Scientists identify potential targets for new autoimmune disease treatments

April 17, 2018, eLife

Researchers have provided new insight into how a gene associated with autoimmunity contributes to disease in humans.

Their findings, published in the journal eLife, could have significant implications for the development of novel treatments for conditions where the body is attacked accidentally by the immune system.

The adaptive immune system needs to be able to eliminate all potential external threats while still maintaining tolerance towards normal tissues. Failure to do so can result in different types of autoimmune , which can include type 1 diabetes, rheumatoid arthritis and . T cells play an important role in this, as variants in human genes related to the cells' function are the most common mutations associated with such conditions. A team of US scientists are now studying how one autoimmunity-associated gene, Histone Deacetylase 7 (HDAC7), can contribute to disease.

"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 recognise and attack self-derived tissues," says Eric Verdin, President and CEO of The Buck Institute for Research on Aging, California, and lead author of the current 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."

To address this question, Verdin and his team altered and studied the function of HDAC7 in a combination of cell cultures and genetically modified mice. They discovered that the gene regulates both the elimination of self-reactive T cells and the development of a specialised class of T cells called invariant natural killer T (iNKT) cells. The same interference with HDAC7 function that blocks negative selection also blocks the development of these cells, which are specialised to provide rapid defense against bacterial invasion in the same tissues - namely the liver, pancreas, and the digestive system - that developed disease in the mice and also more often in humans with a mutated HDAC7 gene. "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, Staff Scientist in Verdin's lab at the Buck Institute. "They also suggest that defects in 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 that are associated with human disease."

Explore further: Identified a key protein in the generation of B lymphocytes

More information: Herbert G Kasler et al, Histone deacetylase 7 mediates tissue-specific autoimmunity via control of innate effector function in invariant Natural Killer T-Cells, eLife (2018). DOI: 10.7554/eLife.32109

Related Stories

Identified a key protein in the generation of B lymphocytes

October 17, 2016
Researchers of the Cellular Differentiation Group at the Epigenetics and Cancer Biology Program at IDIBELL, led by researcher Maribel Parra, have identified a transcriptional repressor, the histone deacetylase HDAC7, involved ...

Scientists discover how gene mutation triggers immune disease

January 30, 2018
Scientists discovered how a gene mutation affects T cell function to promote immune disorders and then tested a treatment based on the discovery—successfully fixing donated immune cells from a 16-year-old boy with an abnormally ...

Scientists make critical insights into T-cell development

August 11, 2017
Mutations in the gene encoding the enzyme protein tyrosine phosphatase N2 (PTPN2) have been associated with the development of autoimmune disease including Type 1 diabetes, Crohn's Disease and rheumatoid arthritis.

Large-scale genetic study defines relationship between primary sclerosing cholangitis and other autoimmune diseases

April 21, 2013
For the first time, scientists show that a leading cause of liver transplant, primary sclerosing cholangitis (PSC), is a distinct disease from inflammatory bowel disease, opening up new avenues for specific PSC treatments.

Immune cell death safeguards against autoimmune disease

September 6, 2012
Researchers at the Walter and Eliza Hall Institute have discovered that a pair of molecules work together to kill so-called 'self-reactive' immune cells that are programmed to attack the body's own organs. The finding is ...

Recommended for you

Researchers discover unique immune cell likely drives chronic inflammation

December 11, 2018
For the first time, researchers have identified that an immune cell subset called gamma delta T cells that may be causing and/or perpetuating the systemic inflammation found in normal aging in the general geriatric population ...

Macrophage cells key to helping heart repair—and potentially regenerate, new study finds

December 11, 2018
Scientists at the Peter Munk Cardiac Centre have identified the type of cell key to helping the heart repair and potentially regenerate following a heart attack.

New light-based technology reveals how cells communicate in human disease

December 11, 2018
Scientists at the University of York have developed a new technique that uses light to understand how cells communicate in human disease.

Study identifies a key cellular mechanism that triggers pneumonia in humans

December 11, 2018
The relationship between influenza and pneumonia has long been observed by health workers. Its genetic and cellular mechanisms have now been investigated in depth by scientists in a study involving volunteers and conducted ...

Immune cells sacrifice themselves to protect us from invading bacteria

December 11, 2018
Immune systems are working overtime as winter approaches. Stomach flu can turn the strongest individual into a bedridden convalescent. Viruses are spreading in kindergartens. This year's flu is approaching in full swing. ...

Successful anti-PD-1 therapy requires interaction between CD8+ T cells and dendritic cells

December 11, 2018
A team led by a Massachusetts General Hospital (MGH) investigator has found that successful cancer immunotherapy targeting the PD-1 molecule requires interaction between cytotoxic CD8+ T cells, which have been considered ...

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.