Multiple Sclerosis: The Role of Cytokines and Therapeutic Applications Abstract: Multiple Sclerosis (MS) is a chronic autoimmune neurological disease that debilitates an estimated 2.3 million people worldwide (“What is MS,” n.d.). With no identifiable cause and a cure yet to be discovered, emphasis must be placed on advancing treatments and therapies. Although its pathogenesis is not completely understood, researchers are well aware that the immune response during MS revolves around inflammatory mediators called cytokines. Over the last few decades, substantial progress has been achieved in MS research and knowledge of cytokines in MS has considerably increased, allowing for the development of numerous drugs, including the successful Glatiramer …show more content…
Acetate and Interferon-Beta. In order to improve the lives of MS patients, future research should continue to focus on the interaction between cytokines and effective drugs. Key words: Multiple Sclerosis, Cytokines, Glatiramer Acetate, Interferon-Beta Introduction: Multiple Sclerosis dates to the Middle Ages, as drawings and descriptions indicate characteristics of the now recognized disease (Rolak, 2016, p.2). However, it was Professor Jean-Martin Charcot who initiated and promoted serious further study. In 1868, Charcot analyzed a young woman presenting unique symptoms, and after her death, examined her brain, while carefully noting down his observations and findings (Rolak, 2016, p.2). Since then, scientists have shown dedicated interest into unraveling the mysteries of MS. With the discoveries of an animal model of MS (experimental allergic encephalomyelitis), the founding of the The National MS Society, and laboratory advancements, scientists were able to build a stronger comprehension of the disease and begin clinical trials. The etiology of MS is still not understood, but various conjectures point to environmental, genetic, or viral components. The disease exists in four clinical factors: relapsing remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (Loma & Heyman, 2011). All forms of the disease are progressive, but only RRMS is characterized by periods of relapse and remission throughout the entirety of the disease (“What is MS,” n.d.). Patients often experience symptoms such as changes in vision, changes in bladder function, and sensory loss. Treatment for MS must focus on several aspects of the disease in order to ameliorate the lifestyle of the MS patient. Disease modifying medications work to slow down the progression of the disease, while also reducing relapses and exacerbations (“What is MS,” n.d.). These medications often contain immunomodulatory, immunoregulatory, and neuroprotective properties to reduce disease activity. For serious relapses, corticosteroids are often employed, and to manage symptoms, a large number of drugs are available (“What is MS,” n.d.). Lastly, the patient is recommended to go through rehabilitation therapy, as many cognitive and motor functions are weakened (“What is MS,” n.d.). Pathogenesis and progression: Cytokines: In general, cytokines are secreted proteins that aid in cell to cell interaction (Zhang et.al.
2007). However, in context to the body’s immune response, cytokines are inflammatory molecules that rush to the site of infection or injury with the goal of influencing the inflammation process (Yarlagadda et. al. 2009). During both the innate and adaptive immune responses of MS, the effector function of T cells is significantly altered, as both toll-like receptors and antigen presenting cells trigger T cells to differentiate into Th1, Th2, or Th17 phenotypes. When polarized to these phenotypes, the T cells begin to secrete the pleiotropic cytokines, thus making T cells the predominant producer of cytokines (Loma & Heyman, 2011). Cytokines can be categorized into two broad categories: proinflammatory and anti-inflammatory; many, however, evidently share properties from both groups. While proinflammatory cytokines, secreted by Th1 and Th17 cells, work to promote inflammation and “launch the immune response,” anti inflammatory cytokines, secreted by Th2 cells, work to counteract the proinflammatory response and “block or dampen the immune response.” (Yarlagadda et. al. 2009). Throughout the course of MS, both proinflammatory and anti inflammatory cytokine levels are upregulated; proinflammatory cytokine levels are greater during relapse and antiinflammatory cytokine levels are greater during remission (Martins et. al 2015) (Amedei et. al. 2012). Despite this knowledge however, it has been found that even proinflammatory cytokines hold protective properties, as inflammation is a protective mechanism (T. Makar, Interview, December 22, 2016). Therefore, both categories of cytokines are vital to the immune response. However, attempting to restore the balance between the two during a relapse may reduce the intensity and duration of the
