Looking at a gene known as HDAC7, researchers from The Buck Institute of Research on Aging have found out how it can contribute to autoimmune diseases. Their work was published in eLife yesterday.
"Our previous work has shown that interference with the normal functioning of HDAC7 can block an important process during the development of T cells, called negative selection, which is required for eliminating cells that recognize and attack self-derived tissues," says Eric Verdin, lead author of the study.
"Defects in this process are clearly associated with autoimmunity, and we have confirmed that altering HDAC7 function in mice causes autoimmune diseases. However, even though a particular mutation in HDAC7 allows T cells that are reactive to many different tissues to survive when they should have been eliminated, only a few tissues in the animals actually develop disease—remarkably the same ones which are affected in the diseases associated with HDAC7 variants in humans. We wanted to find the mechanism that underlies this unlikely coincidence."
In this study the team using a combination of cell culture technology and genetically modified mice to study HDAC7's function. They found that the gene regulated the elimination of self-reactive T cells, as well as the development of invariant natural killer T (iNKT) cells, which provide defense against bacterial invasion. So when they saw that negative section was blocked, they also saw that the development of iNKT cells was blocked, which then led to an increase in disease development in mice and humans. These findings show that the mutated HDAC7 is likely the root of the disease development. "Importantly, when we restored the cells in mice, we saw that their disease symptoms were improved," Verdin adds.
"Together, our results provide evidence that HDAC7 and the network of genes surrounding it could be effective targets for interventions in human inflammatory diseases of the bowel, pancreas, and liver," concludes co-author Herbert Kasler. "They also suggest that defects in cells such as iNKTs may play an underappreciated role in these diseases, which we would like to explore further."
"Additionally, our next steps will be to identify the other key genes involved in HDAC7's regulation of iNKT cell development, evaluate their targeting in mouse models of the same diseases, and search for more variants in HDAC7 and its network of genes that are associated with human disease."