What Causes MS? Scientists have learned a great deal about MS in recent years; still, its cause remains elusive. Many investigators believe MS to be an autoimmune disease-one in which the body, through its immune system, launches a defensive attack against its own tissues. In the case of MS, it is the nerve-insulating myelin that comes under assault. Such assaults may be linked to an unknown environmental trigger, perhaps a virus. The Immune System To understand what is happening when a person has MS, it is first necessary to know a little about how the healthy immune system works. The immune system - a complex network of specialized cells and organs - defends the body against attacks by "foreign" invaders such as bacteria, viruses, fungi, and parasites. It does this by seeking out and destroying the interlopers as they enter the body. Substances capable of triggering an immune response are called antigens. The immune system displays both enormous diversity and extraordinary specificity. It can recognize millions of distinctive foreign molecules and produce its own molecules and cells to match up with and counteract each of them. In order to have room for enough cells to match the millions of possible foreign invaders, the immune system stores just a few cells for each specific antigen. When an antigen appears, those few specifically matched cells are stimulated to multiply into a full-scale army. Later, to prevent this army from overexpanding, powerful mechanisms to suppress the immune response come into play. T cells, so named because they are processed in the thymus, appear to play a particularly important role in MS. They travel widely and continuously throughout the body patrolling for foreign invaders. In order to recognize and respond to each specific antigen, each T cell's surface carries special receptor molecules for particular antigens. T cells contribute to the body's defenses in two major ways. Regulatory T cells help orchestrate the elaborate immune system. For instance, they assist other cells to make antibodies, proteins programmed to match one specific antigen much as a key matches a lock. Antibodies typically interact with circulating antigens, such as bacteria, but are unable to penetrate living cells. Chief among the regulatory T cells are those known as helper (or inducer) cells. Helper T cells are essential for activating the body's defenses against foreign substances. Yet another subset of regulatory T cells acts to turn off, or suppress, various immune system cells when their job is done. Killer T cells, on the other hand, directly attack diseased or damaged body cells by binding to them and bombarding them with lethal chemicals called cytokines. Since T cells can attack cells directly, they must be able to discriminate between "self" cells (those of the body) and "nonself" cells (foreign invaders). To enable the immune system to distinguish the self, each body cell carries identifying molecules on its surface. T cells likely to react against the self are usually eliminated before leaving the thymus; the remaining T cells recognize the molecular markers and coexist peaceably with body tissues in a state of self-tolerance. In autoimmune diseases such as MS, the detente between the immune system and the body is disrupted when the immune system seems to wrongly identify self as nonself and declares war on the part of the body (myelin) it no longer recognizes. Through intensive research efforts, scientists are unraveling the complex secrets of the malfunctioning immune system of patients with MS. Components of myelin such as myelin basic protein have been the focus of much research because, when injected into laboratory animals, they can precipitate experimental allergic encephalomyelitis (EAE), a chronic relapsing brain and spinal cord disease that resembles MS. The injected myelin probably stimulates the immune system to produce anti-myelin T cells that attack the animal's own myelin. Investigators are also looking for abnormalities or malfunctions in the blood/brain barrier, a protective membrane that controls the passage of substances from the blood into the central nervous system. It is possible that, in MS, components of the immune system get through the barrier and cause nervous system damage. Scientists have studied a number of infectious agents (such as viruses) that have been suspected of causing MS, but have been unable to implicate any one particular agent. Viral infections are usually accompanied by inflammation and the production of gamma interferon, a naturally occurring body chemical that has been shown to worsen the clinical course of MS. It is possible that the immune response to viral infections may themselves precipitate an MS attack. There seems to be little doubt that something in the environment is involved in triggering MS. Genetics In addition, increasing scientific evidence suggests that genetics may play a role in determining a person's susceptibility to MS. Some populations, such as Gypsies, Eskimos, and Bantus, never get MS. Native Indians of North and South America, the Japanese, and other Asian peoples have very low incidence rates. It is unclear whether this is due mostly to genetic or environmental factors. In the population at large, the chance of developing MS is less than a tenth of one percent. However, if one person in a family has MS, that person's first-degree relatives-parents, children, and siblings-have a one to three percent chance of getting the disease. For identical twins, the likelihood that the second twin may develop MS if the first twin does is about 30 percent; for fraternal twins (who do not inherit identical gene pools), the likelihood is closer to that for non-twin siblings, or about 4 percent. The fact that the rate for identical twins both developing MS is significantly less than 100 percent suggests that the disease is not entirely genetically controlled. Some (but definitely not all) of this effect may be due to shared exposure to something in the environment, or to the fact that some people with MS lesions remain essentially asymptomatic throughout their lives. Further indications that more than one gene is involved in MS susceptibility comes from studies of families in which more than one member has MS. Several research teams found that people with MS inherit certain regions on individual genes more frequently than people without MS. Of particular interest is the human leukocyte antigen (HLA) or major histocompatibility complex region on chromosome 6. HLAs are genetically determined proteins that influence the immune system. The HLA patterns of MS patients tend to be different from those of people without the disease. Investigations in northern Europe and America have detected three HLAs that are more prevalent in people with MS than in the general population. Studies of American MS patients have shown that people with MS also tend to exhibit these HLAs in combination-that is, they have more than one of the three HLAs-more frequently than the rest of the population. Furthermore, there is evidence that different combinations of the HLAs may correspond to variations in disease severity and progression. Studies of families with multiple cases of MS and research comparing genetic regions of humans to those of mice with EAE suggest that another area related to MS susceptibility may be located on chromosome 5. Other regions on chromosomes 2, 3, 7, 11, 17, 19, and X have also been identified as possibly containing genes involved in the development of MS. These studies strengthen the theory that MS is the result of a number of factors rather than a single gene or other agent. Development of MS is likely to be influenced by the interactions of a number of genes, each of which (individually) has only a modest effect. Additional studies are needed to specifically pinpoint which genes are involved, determine their function, and learn how each gene's interactions with other genes and with the environment make an individual susceptible to MS. In addition to leading to better ways to diagnose MS, such studies should yield clues to the underlying causes of MS and, eventually, to better treatments or a way to prevent the disease.