Autoimmunity: Japanese Researchers Identify Proteins Tet2 And Tet3 That Can Prevent Autoimmunity Issues
In normal roles, the immune system is supposed to protect from external microbial invaders, but sometimes it turns its efforts inward, potentially resulting in autoimmune diseases.
Researchers from Osaka University In a new study have discovered how reversible modifications to DNA by certain proteins protect from autoimmune diseases, and conversely, how the absence of these proteins paves the way to autoimmunity.
The DNA provides specific codes to produce specific proteins. Nonetheless, not all parts of DNA are accessible in all cells at all times. The regulated production of proteins ensures that different cells and organs can be developed from the same DNA code. An important regulatory mechanism is the reversible addition (methylation) or removal (demethylation) of chemical bonds, so-called methyl groups, to segments of DNA. This modifies the readout of DNA segments. Proteins of the ten-eleven translocation (Tet) family are known DNA demethylases, which decrease the production of certain proteins in immune cells. How Tet proteins play into the development of autoimmune diseases has remained unknown until now.
The research findings are published in the journal: Nature Immunology https://www.nature.com/articles/s41590-020-0700-y
Corresponding author of the study Dr Tomohiro Kurosaki told Thailand Medical News, "Epigenetics deals with how reversible changes in DNA affect gene activity and protein expression. Disrupting this machinery can have dramatic effects on cellular function. The goal of our study was to understand how epigenetic control in a specific type of immune cells, called B cells, affects the development of autoimmune diseases."
In order to achieve their goal, the researchers developed a novel mouse line in which B cells did not produce the epigenetic regulator proteins Tet2 and Tet3.
The study team found that these mice developed a mild form of systemic lupus erythematosus, an autoimmune disease that can affect the joints, skin, kidneys and other organs, and for which there is currently no curative treatment. Similar to human patients, the mice showed increased serum levels of autoantibodies and damage to their kidneys, lungs and liver.
Lead author of the study Dr Shinya Tanaka added, "These findings suggest that Tet2 and Tet3, as well as proteins whose expression is regulated by Tet2 and Tet3, might play a fundamental role in the development of systemic lupus erythematosus. We wanted to gain a deeper molecular understanding of the mechanism behind the effects of Tet2 and Tet3 on the immune system."
The team next investigated a different type of immune cell, called T cells, which often interact with B cells, and found that T cells were excessively activated in the Tet2/Tet3 knockout mice. By examining the molecular interaction between B and T cells closer, the researchers found that the protein CD86 was produced at higher levels in B cells of Tet2/Tet3 knockout mice, leading to aberrant T cell activation and autoimmunity.
Dr Kurosaki. "These are striking results that show how Tet proteins suppress autoimmune diseas
es by inactivating B cells and thus ultimately preventing them from attacking our bodies. Our findings provide new insights into the contribution of epigenetics to the development of autoimmune disease. Regulating Tet proteins and their downstream effectors could be a novel treatment for autoimmune diseases."
The Japanese researchers are also working on possible therapeutics that can help in preventing the autoimmune process.
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