New Multiple Sclerosis Study Reveals Protein’s Role in Disease Activation

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multiple sclerosis and the blood-brain barrier

In a new study entitled “Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation,” a team of scientists discovered the mechanism by which autoreactive T cells are capable of penetrating a patient’s brain and induce multiple sclerosis. The study was recently published in the advance online issue of Nature Immunology.

Multiple sclerosis is a neurological autoimmune disease characterized by the self-reactivity of T cells (key cells of the immune system) that trigger an attack, after cells have infiltrated the brain and spinal cord, against myelin (the substance that insulates nerve cells). With time, inflammation results in damage to myelin that impairs the normal functioning of the brain. A barrier called blood-brain barrier protects the brain from these autoimmune T cells. In multiple sclerosis, however, these cells can overcome the blood-brain barrier, although the mechanisms underlying this phenotype remain unknown.

A team of scientists at the La Jolla Institute for Allergy and Immunology (LJI) tackled this question and discovered that autoimmune T cells are conducted into the nervous system by other cells of the immune system, specifically monocytes and macrophages. As Catherine Hedrick, PhD, a professor in the Division of Inflammation Biology and one of the study’s lead authors, noted in a press release, “Our results show that macrophages and monocytes actively participate in the initiation and progression of multiple sclerosis, which has long been considered a primarily T cell driven disease. They exacerbate the severity of the disease by sending out chemical signals that boost inflammation and attract autoimmune T cells to the central nervous system.”

Iftach Shaked, PhD, a postdoctoral researcher in the laboratory of LJI professor Klaus Ley, PhD and study first author, added, “Multiple sclerosis affects millions of people worldwide. But what’s really puzzling is that we all have autoimmune T cells that recognize myelin basic protein but normally they do not infiltrate the central nervous system and cause disease.”

It is known that stress can play a role in the worsening of symptoms of inflammatory diseases, but the link between cellular stress and neuroinflammation remains poorly understood. Here, the team discovered that a protein known as Nr4a1 (an established factor responding to inflammatory and stress signals) prevented autoreactive T cells from infiltrating the central nervous system in mouse models of human multiple sclerosis. The team found Nr4a1 protein inhibited the production of norepinephrine. In the absence of Nr4a1, monocytes and macrophages continually produce norepinephrine, leading to the activation of macrophages and triggering a massive flow of T cells into the central nervous system.

“Monocytes and macrophages have a way to amplify inflammation in the central nervous system, which really shows that myeloid cells play an unexpected and important role in diseases of the brain,” Dr. Shaked explained.

The findings established Nr4a1 as a key regulator of norepinephrine and showed how its absence potentiates multiple sclerosis, therefore providing new therapeutic avenues for the disease.

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  1. kathleen says:

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