New research helps scientists understand the genetic cause of immune disease

By Samantha Black, PhD, The Science Advisory Board editor in chief

September 24, 2019 -- Research published in Nature Genetics on September 23 helps narrow down the search for molecular drivers for immune disease which could result in the identification of new drug targets and development of new therapies illnesses such as asthma, multiple sclerosis, and arthritis.

This study was conducted through a collaboration between Wellcome Sanger Institute, GSK and Biogen, under the Open Targets imitative. The results suggest that a variety of immune diseases in a diverse population are triggered by memory CD4+ T cells.

Immune related diseases such as asthma, multiple sclerosis, and arthritis impact millions of people worldwide each year. Asthma alone affects over 25 million individuals in the US. Little is known about the immunological etiology that triggers negative immune responses in these cases. Previous research has offered genetic variations as a cause of these immune diseases; however, these genetic variants are poorly understood. Moreover, immune reactions are incredibly complex, requiring many compounds and complicated pathways making them difficult to investigate.

The team set out to better understand which immune cell states are important for immune diseases in order to find potential new drug targets for asthma and irritable bowel disease (IBD). In the study the researchers identified which parts of the genome where activated in 3 types of immune cells from healthy volunteers and compared them to the genetic variants thought to be associated with immune disease. To accomplish this, they stimulated T cells and macrophages in the presence of 13 cytokines and profiled active and open chromatin regions. This mimicked immune disease inflammation.

The researchers determined that early activation memory T cells were the most active DNA across many genetic variants. The initial activation of these T cells indicates that they are important in disease development. Moreover, they found that cytokines, key regulatory molecules, play a relatively subtle role in DNA activity and even lesser role in the diseases studied.

"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." said Blagoje Soskic, a lead author on the paper from the Wellcome Sanger Institute and Open Targets.

"There are thousands of different cell types and states in the body, and finding the cause of autoimmune diseases is like finding a needle in a haystack. We have identified early activation of memory T cells as being particularly relevant to immune diseases, and will now be able to dive deeper into studying how this is regulated, to discover genes and pathways that could be used as drug targets" said Gosia Trynka, the senior author from the Wellcome Sanger Institute and Open Targets.


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