Multiple Sclerosis

Multiple sclerosis (MS) is a debilitating neurological disease triggered by infiltration of the brain and spinal cord by T lymphocytes that attack and destroy myelin, the fatty substance that surrounds and insulates nerve fibers.

Overview

Over time, resulting bouts of inflammation permanently damage the myelin sheath and disrupt nerve transmission to and from the brain. When that happens, patients experience dizziness or balance disorders, mobility problems, numbness, fatigue, and even depression.

Currently, there is no cure for MS. Patients are encouraged to try to manage symptoms via stress reduction and treatment with immunosuppressive corticosteroids or other “disease-modifying” therapies (DMTs), such as interferon. At best, these interventions decrease attack frequency and severity, but they are not a cure.

Several LJI investigators are exploring novel approaches to treat groups of autoimmune disorders that include MS. Among them is Amnon Altman, Ph.D., who discovered that an enzyme called protein kinase C theta (PKCθ) is essential for T cell activation and survival. He is now pursuing whether blocking PKCθ activity would benefit patients with MS, rheumatoid arthritis (RA) or other autoimmune diseases.

Also, LJI’s Anjana Rao, Ph.D., has applied next-generation DNA sequencing technologies to show how loss of proteins of the TET family disrupts “epigenetic” modification of DNA called methylation. DNA methylation is most often associated with gene silencing, and TET proteins catalyze DNA demethylation. Thus, their loss, which is documented in some cancers, could up-regulate genes that foster tumor formation. Interestingly, TET protein loss also provokes expression of inflammatory factors that trigger autoimmunity, suggesting that restoring normal TET protein function could have both an anti-autoimmune or anti-cancer effects.

Crossing Barriers
Specific to MS, an ongoing question is how autoimmune T cells, which are usually kept out of the brain by an impenetrable vascular network known as the blood-brain barrier, gain entry into the central nervous system in the first place. LJI’s Catherine Hedrick, Ph.D., recently discovered that T cells are granted access to that protected space by other immune cells and by macrophages, a subset of immune cells better known as the immune system’s cleanup crew.

Working in a mouse model of MS, she found that macrophages emit a siren song of chemical signals that attract autoimmune T cells to the central nervous system and act to exacerbate inflammation and disease severity. Analysis of a small pilot study of patients with multiple sclerosis confirmed that the same communications channels may be used to send communiqués between the brain and immune system in human subjects.

FACULTY MEMBERS

Amnon Altman, Ph.D.
Michael Croft, Ph.D.
Catherine “Lynn” Hedrick, Ph.D.
Anjana Rao, Ph.D.

From The Lab

May 24, 2016 // Multiple Sclerosis News Today

New research center at UC San Diego to focus on microbiome and immunology

Nov 2, 2015

The innate immune system modulates the severity of multiple sclerosis

Nov 19, 2015 // Neurology Advisor

Macrophages, monocytes amplify neuroinflammation in multiple sclerosis