Early-life Trauma Affects MS Development, Treatment in Mice

Childhood trauma can affect disease progression of multiple sclerosis (MS) and treatment in adulthood, a study in mice suggests.

The study shows that mice that experienced early-life trauma were more likely to develop an autoimmune condition and less likely to respond to common treatment with interferon beta.

The study, “Early-life-trauma triggers interferon-β resistance and neurodegeneration in a multiple sclerosis model via downregulated β1-adrenergic signaling,” was published in the journal Nature Communications.

MS is a progressive, multifactorial disease with both genetic and environmental factors contributing to it. Childhood trauma (early-life) trauma — emotional neglect or physical abuse, for instance — has been associated with higher relapse rates in MS. However, the underlying mechanism through which it alters MS progression remains unknown.

To address this question, researchers at the University of Illinois Urbana-Champaign investigated how childhood trauma affected disease severity and susceptibility in mice with experimental autoimmune encephalitis (EAE,  a mouse model of MS).

Researchers induced emotional and physical distress in mice when they were young by separating them from their mother and father and by giving them a saline injection, and compared them to mice without childhood stress.

“Mice that had early-life trauma were more susceptible to EAE disease development and suffered prolonged motor paralysis with severe neuronal damage in the central nervous system, which we found was caused by a heightened immune response,” Yee Ming Khaw, graduate student and first author of the study, said in a press release.

Researchers found that EAE triggers the immune system through a receptor that binds to norepinephrine (a stress hormone). In mice, childhood stress caused a longer release of this hormone and activation of its receptor, which subsequently leads to a reduction in the levels of this receptor in immune cells, lowering the response capability of the immune system against stress or inflammation.

Mice subjected to early stress also were resistant to treatment with interferon beta. In turn, this common MS treatment was able to reduce disease progression in mice without childhood stress.

Treatment with a compound that boosts norepinephrine response was found to prevent paralysis and to slow damage to the spinal cord, making mice able to respond to treatment with interferon beta.

“This receptor activator may be a therapeutic drug for MS patients with a history of childhood trauma,” said Makoto Inoue, PhD, the study’s senior author.

According to the team, the results “add to emerging evidence that [norepinephrine receptor] agents may be clinically useful as an immunomodulatory therapy for patients with MS who experienced [early-life trauma]. Further epidemiological studies are needed to expand our understanding of the relationship between chronic stress during childhood and MS phenotype to determine biomarkers and targeted therapeutics,” they wrote.

Researchers are planning to analyze the mechanisms of this receptor in more detail. In translational studies with MS patients, they want to understand if the stimulation of the receptor has the same benefits as seen in mice.

“We believe that the best approach to addressing autoimmune diseases in individuals with a history of childhood trauma or other risk factors is a comprehensive and personalized medicine approach that addresses the whole person,” Inoue said.