Target Tissues of Immune Attacks Too Often Ignored in Research, Study Says

To fully understand autoimmune diseases like multiple sclerosis (MS), it is necessary to study not just the immune system, but also the tissue that the immune system is attacking, a study suggests.

“We must move away from the present ‘immune-centric-only’ view of autoimmune diseases,” Decio Eizirik, MD, PhD, study co-author and scientific director of the Indiana Biosciences Research Institute Diabetes Center, said in a press release.

“Indeed, trying to understand these diseases focusing on the immune system only, and forgetting the target tissues, may be similar to attempting to fly a plane with only one wing,” Eizirik said.

The study reporting these findings, “Gene expression signatures of target tissues in type 1 diabetes, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis,” was published in the journal Science Advances.

The immune system is responsible for defending the body against disease-causing invaders, like viruses and bacteria. In the broadest sense, its job is to attack anything that is not a normal part of the body while leaving healthy tissue alone.

Autoimmune diseases occur when the immune system erroneously attacks healthy tissue: in MS, the nervous system is the target of this immune attack. Other tissues are targeted in other autoimmune diseases. For instance, in type 1 diabetes (T1D), the immune system attacks cells in the pancreas, called beta cells, that are responsible for making insulin.

Different autoimmune diseases share commonalities, but they are often studied separately. Additionally, most research in autoimmune diseases focuses on the immune system, not the tissue that is being attacked.

“There is increasing evidence that the target tissues of these diseases are not innocent bystanders of the autoimmune attack but participate in a deleterious dialog with the immune system that contributes to their own demise,” the researchers wrote.

“Against this background, we hypothesize that key inflammation-induced mechanisms, potentially shared between [different autoimmune diseases] may drive similar molecular signatures at the target tissue level,” they added.

To test this idea, the researchers analyzed gene expression data from the target tissue of four autoimmune diseases. Gene expression refers to the extent that different genes are “turned on or off” in cells.

The four diseases analyzed (and the corresponding target tissue) were: MS (nervous system tissue), T1D (beta cells), systemic lupus erythematosus (kidney tissue), and rheumatoid arthritis (joint tissue).

Researchers analyzed tissue from people with each disease, as well as tissue from healthy individuals for comparison. The number of samples available varied among diseases, from five patients and five controls for MS, up to 57 patients and 28 controls for rheumatoid arthritis.

The analysis identified some notable commonalities among the gene expression profiles in each of the four target tissues. For instance, across all four diseases, target tissues had increased expression of genes involved in interferon signaling, which is an important biological pathway that regulates inflammation. Other inflammation-related pathways, such as antigen presentation, also had increased expression in the target tissues.

“In support of the robustness of the present findings, these similarities were present despite the fact that the original … data were obtained by different research teams, using different extraction and sequencing processes, and that there were major differences between the studies regarding age and sex of the patients and respective controls,” the researchers wrote.

Genes with decreased expression tended to vary more disease-to-disease. For example, in MS samples, there was decreased expression of genes involved in the production of myelin — the fatty “sheath” around nerve cells that is attacked in MS — whereas in type 1 diabetes decreased expression was seen in genes involved in insulin production.

Based on the results, the team suggested that targeting mechanisms that are similar across these diseases, like the interferon pathway, could be a treatment approach worth exploring.

“Discovering similar disease-specific signatures may allow the identification of key pathways that could be targeted for therapy, including the repurposing of drugs already in clinical use for other diseases,” the researchers wrote.

For example, researchers noted that inhibitors of the protein TYK2 — which is involved in the interferon pathway and was found to be present in all target tissues of the four autoimmune diseases analyzed — are currently in clinical testing in another autoimmune disease, psoriasis.

“Drugs that are effective in one autoimmune disease could be equally beneficial for another and quickly repurposed to make a big impact for people living with that disease,” said Frank Martin, PhD, director of research at the diabetes-focused nonprofit JDRF, who was not directly involved in the study.

“As a whole, these observations suggest that future research on the genetics and pathogenesis of autoimmune diseases should focus on both the immune system and their target tissues and on their dialog,” the researchers concluded.