October 3, 2018
Autoimmune disease is the third of the top 10 catastrophic illnesses in Taiwan. An autoimmune disease is a condition that one’s immune system mistakenly attacks healthy cells or organs in one’s own body. Patients with autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis need to receive treatments throughout their lives. Treatment and symptom alleviation are long-standing challenges in the medical field.
Overproduction of the proinflammatory cytokine IL-17A is a key causal factor of autoimmune diseases. Thus, IL-17A is an emerging therapeutic target for autoimmune and inflammatory diseases; however, the underlying mechanism of IL-17A overproduction remains unclear. After investigating for 7 years, Dr. Tse-Hua Tan, distinguish investigator, and Dr. Huai-Chia Chuang, assistant investigator, of the National Health Research Institutes (NHRI) finally discover a key mechanism controlling IL-17A overproduction. This finding will help develop novel therapeutic strategies for autoimmune diseases.
Dr. Tse-Hua Tan commented that current IL-17A inhibitors are all biological agents, namely anti-IL-17A monoclonal antibodies, which block IL-17A outside the cells; however, the protein drug is much more costly than the small-molecule compound inhibitors. This finding provides an upstream target ”AhR-RORγt complex” for controlling IL-17A overproduction inside the cells. Small molecules that inhibit the AhR-RORγt complex could be cost-effective therapeutic agents for IL-17A-mediated autoimmune disease. This novel target controlling IL-17A overproduction and autoimmune disease has been published in Science Advances on September 12.
[Adapted from Science Advances, 2018]
In 2011, the research team of Dr. Tse-Hua Tan and Dr. Huai-Chia Chuang, has reported that the kinase MAP4K3/GLK is a key pathogenic factor for autoimmune diseases. MAP4K3/GLK is found in higher-than-normal amounts in peripheral blood T cells of patients with autoimmune diseases. Now, the team further discovers that GLK overexpression in T cells induces a novel signaling cascade for inflammation and autoimmune responses. To mimic GLK overexpression in human patients’ T cells, the research team generated a T-cell-specific GLK transgenic mice. The transgenic mice spontaneously develop autoimmune diseases and inflammation in multiple organs. After characterizing various proinflammatory cytokines in the mouse sera, they found the pathogenic cytokine IL-17A levels are specifically increased in the serum of GLK transgenic mice.
The research team has studied the mechanism of IL-17A overproduction using several knockout mice and biochemical approaches for 7 years. They found that overexpression of the kinase GLK induces the AhR-RORγt complex and subsequent IL-17A overproduction, leading to autoimmune diseases. Most importantly, the AhR-RORγt complex specifically induces IL-17A overproduction but not other cytokines. Conversely, inhibition of the AhR-RORγt complex will not affect the production of other cytokines and maintain normal biochemical functions without any side effects. Thus, the AhR-RORγt complex is a novel therapeutic target for autoimmune diseases.
Dr. Tan commented that this finding has an immense potential in clinical application. The research team has applied a patent on the discovery and clinical application with US Patent and Trademark Office. The team will continue to develop inhibitors of the AhR-RORγt complex and plans to collaborate with biotech companies for drug development. The research team looks forward to developing a novel treatment for autoimmune diseases.
For the full text of our publication in Science Advances, please visit: http://advances.sciencemag.org/content/4/9/eaat5401
Media contact:
Dr. Tse-Hua Tan, Distinguished Investigator and Director, Immunology Research Center, National Health Research Institutes, TEL: +886-37-246-166 Ext. 37601, E-mail: ttan@nhri.org.tw
Dr. Huai-Chia Chuang, Assistant Investigator, Immunology Research Center, National Health Research Institutes, TEL: +886-37-246-166 Ext. 37616, E-mail: cinth@nhri.org.tw
Nathalie Huang, Secretariat, National Health Research Institutes, TEL: +886-37-246-166 ext.32113, E-mail: nathalie@nhri.orgt.tw