CAMBRIDGE, U.K.—With strong financial backing from Open Targets, a battery of scientists is working to identify specific variations in DNA that correspond with different immune diseases, including asthma, multiple sclerosis and arthritis. Collating data from the Wellcome Sanger Institute, GlaxoSmithKline (GSK) and Biogen, the Open Targets initiative is locating thousands of distinctions between individuals to help science better understand why the immune system sometimes turns on itself.
Immune diseases are characterized by conditions in which the immune system mistakenly attacks the body, recognizing one’s own cells as foreign and correspondingly sending an army of proteins, or autoantibodies, to combat the perceived invader. Scientists have long struggled to understand what causes the body to mis-identify itself, in the hopes of finding a cure for what are sometimes debilitating conditions.
Previous research has shown thousands of genetic variants that are more common in patients with immune diseases than in healthy people. According to the Sanger Institute, many of these genetic variants are in poorly understood areas of the genome. Coupled with the signaling proteins (cytokines) released to allow communication between the immune cells during inflammation, and the picture becomes even more complex, making it extremely difficult to pinpoint what is causing the disease.
Through the Open Targets Platform, which integrates publicly available information about specific diseases to provide summaries of evidence for the involvement of specific genes with a selected disease, scientists explored thousands of variants that contribute to immune disease instances. In the study, which appeared in the journal Nature Genetics, the team looked at which parts of the genome were active in three types of immune cells from healthy volunteers and compared them to the genetic variants found in different immune diseases. They also added different cytokines, creating a total of 55 different cell states, to mimic immune disease inflammation and to understand the effects of the signaling chemicals in these cells.
According to the study, the researchers found 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.
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.”
Added Dr. Rab Prinjha, chair of the Open Targets governance board and head of the Adaptive Immunity and Immuno-Epigenetics Research Unit at GSK: “At GSK, we deploy both genetics and genomics to identify which parts of the immune system are central to a range of human diseases and to yield better validated targets that could become transformational medicines. To investigate the science of the immune system, functional genomics helps us better understand the role that individual genes may or may not play in triggering pathogenic immune mechanisms. This paper is yet another result from our five-year collaboration with Open Targets to advance the field and shows our focus on advanced technologies to drive our science.”
“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,” noted Dr. Gosia Trynka, the senior author from the Wellcome Sanger Institute and Open Targets. “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.”