Cover Story: The MS Process and Targets for Treatment
A look at the immune system in MS and disease-modifying therapies
Written by Susan Wells Courtney and Jack Burks, MD
The disease processes occurring with MS are both complex and confounding. Over the past century, details about this disease have been ever-changing, as larger, more rigorous trials and better technology have led to new findings and a greater understanding of what takes place within the central nervous system of individuals with MS.
Much of what researchers have learned comes from observations of lesions (or plaques) in the brain, the hallmark feature of MS and the reason behind the name “multiple sclerosis,” meaning “many scars.” Lesions are areas of inflammation along the nerves in the brain and spinal cord. When the inflammation remits, these areas of damage may either partially repair or form a permanent scar.
While very early studies relied on post-mortem examination of the brain and lesions for initial clues about the disease, highly advanced diagnostic tools and procedures are able to give scientists an inside view of the intricate components found with the lesions and surrounding areas of the brain and spinal cord. In addition to improved magnetic resonance imaging (MRI) techniques, other technical advancements include magnetization transfer imaging (MTI), spectroscopy, and functional imaging. Analysis of the spinal fluid is also helpful in showing evidence of the disease process taking place.
Where Does MS Damage Occur?
Of the countless variables involved, scientists know that MS is a chronic condition, whose effects are limited to the central nervous system (CNS), consisting of the brain, optic nerves, and spinal cord. The areas of inflammation, damage, and scarring, are referred to as lesions (or plaques). These are most often found in periventricular regions (around blood vessels) of the brain, but also occur in the optic nerves, brainstem, and spinal cord.
The effects of MS in the brain are also more far-reaching than originally thought. Axons, which are the wire-like nerve fibers with a protective myelin covering, are found in the white matter of the brain. This is where lesions are usually found and the damage was thought to be limited to this area. Normal-appearing white matter (NAWM) refers to areas of white tissue in the brain that occur around and between lesions. An axon is just one part of the entire CNS nerve cell, called a neuron, which also has a cell body. The neuron’s cell body is usually in the gray matter of the brain, which is a layer of cells covering the white matter. The effects of MS are now known to reach many areas of the brain, including white, gray, and normal-appearing white matter.
The damage seen in MS lesions was initially believed to involve only the myelin of the CNS. Myelin is a fatty protein that serves as a protective covering to the nerves that carry messages to and from the brain. These nerves are similar to electric wires, with their ability to carry electrical impulses and their need for a protective covering, so no electrical impulses are lost. Newer studies found that damage to the nerves (or axons) themselves occurs early in the disease, frequently in advance of any clinical (outward) symptoms experienced by the patient. This damage to the myelin and axons is what causes the many symptoms associated with MS.
MS is often “clinically silent,” meaning that disease activity is taking place internally, while no new signs or symptoms of the disease are experienced externally, i.e., clinically. In addition to outward symptoms and changes in function, disease activity is measured by the number, size, and inflammation of lesions, as seen on an MRI.
Types of MS
The majority of patients (85 percent) begin with a relapsing-remitting form of MS (RRMS). With this type, individuals experience symptom flare-ups (also referred to as “exacerbations” or “relapses”), lasting from a few days to a few months. Corresponding flare-ups of inflammation and lesion formation may be viewed on an MRI. These are followed by a complete or partial remission, which for many, can last for months or years.
This remission can be deceptive, however, because of the clinically silent aspect of MS. Lesion flare-ups and inflammation within the CNS occur at least 10 times as often as clinical attacks. Without the benefit of an MRI, patients and medical professionals can only identify outward symptoms and clinical attacks, and are not aware of the degree of disease progression within the CNS.
Without treatment, many people with RRMS will eventually advance to secondary-progressive MS (SPMS). They may either experience relapses with less recovery, or have no relapses at all. Primary-progressive MS (PPMS) patients (10 percent of the MS population), have fluctuations of symptoms, but no documented relapses. Progressive-relapsing MS (PRMS) patients (less than 5 percent of the MS population), experience progression from the beginning, but also have superimposed relapses. Progression indicates a gradual course of nerve degeneration, with less involvement of inflammation in the disease process.
MS Inflammation and Degeneration
The damage seen with MS appears to be an integrated two-part process, involving both inflammation and degeneration. Acute relapses result from acute inflammation and axonal demyelination. Disease progression reflects neurodegenerative processes, such as axonal/neuronal damage and brain atrophy.
