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24 September, 2019 - 11:04 By Kate Sweeney

Cell sleuths pave way to cures for immune diseases

Wellcome Trust Sanger Institute

Novel treatments for a range of immune diseases such as asthma, multiple sclerosis and arthritis are a step closer thanks to under-the-hood research by science sleuths at the Wellcome Sanger Institute in Cambridge and collaborators GSK and Biogen.

Working under the Open Targets initiative, the collaborators have already identified that thousands of differences in DNA between individuals, associated with immune diseases, are linked with the switching-on of a specific subtype of immune cells.

The findings by the DNA detectives will help narrow the search for the molecular pathways involved in immune diseases and hopefully trigger drug targets for developing new treatments.

The immune system fights infections. But if something goes wrong, the cells in our immune system can mistakenly cause inflammation – leading to immune diseases like asthma, multiple sclerosis and inflammatory bowel disease (IBD). 

These diseases affect millions of people worldwide, with more than five million asthma patients in the UK alone, yet it has not been not known what triggers the immune system to respond in this way, or even the exact cell types involved.

Previous research identified that there were thousands of genetic changes – known as genetic variants – that were more common in patients with immune diseases than in healthy people.

Understanding these genetic changes could provide clues to the causes and biological pathways involved in immune disease and, in time, lead to identifying new drug targets.

Many of these genetic variants are in poorly understood areas of the genome and are thought to be involved in regulating functions of immune cells. 

Cytokines – the signalling proteins released to allow communication between the immune cells during inflammation – further confuse the picture, making it tough to pinpoint what is causing a disease.

Sanger and colleagues aim to understand which immune cell states are most important for immune diseases; they probed which parts of the genome were active in three types of immune cells from healthy volunteers and cross-checked these positions against all the genetic variants implicated in different immune diseases. 

They also added different cytokines, creating a total of 55 different cell states, to mimic immune disease inflammation and understand the effects of the signalling chemicals in these cells.

The study revealed that one particular cell type and cell state – early activation of memory T cells – had the most active DNA across the same regions as the genetic variants implicated in immune diseases. 

This pointed towards the initial activation of these T cells being important in disease development. Surprisingly, the research showed that the cytokines generally only had subtle effects on the DNA activity and played a lesser role in most of the diseases studied.

To enable the complex analysis, the researchers developed a new computational method – called CHEERS – which enabled them to identify cell states relevant for immune diseases. 

Openly available, this resource could also be used to find links between genetic variation and mechanisms for other complex diseases.

Dr Blagoje Soskic, a lead author on the paper from the Wellcome Sanger Institute and Open Targets, said: “Our study is the first in-depth analysis of immune cells and cytokine signals in the context of genetic differences linked to immune diseases.

“We found links between the disease variants and early activation of memory T cells, suggesting that problems with regulating this early T cell activation could lead to immune diseases.”

• Image courtesy – the Wellcome Trust Sanger Institute

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