Mar. 8, 2000 Scientists at Emory University School of Medicine have uncovered a significant connection between mast cells -- a type of immune cell -- and the development of multiple sclerosis, an auto-immune disease that attacks the central nervous system. Until now, research into the mechanisms of multiple sclerosis (MS) has been focused almost exclusively on errant responses by immune T cells that attack the body's own tissues.
The new discovery, made in a mouse model of MS that is very similar to the human form of the disease, provides an entirely new perspective on how nerves are damaged in this disease. It holds particular significance because extensive research already has led to the development of drugs that effectively block the action of mast cells in other diseases. The Emory discovery was reported in the March 5 issue of the Journal of Experimental Medicine. Emory University pathologists Melissa A. Brown, Ph.D. and Ginny Secor, a doctoral student in Dr. Brown's laboratory, pieced together several parts of a research puzzle to develop their hypothesis that mast cells are linked to MS. Dr. Brown's earlier work focused on the regulation of cytokine gene expression in T and mast cells. Cytokines are proteins that act to orchestrate signals between immune cells
In multiple sclerosis, genetic and/or environmental factors are thought to cause the immune system to mistakenly attack the protective myelin sheath that insulates nerve cells. This results in patchy scarring, or plaques, that impair communication throughout the central nervous system. Although not fatal, multiple sclerosis causes progressively debilitating symptoms in many of its victims, decreasing life expectancy by an average of six years. Problems include weakness, numbness, infections and difficulty performing mental tasks. There is no cure for the disease, and only a few drugs can slow its progression. MS affects approximately 1.1 million people worldwide, including nearly 350,000 Americans. Symptoms usually begin between 15 and 40 years of age.
The investigators first realized that many of the cytokines implicated in MS are produced by mast cells. Next, they uncovered little-known research showing that mast cells are prevalent in the central nervous system. They then linked this finding to their knowledge that mast cells not only produce cytokines but also are major producers of proteases‹enzymes that have been shown in the laboratory to have profound effects on degrading the myelin sheath that lines nerves.
Now believing that mast cells might play a key role in MS development, Dr. Brown and Ms. Secor tested their hypothesis using a type of mutant mouse that is deficient in mast cells. They injected myelin proteins designed to induce the mouse counterpart of multiple sclerosis, a disease called experimental allergic encephalomyelitis (EAE). The mice exhibited significantly reduced disease incidence, delayed disease onset and decreased mean clinical scores as compared to normal control animals. After reconstituting the deficient mice with mast cells, disease susceptibility and severity were restored to the levels observed in the normal mice.
"Clinicians and most researchers have not seriously considered the potential role of mast cells in multiple sclerosis, so we are particularly excited about these findings," said Dr. Brown, especially because mast cells have been well studied in the respiratory tract and the skin as effector cells in hay fever, asthma and atopic dermatitis. In allergy and asthma, compounds such as cromolyn sodium antihistamines have been developed that can either block the release of mast cell mediators or block their activity."
Dr. Brown does not dismiss the fact that T cells play a significant role in MS as well, perhaps with the help of mast cells. "Mast cells may be influencing the development of a type of T-cell that causes the destruction of the myelin sheath," she points out. "They also may be releasing agents in the central nervous system such as histamine, which we know causes vasodilation (leaking of the blood vessels). This in turn could open up the blood/brain barrier, which is normally resistant to large influxes of immune cells, and thus allow destructive T-cells easy access into the central nervous system. Mast cells also release proteases that could directly damage the myelin sheath. We now know that mast cells are located in close proximity to blood vessels in the central nervous system."
A big question remains, explains Dr. Brown, as to whether drugs already used to treat respiratory tract diseases such as allergy and asthma would be effective in treating multiple sclerosis, or would need to be modified in order to gain entry into the central nervous system. In further research funded by the National Multiple Sclerosis Society, Dr. Brown, Ms. Secor and colleagues will now perform similar types of experiments using mast cells with specific genetic alterations to define the mechanism underlying the influence these cells have on the MS disease process.
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