Igniting the rheumatoid arthritis flame through a cellular cascade

May 30, 2018, Osaka University
An inflammatory cellular cascade instigated by an arthritogenic T helper subset and enhanced by GM-CSF-producing synovial-resident innate lymphoid cells. Credit: Osaka University

Chronic inflammatory disorders, including autoimmune diseases such as rheumatoid arthritis, involve the action of various inflammatory molecules (cytokines) produced by cells of the immune system. One such cytokine, IL-17, is produced by Th17 cells, which are white blood cells that provide host defense against pathogens, as well as mediating inflammatory reactions. Although Th17 cells are lead players in autoimmune disease, the way in which they control other inflammatory cells had been unclear.

Now, an international team of researchers led by Osaka University has used a mouse model of rheumatoid arthritis to investigate how Th17 interact with other cells at the site of inflammation and influence cytokine production. They reported their findings in the journal Immunity.

Several inflammatory cytokines, including IL-6 and TNFα, cause joint inflammation in rheumatoid arthritis. The disease progresses through the interaction of T cells of the immune system with specialized cells in the joint lining (synovium), which promotes the destruction of bone and cartilage. The recent development of new anti-rheumatic drugs such as TNF and IL-6 inhibitors has dramatically improved the quality of life of many patients with rheumatoid arthritis, but treatment for 30% of these patients remains a challenge. Therefore, novel therapies are eagerly awaited.

The inflammatory cytokine GM-CSF activates cells involved in innate and adaptive immune systems, which represent non-specific defense mechanisms and specific learned responses to foreign substances, respectively. GM-CSF particularly triggers scavenger (macrophages) and immune cell messengers known as .

The team found that GM-CSF was crucial for the development of arthritis in the mouse model. "GM-CSF produced both by stromal cells of the connective tissue and T cells contributed to joint inflammation in the mice, but only stromal cell-derived GM-CSF was needed to initiate arthritis," study first author Keiji Hirota explains. "We also showed that stromal cells secreted GM-CSF in response to stimulation by IL-17 from inflammatory Th17 cells."

GM-CSF was also found to be secreted by a group of innate immune cells, which expanded in number within inflamed joints in response to IL-17 production by Th17 cells and other inflammatory cytokines. This contributed to the maintenance and development of in the mice.

"Our findings outline an inflammatory network controlled by autoimmune Th17 cells and involving and innate immune cells, which leads to the onset and development of autoimmune arthritis," corresponding author Shimon Sakaguchi says. "By selectively removing GM-CSF-producing cells from the mouse synovium, we significantly reduced the severity of arthritis. This suggests the usefulness of developing such a novel immunotherapeutic approach that targets the cellular network to reduce chronic joint inflammation."

Explore further: Maintaining sufficient vitamin D levels may help to prevent rheumatoid arthritis

More information: Keiji Hirota et al, Autoimmune Th17 Cells Induced Synovial Stromal and Innate Lymphoid Cell Secretion of the Cytokine GM-CSF to Initiate and Augment Autoimmune Arthritis, Immunity (2018). DOI: 10.1016/j.immuni.2018.04.009

Related Stories

Maintaining sufficient vitamin D levels may help to prevent rheumatoid arthritis

November 20, 2017
Maintaining sufficient vitamin D levels may help to prevent the onset of inflammatory diseases like rheumatoid arthritis, research led by the University of Birmingham has discovered.

Inflammatory immune cells can flip the genetic script

April 30, 2015
A type of immune cell that promotes inflammation during the immune response, TH17, can convert into another type of cell that reduces inflammation, Yale researchers have found. The finding, published April 29 in Nature, points ...

Rheumatoid arthritis—new therapeutic approach suppresses joint inflammation

May 9, 2018
Rheumatoid arthritis (RA) is a chronic condition characterised by uncontrolled inflammation in the joints. It involves several types of immune cells, macrophages playing a particularly crucial role. Working as part of an ...

Scientists discover new mechanism that leads to inflammation in rheumatoid arthritis

March 2, 2017
New research findings published in the Journal of Leukocyte Biology, suggest that synovial CD4+ T cells that produce IL-21 contribute to joint inflammation by activating synovial fibroblasts in rheumatoid arthritis patients. ...

Researchers identify factors responsible for chronic nature of autoimmune disease

January 4, 2017
Researchers from Schepens Eye Research Institute of Massachusetts Eye and Ear have uncovered two factors responsible for the chronic, lifelong nature of autoimmune disorders, which tend to "flare up" intermittently in affected ...

Cellular stress increases the probability of developing autoimmune diseases

June 14, 2017
A team of researchers led by Marc Veldhoen at the Instituto de Medicina Molecular (iMM), Lisboa, has found that cellular stress enhances the activation of immune cells implicated in many chronic inflammatory conditions, increasing ...

Recommended for you

New study shows how gut immune cells are kept in control

June 22, 2018
Every day, the human gut works on a fine-tuned balance that ensures the retention of essential nutrients while preventing infection by potential armful microbes. Contributing to this surveillance system is a specialised group ...

Human immune 'trigger' map paves way for better treatments

June 21, 2018
A discovery about how human cells are 'triggered' to undergo an inflammatory type of cell death could have implications for treating cancer, stroke and tissue injury, and immune disorders.

Our intestinal microbiome influences metabolism—through the immune system

June 21, 2018
Research tells us that the commensal or "good" bacteria that inhabit our intestines help to regulate our metabolism. A new study in fruit flies, published June 21 in Cell Metabolism, shows one surprising way they do this.

Fetal T cells are first responders to infection in adults

June 20, 2018
Cornell University researchers have discovered there is a division of labor among immune cells that fight invading pathogens in the body.

How a thieving transcription factor dominates the genome

June 20, 2018
One powerful DNA-binding protein, the transcription factor PU.1, steals away other transcription factors and recruits them for its own purposes, effectively dominating gene regulation in developing immune cells, according ...

Severe stress may send immune system into overdrive

June 19, 2018
(HealthDay)—Trauma or intense stress may up your odds of developing an autoimmune disease, a new study suggests.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.