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Innate immune system modulates the severity of multiple sclerosis: focus on Nr4a1


Multiple sclerosis is triggered by self-reactive T cells that successfully infiltrate the brain and spinal cord where they launch an aggressive autoimmune attack against myelin. Over time, the resulting bouts of inflammation permanently damage the myelin sheath and the nerve fibers it protects, disrupting nerve signals traveling to and from the brain.

But the molecular cues that enable autoimmune T cells, which are usually kept at bay by the blood-brain barrier, to slip into the central nervous system had remained unclear.
In a study, published in the Nature Immunology, researchers at the La Jolla Institute for Allergy and Immunology report that these disease-causing autoimmune T cells are lured into the nervous system by monocytes and macrophages, a subset of immune cells better known as the immune system's cleanup crew.

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.

By revealing the molecular mechanisms that control neuroinflammation, these findings add a new layer of complexity to understanding of multiple sclerosis and support the growing appreciation of the significance of the crosstalk between the peripheral immune system and the brain.

Stress can worsen symptoms of inflammatory diseases such as multiple sclerosis but the molecular mechanisms linking cellular stress signaling and neuroinflammation had remained unclear.

Researchers hypothesized that Nr4a1may be a key factor in the prevention of autoimmunity affecting the central nervous system.

To address the importance of Nr4a1 in brain autoimmunity, the researchers induced experimental autoimmune encephalomyelitis ( EAE ), a model of multiple sclerosis, in mice with and without Nr4a1.
In the absence of Nr4a1, auto-reactive T cells infiltrated the central nervous system much earlier and in greater numbers exacerbating the progression and severity of the disease when compared to the control group.

Researchers discovered that Nr4a1 represses the production of norepinephrine, a major mediator of the body's response to physiological and psychological stressors. Without Nr4a1 to put a damper on production, monocytes and macrophages increase secretion of norepinephrine, which in turn leads to the activation of macrophages, thereby amplifying neuroinflammation and causing a massive influx of T cells into the central nervous system.

Nr4a1 regulates the production of norepinephrine by limiting the amount of tyrosine hydroxylase, the enzyme that controls a bottleneck in the biosynthesis of norepinephrine. When Nr4a1 is missing, tyrosine hydroxylase is highly expressed in monocytes and macrophages leading to more severe disease. Conversely, deletion of tyrosine hydroxylase in myeloid cells protects mice from the disease.

A small pilot study indicated that the same communications channels might be used to send messages between the brain and the peripheral immune system in patients with multiple sclerosis.
Monocytes and macrophages have a way to amplify inflammation in the central nervous system. ( Xagena )

Source: La Jolla Institute for Allergy and Immunology, 2015

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