Trigger for MS and Other Immune Diseases May Be T-cells in Early Activation State, Study Reports

A specific type of immune cell in a particular activation state is linked to such immune diseases as multiple sclerosis (MS) and inflammatory bowel disease (IBD), a collaborative research study found.

Disease-associated genetic variants — changes in DNA sequences or mutations in genes — can affect the response of immune memory CD4-positive T-cells, in particular during an early activation state, which may contribute to the development of several immune-related diseases. (Activated cells are cells, like T-cells, that change in response to a stimulus.)

This finding adds a new layer of knowledge that may help researchers to better understand and treat inflammatory diseases.

“Our study is the first in depth analysis of immune cells and cytokine signals in the context of genetic differences linked to immune diseases,” Blagoje Soskic, its lead author, said in a news release.

The study, “Chromatin activity at GWAS loci identifies T cell states driving complex immune diseases,” was published in the journal Nature Genetics.

Much work has been done to identify potential genetic variants (genetic changes) that may be involved in disease. Several studies suggest that many of these genetic risk factors are located in regions of the genome that are related to CD4-positive T-cells and macrophages — two types of immune cells.

These cells are important elements of the body’s protective system, as they act as the first responders to potential threats like viruses.

In addition, pro-inflammatory signals (like those triggered by interferon-alpha or interleukin-4) have also been found to be essential for the proper differentiation of T-cells and macrophages, and to elicit an appropriate immune response.

Researchers with the Wellcome Sanger Institute, in collaboration with GSK and Biogen, set up an experimental analysis protocol to more closely look on how these immune cells could be linked to human diseases.

The scientists developed a new computational method, which they called CHEERS (Chromatin Element Enrichment Ranking by Specificity), that allowed them to identify cell states relevant for immune diseases.

This new computer algorithm combines detailed information on genetic variants and active DNA sequences, while being able to differentiate them from closely related cell types.

Analysis of the genetic patterns of CD4-positive T-cells and macrophages using CHEERS revealed that genetic variants known to be associated with MS, rheumatoid arthritis, IBD, psoriasis, asthma, and type 1 diabetes were mainly affecting T-cells. Their impact, or enrichment, was particularly strong in DNA regions that are specifically active early in the activation of memory T-cells.

“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,” Soskic said.

Further analyses showed that changes in the genetic pattern of memory T-cells were modulated by particular environmental signals, depending on the particular disease.

For instance, MS-associated variants were significantly enriched after interleukin-27 (IL-27) stimulation in early memory T-cell activation. “This is concordant with previous studies that reported elevated levels of IL-27 in the cerebrospinal fluid of patients with multiple sclerosis,” the researchers wrote.

Supported by these findings, the team believes that variants associated with immune-mediated diseases are important contributors to genetic regulation during the early activation of CD4+ T-cells, particularly in memory T-cells.

“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,” said Gosia Trynka, a PhD with the Sanger Institute and the study’s senior author.

“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,” Trynka added.

This study was funded in part by the Open Targets, a public-private collaboration between pharmaceutical companies and not-for-profit research institutions with the goal of improving the success rate of medicines in development.