relapse. Proinflammatory cytokines include interleukin-12 (IL-12), interleukin-17 (IL-17), and tumor necrosis factor alpha (TNF-a). Anti-inflammatory cytokines include interleukin-1 receptor antagonist (IL-1ra), interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin-11(IL-11), interleukin-13 (IL-13), and transforming growth factor (TGF-B) (Opal et al. n.d.). Interleukin-6 (IL-6) and interferon-gamma (IFN-y) are prime examples of cytokines that displays both proinflammatory and anti-inflammatory properties. Proinflammatory Cytokines: Interleukin-17 (IL-17) IL-17 is a Th1 cytokine whose immunopathogenic function can be simply put as contribution to the progression of Multiple Sclerosis. This cytokine is produced by TH17 cells, mainly driven and expanded by interleukin-23, another proinflammatory cytokine of the same family (Amedei et. al. 2012). Immunohistochemistry staining shows a strong positive correlation between chronic lesion areas and levels of IL-17. Some studies argue, however, that IL-17’s properties are overexpressed and abundant, and thus redundant in the CNS, as they are shared among multiple cytokines of the TH17 family; this was come to a conclusion after a study that exampled no further development of EAE in mice with all IL-17 genes versus IL-17 deficient mice and IL-17F deficient mice (Haak, et. al. 2008). Interleukin-12 (IL-12) IL-12 is a proinflammatory t-helper type 1 cell (TH1) and is significantly upregulated during the pathogenesis of Multiple Sclerosis (Martins et. al. 2015). IL-12 effectively induces IFN-y (widely regarded as a proinflammatory cytokine) through T cells. Numerous studies using EAE have also demonstrated that IL-12 promotes the Th1 response (“Handbook of Multiple Sclerosis”, 2001, p.654). To clarify, Th1 responses produce the proinflammatory responses and limit the anti-inflammatory response, which is known as the Th2 response. Th2 cells attempt to counter the Th1 response, thus the balance of proinflammatory and anti-inflammatory cytokines comes into play again (Berger, 2000). Studies performed on IL-12 indicated the critical role of IL-12 in the pathogenesis of Multiple Sclerosis, as IL-12 knockout mice (mice without the interleukin-12 gene) showed resistance to EAE induction (“Handbook of Multiple Sclerosis”, 2001, p.654). Interleukin-18 (IL-18), another proinflammatory cytokine in the same family of cytokines as IL-12 displays similar immunoregulatory functions as IL-12, “IL-18, or IFN-y inducing factor, is a cytokine that shares structural features with the IL-1 family of proteins and functional properties with IL-12” (“Handbook of Multiple Sclerosis”, 2001, p.654). Interferon-gamma (IFN-y) INF-y is an immunomodulatory cytokine that examples a Th1 cytokine that also displays anti-inflammatory properties in the pathogenesis, although is is widely regarded as solely a proinflammatory cytokine (Arellano et. al. 2015). In his work, Arellano explains that initially, numerous studies highlighted IFN-y’s proinflammatory role; IFN-y is associated with lesions of demyelination and treatment against it ameliorated progression and symptoms (2015). Further studies, however, have found that IFN-y also holds neuroprotective properties as well, and in respect to the progression of Multiple Sclerosis, IFN-y regulates EAE by controlling the infiltration of macrophages and neutrophils in the CNS, as well as potently inducing nitric oxide (Arellano et. al. 2015). These functions result in two effects on the progression of the disease: an inhibition of T cell proliferation and a suppression of EAE. As it pertains specifically to the stage of Multiple Sclerosis, IFN-y furthers the progression of the disease during a relapse or exacerbation, but suppresses the disease during the recovery phases (Arellano et. al. 2015). Ultimately, IFN-y has been proved to be both beneficial and detrimental during the progression of MS, and more research must be conducted to establish whether it is a viable target of treatment. Tumor Necrosis Factor- alpha (TNF-a) TNF-a is another Th1 cytokine that also holds numerous anti-inflammatory properties. It affects the blood brain barrier by increasing endothelial permeability, aiding in demyelination, and damaging oligodendrocytes (Martins et. al. 2015). TNF-a has also been established as having a key role in exacerbating the inflammation process. Despite its inflammatory processes, however, TNF-a also may be responsible for certain anti-inflammatory functions. For one, the altered permeability of the blood brain barrier may actually be beneficial as it increases the production of IL-10 and downregulates IL-12 (Magnano et. al. 2004). Additionally, some studies have shown a possibility the TNF-a soluble receptor being neuroprotective of the CNS (Magnano et. al. 2004). Such conflicting studies suggest the difficulty in establishing a definite relationship between TNF-a and Multiple Sclerosis. Current research, concerning TNF-a as a target, is focused on TNF-a antagonists. TNF antagonists are TNF inhibitors that are often used during MS related therapies. Anti inflammatory Cytokines: Individual Cytokines Role in disease Glatiramer Acetate Mechanisms of Action Effect on levels of cytokines Interferon-Beta Mechanisms of Action Effect on levels of cytokines Future Outlook Emphasis must be placed on treatment for future research in treatment.
