Multiple sclerosis is a devastating disease of the central nervous system. The disease effects over 350,000 people in the United States. Multiple sclerosis is a progressive autoimmune disease that is characterized by relapsing and remitting states that leads to greater and greater degree of disability caused by the disease. Disability that is caused by a patientís own cells attacking their body.
The autoimmune response for the disease state in Multiple Sclerosis is an attack upon the myelin sheath of the central nervous system. The myelin sheath lines the axons of neurons within the brain. Normally a nerve impulse is transmitted down the axon due to the creation of an electrogradient inside the cell by the action of ion channels. The myelin sheaths act as an insulator, preventing the leakage of ions out of the axon. Since the electrogradient is easily maintained once it is created, the nerve impulse travels at greater speed. In Multiple sclerosis the lack of insulation leads to nerve impulses traveling at greatly reduced speeds, to the point of signal disruption. This signal disruption leads to the patients being unable to control their own bodies. (Compston)
What begins the autoimmune response in multiple sclerosis is unknown. Some studies have pointed the finger at bacterial or viral infection. Other studies have indicated genetic factors in the actions of the disease. Research has indicated that there are multiple factors in the cause of the disease. (Compston) Whatever the cause, the disease begins when a T cell is activated and recognizes the proteins along the myelin sheath. Once the T cell is activated it is able to pass through the brain blood barrier. In the brain the T cell stimulates the response of monocytes/macrophages by releasing INF-g (Fig1). The antigen in the illustration being presented by the T cell
and the signaling between the two cells leads to an attack on the oligodendrocytes of the myelin sheath. The oligondendrocytes form the myelin sheath by wrapping their cytoplasmic extensions around the axon, the same way fingers wrap around a pencil when you grasp one in the palm of your hand. Macrophage/monocyte damages the oligendrocytes by release of antimicrobial chemicals. Leading to the demyelination of the axon.
Because of the autoimmune nature of the disease, researchers have looked for a treatment that would suppress the immune system. That insight lead to the use of interferon beta as a treatment for the disease. INF-b has been successful in the reduction of the number of episodes of relapse and the severity. Research into the mechanism of INF-b indicated IL-12 as a main factor. This was shown from experiments with knock out mice and experimental allergic encephalomyelitis (EAE). EAE is the mouse model for multiple sclerosis. To determine the effect of INF-b on EAE, mice had the genes for select cytokines "knocked out" (disabled). The knockout IL-12 mice were found to be resistant to EAE. (Segal)
In humans, INF-b was found to have comparable results to experiments in mice. The effect of INF-b was found to induce a decrease in the production of IL-12. (Byrnes) Levels of IL-12 were observed using immunoassay with tagged antibodies. Thus IL-12 is a major factor in the mechanism of multiple sclerosis.
Interleukin 12 is an immuneregulatory cytokine. Interleukin 12 is made up of two chains, the alpha and Beta chains. So named because the beta chain contains beta sheath and the alpha is made up of alpha helices. The beta chains is bigger and research
has shown that it is the reactive part of the cytokine. Interleukin 12 is produced by antigen presenting cells of the immune systems. Antigen presenting cells include dendritic cells and macrophages.
