of the Institute for the Advanced Study of Human Biology, Kyoto University, Associate Professor Hiroyuki Yoshitomi of the Graduate School of Medicine at Kyoto University, Vice-Director/Principal Investigator Hideki Ueno, and Professor Shuichi Matsuda of the Graduate School of Medicine at Kyoto University analyzed synovial tissue from rheumatoid arthritis patients. From this they revealed that "IGFL2," an evolutionarily new cytokine that emerged in primates, controls rheumatoid arthritis inflammation through helper T cells. IGFL2 could become a new therapeutic target as it also increases in the blood of patients with high disease severity, making it promising as a marker for treatment efficacy and diagnosis. Yoshitomi stated, "We want to improve its accuracy as a marker by utilizing samples from the KURAMA cohort and ANSWER cohort. We are currently in discussions with pharmaceutical companies regarding therapeutic drugs targeting IGFL2." The group's findings were published in Science Immunology.
Provided by WPI-ASHBi, Kyoto University
Rheumatoid arthritis (RA) is an autoimmune disease that causes inflammation due to immune system abnormalities, with an estimated 1 million patients in Japan. Since the 2000s, biological drugs have emerged and demonstrated significant therapeutic effects, but approximately 30% of patients still have insufficient treatment responses.
In RA, the synovium, which normally allows smooth joint movement and provides nutrition, becomes inflamed and thickens, causing immune cells to attack joints and surrounding tissues. In model mice, Th17 cells that produce IL-17 are involved, and inflammation can be suppressed by administering inhibitors, but this is not effective in human rheumatoid arthritis patients. Meanwhile, T peripheral helper (TPH) cells have been identified from human patients, suggesting some involvement.
The research group collected synovium surgically removed from 11 RA patients and performed single-cell RNA analysis. Analysis of 58,363 joint helper T cells revealed 12 fractions including TPH cells. Among these, only TPH cells correlated with patient disease severity (inflammation intensity). In TPH cells, IGFL2 and IGFLR1 (IGFL2 receptor) were discovered as characteristic new cytokines. IGFL2 was expressed specifically in TPH cells, while IGFLR1 was also expressed in other T cells. Furthermore, single-cell analysis of all synovial cells revealed that IGFL2 was expressed only in helper T cells, while IGFLR1 was broadly expressed in B cells, macrophages, and other cells.
Murakami hypothesized that "TPH cells might influence all immune cells in the synovium through IGFL2." When naive helper T cells were stimulated with T cell activation reagents, TGF-β, and IGFL2 and analyzed by flow cytometry, it was found that adding both TGF-β and IGFL2 resulted in high expression of CXCL13 (a protein secreted from cells that attracts and activates B cells). It was also revealed that adding IGFL2 to monocytes induced inflammation-related genes. Conversely, when IGFL2 production by TPH cells was suppressed, expression of inflammation-related genes in monocytes was suppressed. This means IGFL2 controls inflammation in synovial cells and can be a therapeutic target.
Additionally, blood samples from 30 RA patients and 30 healthy individuals were collected and analyzed. IGFL2 was significantly higher in RA patients, showing an AUC of 0.916, which is of a higher sensitivity than the 0.86 of anti-cyclic citrullinated peptide antibodies currently used for diagnosis. Furthermore, when blood IGFL2 concentrations were compared between remission and non-remission patients, the concentration was significantly higher in non-remission patients.
IGFL2 does not exist in rodents like mice; it is a primate-specific humoral factor found in gibbons and later primates, though its function was completely unknown. By analyzing synovial cells from rheumatoid arthritis patients, this study revealed its function and utility, once again demonstrating the importance of research using human cells. Yoshitomi stated, "The synovium was provided by patients with their consent when they underwent surgery. It's important to make 100% use of these specimens."
Journal Information
Publication: Science Immunology
Title: Human CD4+ T cells regulate peripheral immune responses in rheumatoid arthritis via insulin-like growth factor-like family member 2
DOI: 10.1126/sciimmunol.adr3838
This article has been translated by JST with permission from The Science News Ltd. (https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.