Multiple sclerosis (MS) is a disease affecting the myelination of the central nervous system, leading to numerous issues regarding muscle strength, coordination, balance, sensation, vision, and even some cognitive defects. Unfortunately, the etiology of MS is not known, however, it is generally thought of and accepted as being an autoimmune disorder inside of the central nervous system (Rietberg, et al. 2004). According to a study (Noonan, et al. 2010) on the prevalence of MS, the disease affects more than 1 million people across the world, and approximately 85% of those that are affected will suffer from unpredictably occurring sessions of exacerbations and remissions. The report (Noonan, et al. 2010) found that the prevalence of MS was much higher in women than in men, and that it was also higher in non-Hispanic whites than in other racial or ethnic groups throughout the 3 regions of the United States that were studied.
So what is happening chemically to the people with MS? The disease is an Autoimmune which this will destroy the cells which are in your body. The immune system is going to attack the tissue which it is going to affect the Myelin. When the Myelin is damaged which is when the T cells over react , and cause them to damaged. That is what happens Chemically with MS people.
Around the world, many people are living with neurologically debilitating disorders like multiple sclerosis. Multiple sclerosis is best described as a pathological “inflammatory-mediated demyelinating disease of the human central nervous system,” and affects more than 2.5 million people globally (Trapp & Nave, 2008).
Just like lupus, Multiple sclerosis is a chronic immune system disease that affects the central nervous system. The cause of this condition is unknown; however, some of the causes are violent trauma to the head or spinal cord, and or an immune system attack, which causes the body to attack the myelin sheaths around the neurons in the ascending and descending pathways and most of all genetic and environmental factors. Rosner (2008) notes that, multiple sclerosis is the common cause ...
According to National Multiple Sclerosis Society, Multiple Sclerosis (MS) is an unpredictable, often disabling disease of the central nervous system (CNS) that disrupts the flow of information within the brain, and between the brain and body. The central nervous system (CNS) comprises of the brain and the spinal cord. CNS is coated and protected by myelin sheath that is made of fatty tissues (Slomski, 2005). The inflammation and damage of the myelin sheath causing it to form a scar (sclerosis). This results in a number of physical and mental symptoms, including weakness, loss of coordination, and loss of speech and vision. The way the disease affect people is always different; some people experience only a single attack and recover quickly, while others condition degenerate over time (Wexler, 2013). Hence, the diagnosis of MS is mostly done by eliminating the symptoms of other diseases. Multiple sclerosis (MS) affects both men and women, but generally, it is more common in women more than men. The disease is most usually diagnosed between ages 20 and 40, however, it can occur at any age. Someone with a family history of the disease is more likely to suffer from it. Although MS is not
Multiple sclerosis is a chronic degenerative disease of the central nervous system, in which the myelin that covers the nerves is somehow eaten away and scar tissue for multiple sclerosis in its place, interrupting the nerve’s signals. This disease has an unpredictable and uncontrollable course which leads to the loss of vision, hearing, speech, the ability to walk, control of bladder and bowels, sensitivity to touch, vibration and pain, potency and coordination of movements. The list of possibilities is lengthy and horrifying.
Primarily, the term MS refers to a chronic disorder that attacks the central nervous system (CNS). It is most common in temperate continents such as Europe and Australia with Asiatic and African continents having a lower risk of the disease (Wiley Online Library, 2013). A search organised by the Multiple Sclerosis Society (2013) has estimated that there are 127,000 people living with MS in the United Kingdom. Further research by Chipps, Clanin, and Campbell (1992, pp. 158-167) shows that MS disorder more likely affects women than men with its symptoms occurring between the ages of 20 and 40 in most cases and is quite uncommon in childhood and old age. The nerve cells known as neurons in the brain constantly transmit and receive signals. They invoke emotions, activities and cognition that constitute the day to day experiences of humans. Under normal circumstances, these signals travel on a protected insulation path known as the myelin sheath. This insulation is vital as it enables signals to reach their target. In Multiple Sclerosis, the myelin sheath gets disintegrated causing the nerve fibre to be damaged leading to a disruption in the abili...
Multiple Sclerosis (MS) is a debilitating autoimmune disease. The Central Nervous System (CNS) is attacked by the immune system; creating lesions that interrupt the correct signaling of nerves, spinal cord, and brain (Frankel, & James, 2011). Inhibiting development of this disease is crucial for maintaining quality of life and fatigue for individuals with MS. There has been vast amount of research on the effect of various exercise training programs, and their benefits for MS (Motl, & Gosney, 2008, Krupp, 2003, Chen, Fan, Hu, Yang, & Li, 2013). Balance, aerobic, and strength training have been the main focus of most researchers; causing an interest in what training mode is most effective for improving quality of life and lower fatigue. It is critical to examine and contrast the effectiveness of a variety of exercise programs, because if training is completed effectively it can drastically improve quality of life and fatigue for individuals with MS.
Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system, directed against the myelin sheath. Leading to demyelination and axonal loss. It’s characterized by spread “plaques” of demielinization typically found in typically found on MRI in the periventricular region, corpus callosum, centrum semiovale and, to a lesser extent, deep white – structures and basal ganglia.(Olek, 2005)
... resulting impairment to the CNS. The first group of mice exhibited a pattern of CNS inflammation that resembled that of the most common subtype of MS, RRMS, with lesions filled with macrophages, a type of immune defender cell. The second group of mice displayed inflammation deep in the CNS tissues and in the optic nerve with lesions filled with neutrophils, another type of immune cell. Both groups of mice were given antibody drugs similar to drugs being developed against MS in humans. The effects were observed over time and results showed that some of the drugs inhibited disease in the first group of mice but did not inhibit disease in the second group. Thus, as Mark Kroenke (2008), the study’s first author and a Ph.D. student in immunology at U-M stated, "That's our proof that these really are different mechanisms of disease" (Kroenke et al., 2008).
It is also estimated that approximately two and half million people are living with the disease... The name multiple sclerosis refers to the scars that are present in the brain and spinal cord is seen on an MRI. An autoimmune disorder is where a person’s immune system mistakes its own white blood cells as invaders and begins to attack itself damaging healthy body tissue. In these types of disorders, the immune system cannot tell the difference between healthy cells and antigens, which are foreign invaders like bacteria and viruses. Because of the damage, it does to the nerve cells; nerve signals can either slow down or stop completely. Inflammation, or the body’s reaction to infection, is what causes this nerve damage to happen. Multiple sclerosis is most commonly seen in the brain, optic nerve, and spinal cord and often leads to physical and cognitive
Multiple Sclerosis (MS) is a complicated chronic deteriorating disease that has an effect on the central nervous system (CNS). This disease causes destruction of the myelin around the nerve fibers. “The exact etiology of Multiple Sclerosis is unknown; however, it is thought to be an immune mediated disease. MS is characterized by CNS inflammation, demyelination, and axonal loss” (Compston & Coles, 2008). Typically, it is described by early relapses and remissions of neurological signs of the CNS. This is known as relapsing-remitting MS (RRMS). MS can be identified by a variety of known risk factors. Multiple Sclerosis can be brought on by a mixture of inherited and environmental risk factors such as smoking or an exposure to a virus like Epstein Barr. The inflammatory process has an interesting role on the central nervous system.
Multiple Sclerosis is a disease of the brain and central nervous system that is potentially disabling. Multiple Sclerosis, commonly called MS, is a disease where the immune system attacks to protective myelin sheaths that cover the nerve fibers, which causes communication problems between the brain and the rest of the body. The disease can cause the nerves themselves to be damaged, either temporarily or, in some cases, permanently. MS is a disease that has the natural tendency to remit spontaneously. MS is an unpredictable disease that is rare and hard to treat as there is currently no cure. However, although there is no cure many of the people who are diagnosed with MS do well with no therapy as there are many medications to help with the
Multiple Sclerosis is a nervous system disease that affects the spinal cord and the brain by damaging the myelin sheaths that protects nerve cells. Destroyed myelin prevents messages from communicating and sending properly from the brain, through the spinal cord, to internal body parts. In the United States, more than 350,000 people are diagnosed with this disease. Anyone can get this disease, but it is more common among Caucasian women. MS symptoms begin between the ages 20-40 and are caused by nerve lesions being present in multiple areas of the Central Nervous System, symptoms differ on the lesion’s location.
Multiple sclerosis is an immune mediated disease, although many researchers argue it is an autoimmune disease. MS causes the body to create an abnormal immune response to the Central Nervous System (CNS). The CNS is the body’s processing center. It consists of the brain, spinal cord and peripheral nerves. The axon of these nerve cells are coated with a myelin sheath, a fatty substance that surrounds the nerve endings. This sheath protects and insulates the axons allowing electrical impulses to pass freely from one nerve cell to the next. MS causes the body’s immune system to produce T-cells that pass from the bloodstream and into the central nervous system. The T-cells directly attack the nerve cells as if they were a foreign substance. They destroy the myelin coating around nerve fibers. When any part of the myelin is damaged scar tissue forms around the nerve ending. This demyelination and scaring causes lesions on the nerves. The lesions prevent impulses from traveling throughout the body and hinders the body’s response to afferent and efferent signals being sent to and from the brain.