Multiple Sclerosis Progression Linked To Immune-cell Substance
A new study suggests that a substance made by immune cells plays a key role in the progression of a disease in animals that closely mimics multiple sclerosis (MS). The findings further suggest that blocking the molecule, known as macrophage migration inhibitory factor (MIF) might prevent the progression of the disease.
Researchers at The Ohio State University Medical Center conducted the study using mice that develop a disease that mimics MS. They compared these animals to similar mice that lacked MIF, an immune-system signaling molecule.
The results show that the animals without MIF develop the initial, acute phase of the disease, but then show no signs of further progression.
The study is published as a Cutting Edge paper in the November 1, 2005, issue of the Journal of Immunology.
“Our results suggest that MIF may be less important for initiating MS, but that it may be necessary for MS progression,” says principal investigator Caroline C. Whitacre, professor of molecular virology, immunology and medical genetics.
“These findings indicate that in the future we can perhaps use MIF levels to predict the onset of a relapse. But more importantly, perhaps this study will lead to drugs that can halt the course of MS by blocking the action of MIF.”
MS is an inflammatory, autoimmune disease which primarily affects the brain and spinal cord. Autoimmune diseases occur when the body's own immune cells destroy tissues in the body. In MS, immune cells destroy the myelin sheath that surrounds nerve fibers in the brain and spinal cord. Myelin is a fatty substance that insulates nerve fibers and enables them to transmit impulses.
According to the National MS Society, about 400,000 Americans are living with MS and about 10,400 new cases are diagnosed yearly. The disease usually strikes between the ages of 20 and 40, and it is more common in women. MS symptoms vary from person to person. Some individuals experience unusual fatigue, numbness and tingling; others can have loss of balance and difficulty walking; still others develop slurred speech, double vision, tremors or bladder problems.
In about 85 percent of cases, MS shows a pattern of remission and relapse, with no warning as to when a relapse will occur.
For this study, Whitacre and a group of colleagues used mice that develop the MS-like condition known as experimental autoimmune encephalomyelitis (EAE). The mice develop the disease after being inoculated with a myelin protein. The researchers compared these mice to mice that were identical except that they lacked the gene for MIF.
After inoculation, the mice with the MIF gene showed progressive EAE. In contrast, the mice lacking the MIF gene showed signs of early disease, but after about 20 days, these mice recovered and showed no further sign of progression.
Along with Whitacre, Abhay R. Satoskar, assistant professor of microbiology; Nicole D. Powell, Tracey L. Papenfuss, Melanie A. McClain, Ingrid E. Gienapp, Todd M. Shawler, all of the Department of Molecular Virology, Immunology, and Medical Genetics, worked on the research.
The study also gave the investigators insights into the mechanism by which MIF influences the course of disease. They found that MIF blocked the steroid hormone, corticosterone (known as cortisol, in humans). Animals missing MIF had high levels of the steroid, while those with MIF showed very low levels.
The level of the steroid hormone, in turn, caused important immune-system changes in the animals that are likely to affect the disease.
For example, the mice with MIF (and low levels of the steroid hormone) showed high levels of immune-system cytokines or products that promote inflammation. Mice that lacked MIF (and had high levels of the steroid), on the other hand, showed high levels of immune-system cytokines or products that suppress inflammation .
“Our evidence overall suggests that the inhibition of this steroid hormone by MIF has an important influence on the immune system and in determining whether the disease progresses or not,” Whitacre says.
Funding from the National Institute of Allergy and Infectious Diseases supported this research.
Source: Ohio State University. October 2005.
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