FOXP3 Gene Mutations May Explain Immune System Excitability in MS and Other Diseases

A gene mutation may explain the uncontrolled, inflammatory immune response seen in autoimmune and chronic inflammatory diseases like multiple sclerosis, scientists at the Research Institute of the McGill University Health Centre (RI-MUHC) report. It's a discovery that, they said, appears to be "a big step in the right direction." According to the study, published in the journal Science Immunology, alterations in the FOXP3 gene affect specific immune cells called regulatory T-cells, or Tregs. Those mutations hamper Tregs in performing a crucial regulatory role, leading to a loss of control over the immune system’s response to a perceived threat. “We discovered that this mutation in the FOXP3 gene affects the Treg cell’s ability to dampen the immune response, which results in the immune system overreacting and causing inflammation,” Ciriaco Piccirillo, the study's lead author and an immunologist in the Infectious Diseases and Immunity, Global Health Program, at the RI-MUHC, said in a news release. Tregs are known to be the immune system players responsible for keeping other immune cells under control, preventing them from attacking the host’s own tissues, while maintaining a proper immune response against harmful agents. The normal activity of Treg cells is essential for preventing excessive immune reactions. The FOXP3 gene is also well-known, and documented, to be essential for proper Treg cell function. However, the mechanisms by which FOXP3 gene is involved in Treg cell activities are still poorly understood. In the study, “Suppression by human FOXP3+ regulatory T cells requires FOXP3-TIP60 interactions,” the research team — in collaboration with researchers at University of Pennsylvania, University of Washington School of Medicine, and Teikyo University School of Medicine in Japan — evaluated the impact of a FOXP3 gene mutation in autoimmunity response. Taking advantage of cutting-edge technology, the team studied samples from two patients carrying a common FOXP3 gene mutation, which caused a genetic immune disorder called IPEX. Interestingly, the researchers found that this genetic variant did not reduce the number of Treg cells or the levels of FOXP3 protein. Instead, the mutation altered the way Tregs could suppress other immune cells to prevent overactivation. “What was unique about this case of IPEX was that the patient’s Treg cells were fully functional apart from one crucial element: its ability to shut down the inflammatory response,” said Piccirillo. “Understanding this specific mutation has allowed us to shed light on how many milder forms of chronic inflammatory diseases or autoimmune diseases could be linked to alterations in FOXP3 functions,” added Khalid Bin Dhuban, the study's first author and a postdoctoral fellow in Piccirillo’s laboratory. The team developed a compound capable of restoring Treg cells' ability to control the immune system in the presence of this specific FOXP3 gene mutation. Tested in animal models of colitis and arthritis, two chronic inflammatory diseases, the compound reduced inflammation and restored normal Treg function. Researchers now plan to develop similar drugs that may be of use in other diseases where Treg cells are known to be defective, including multiple sclerosis, type 1 diabetes, and lupus. "Currently, we have to shut down the whole immune system with aggressive suppressive therapies in various autoimmune and inflammatory diseases," said Piccirillo. “Our goal is to increase the activity of these Treg cells in certain settings, such as autoimmune diseases, but we want to turn it down in other settings, such as cancer.” “This discovery gives us key insights on how Treg cells are born and how they can be regulated,” Piccirillo added. “With this discovery, we are taking a big step in the right direction.”

Bioinformatics Approach Identifies Potential Therapies Targeting TNF, a Factor in MS, Other Diseases

Greek researchers have developed a new bioinformatics tool to identify potential therapies for chronic inflammatory diseases. Using this approach, they identified and confirmed the therapeutic potential of two small molecules to target a protein called TNF (Tumor Necrosis Factor) that is active in  multiple sclerosis, rheumatoid arthritis and other diseases. Their…

UV Light May Lead Way to New Treatment for MS and Inflammation

Researchers have found a way to harness inflammation with the help of ultraviolet (UV) light, making it possible to design an anti-inflammatory treatment that is more specific and causes fewer side effects. If this approach can be developed for clinical treatment, it likely will have a large impact on the lives of people with…

Australian Researcher Honored for Discovery That May Lead to Anti-Inflammatory Therapy

Dr. Rebecca Coll, a young researcher at the University of Queensland Institute of Molecular Bioscience, won the 2016 Research Australia Discovery Award for her work in identifying promising anti-inflammatory compounds that are able to block the NLRP3 inflammasome — a key driver of inflammation. The discovery could greatly benefit patients with inflammatory diseases,…

Wheat Proteins Known as ATIs May Worsen Inflammation in People with MS

A group of proteins found in wheat can cause symptoms of such inflammatory health conditions as multiple sclerosis (MS), asthma and rheumatoid arthritis to worsen, and may also promote gluten sensitivity, according to researchers at Johannes Gutenberg University in Germany. These findings, recently presented at United European Gastroenterology (UEG) Week 2016, turn attention away from one…