The main function of Interleukin 12 is in an inflammatory immune response. Part of that function is to signal the differentiation of naïve T cells (T cells that have never come into contact with an antigen) into Th1 cells or inflammatory T cells. The name is due to the inflammatory products that the Th1 cells secrete. Th1 cells increase macrophage and monocyte, activation by the production and release of INF-g. The presence of INF-g also recruits more macrophages to come to the area of infection, leading to inflammation of the area. Th1 cells further stimulate the production of complement proteins by B cells. Complement is a protein cascade that leads to the production of a membrane attack complex that lyses the cell. IL-12 not only activates Th1 cells but the continuing presence enhances the abilities of the cells. Which is effective in an infection but devastating in an autoimmune response. (Segal)
Because of the actions of IL-12, the body must control the production and release of the cytokine. The production and action of Interleukin 12 is controled by the action of Interleukin 10. The two cytokines have a cyclic relationship with one antagonistic to the action of the other. Interleukin 10 is responsible for the differentiation of naïve T cells into Th2 cell. Th2 cells are mainly involved in the activation of B cells to produce antibodies. Figure 2 shows the release and effects of IL-12 during an immune response. IL-12 inhibits the action of IL-10 and leads to amplification of the immune response. At the same time that IL-12 inhibits IL-10, the receptors for IL-10 on immune cells are increased. This allows a release of IL-10 to have greater effect and inhibit the actions of IL-12 at the completion of the immune response. The initial release of either IL-12 or IL-10 is determined by the nature of the invader. (Segal) (Janeway)
Interleukin 12 and MSThe progressive nature of the disease is due to the memory of the immune system. The immune system has the ability to remember the structure of antigens from the invaders it has dealt with. This so-called adaptive immunity allows the immune system to be able to identify and produce the necessary remedy for recognized invaders. In multiple sclerosis, after the initial attack, the myelin sheath is recognized by the immune system as an invader. To begin a new attack only the activation of T cells have to occur. So increased levels of IL-12 have a high probability of beginning the relapsing phase of the disease.
IL-12 has the added effect of inhibiting the Fas mediated lymphocyte apoptosis. Which is an apothosis pathway that is controled by the Fas receptor. (Janeway) Normally a T cell that recognized a self-antigen would be signaled by a Fas binding protein, to begin apoptosis. IL-12 stimulation protects the cell from this effect. In the case of an active immune response against an invader this would prevent T cells involved from being destroyed before the full completion of the immune response. In multiple sclerosis, IL-12 prevents the destruction of the self-recognizing T cells.
Increased Secretion of IL-12
Increased levels of IL-12 were correlated to different disease states of multiple sclerosis. (Van Boxel-Dezaire) Increased levels of IL-12 corresponded to increase damage being observed by magnetic resonance imaging (mri). The levels of mRNA for the IL-12b subunit, where measured to indicate IL-12 levels. The researchers used PCR to amplify the mRNA IL-12b subunit and electrophoresis to compare the amount present within the sample to normal levels. Increased levels of IL-12 positive monocytes were found to correspond to new lensions produced in the brain, as observed by MRI. (Makhlouf) The researchers separated monocytes from blood drawn from multiple sclerosis patients. The cells were lysed and the contents were tagged by antibodies specific for IL-12. The contents were then sorted and counted by a flow cytometer. Both studies show increase IL-12 levels during times of disease relapse. (Makhlouf) (Van Boxel-Dezaire) Other studies have focused on other aspects of IL-12 immune effects.
IL-12 Receptor and MS
Not all research into the disease effects of Multiple Sclerosis has shown a correlation of between presence of IL-12 and disease states. (Onzeni) In the absence of an increase in IL-12 levels over control the researchers decided to look at the levels of the IL-12 receptor on T cells. What they found is that the levels of the receptor were increased. If IL-12 levels remained the same but, receptor levels increased this would increase the potency of IL-12. (Onzeni)
Low IL-10 Levels
Low IL-10 levels in turn leads to higher IL-12 levels. Research has shown that low IL-10 production is related to a genetic polymorphism in the IL-10 gene promoter. The researchers found the defect to be most extreme in cases of progressive Multiple Sclerosis. The researcher even went on to conclude that those having the defect are more susceptible to the onset of Multiple Sclerosis. (De Jong)
From the current research, IL-12 is indicated to be a major factor in the disease activity of multiple sclerosis. This information will allow movement towards better treatments. These new treatments will be developed from knowledge of the actions of IL-12s within the immune system. The obvious choice for a new treatment would be IL-10, due to its antagonistic effect on IL-12. Another approach could be inhibiting the IL-12 receptor. Further research will have to be carried out to gain a greater understanding of the cytokines involved in the autoimmune response of Multiple Sclerosis.
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Copyright © 2002 Joshua Corey and Koni Stone
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