Much of the disease process is thought to be caused by inflammation – which is the body’s natural defense against disease and foreign bodies. Inflammation occurs as disease-fighting cells, such as T and B lymphocytes, as well as other components of the immune system, wage an attack on the invaders. Since the mid-1900s, researchers have found evidence to support the idea that MS is an autoimmune disease – one in which the body’s own immune system attacks the body – in this case, the myelin and nerves of the CNS. To reach the CNS, the lymphocytes must cross the vital blood-brain barrier (BBB), a wall that lines the blood vessels and normally prevents such damaging cells from entering the brain and spinal fluid.
If MS is an autoimmune disease, some unidentified factor has caused the immune system to become activated and misdirected. Such a cause is still a mystery, although evidence grows to support a number of different possible theories. A complex genetic predisposition appears to be involved, with a slightly increased risk for close family members.
Environmental factors also come into play. Among others, these include: how far a person lives from the equator and one’s lack of exposure to vitamin D (naturally derived from sunlight and certain foods); cigarette smoking, pollutants, and other toxins; various diets, including a high intake of saturated fats and/or a low intake of fish oils; as well as viral or bacterial infections. With regard to viral infections, the Epstein-Barr Virus (EBV) appears to have the most evidence as a possible trigger for MS, perhaps following several years of dormancy. Most people are exposed to EBV, a common herpes virus that is often asymptomatic in children. However, EBV can cause mononucleosis in approximately half of the adolescents and adults affected.
Molecular mimicry is one possible reason for the immune system’s attack in MS. This could happen when a foreign protein entering the body has a very similar structure to the myelin’s fatty protein structure. As the T cells are activated and target the foreign protein for destruction, they become misdirected and also attack the myelin. Such a case of mistaken identity would explain why the body’s own myelin and CNS are under attack. Viruses may initiate an autoimmune disease in this fashion. Examples of viruses with a similar structure to myelin include measles, influenza, Epstein-Barr Virus (EBV), and other herpes viruses.
A recent theory explores a possible connection between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS). CCSVI is a complex condition involving a decrease of blood flow from the brain back to the heart, which some researchers theorize could possibly lead to activation of the immune system, excess iron deposits, loss of myelin, and other nervous system damage. (This theory and related studies are discussed in the Research News column of this issue of The Motivator.)
For many years, with the assumption that MS is an autoimmune disease, the inflammation (brought on by the body’s immune system) was thought to come first, followed by resultant degeneration (or damage) caused by this inflammation. New studies have found some evidence that this order may be reversed. This would mean that the degeneration may occur initially, followed by inflammation in an effort to fight whatever is causing the initial damage.
Details from a study in Sydney, Australia, were published in the article, “Multiple sclerosis: distribution of inflammatory cells in newly forming lesions.” (Henderson AP, Barnett MH, Parratt JD, Prineas JW; Annals of Neurology, 2009 December; 66[6]: 739-53.) In this study of 26 active lesions from 11 patients with early MS, the researchers found that the lymphocytes involved in inflammation are absent from early lesions. These lesions showed loss of oligodendrocytes (cells that make myelin) as well as areas of degenerate and dead myelin, along with myelin phagocytes (cells that clean away the dead myelin). Conversely, areas of complete demyelination were “packed” with lymphocytes and other immune-system cells creating inflammation. Some of these advanced lesions also had oligodendrocytes, working to regenerate myelin.
The findings from this study suggest that inflammation may not be the first step in the formation of lesions, and destructive cell-mediated immunity does not cause the initial damage to myelin or oligodendrocytes. The autoimmune response may be a reaction to the damage, and not the cause of the initial attack. If this theory holds true, it will mean that some other factor is causing the initial damage and formation of lesions, and the MS process is not initiated by an autoimmune attack on the CNS. Any of the suspected causes listed earlier may still play a role. More research is needed to confirm these findings, but this study is another important piece in the complex puzzle of MS research and treatment development. If this new theory is correct, current disease-modifying therapies (DMTs) would still be helpful.
Disease-Modifying Therapies
A number of disease-modifying therapies (DMTs) have been developed to interrupt the different stages of the disease process, in an effort to minimize inflammation and lesions, clinical attacks, and the progression of disability. Targets include reducing inflammation and damage by blocking the action of lymphocytes, redirecting the attack of these immune-system cells, preventing these cells from crossing the BBB into the CNS, or other therapeutic strategy. Some of these DMTs have been in use since the early 1990s and have been shown to reduce relapses, slow disease activity, and delay the progression of disability.
These drugs have been of tremendous help to many individuals with relapsing forms of MS, but their use is limited. For instance, not everyone responds to the treatments presently available, particularly individuals with progressive forms of the disease who do not experience disease flare-ups. Side effects, such as flu-like symptoms or injection-site reactions, may prevent some individuals from being able to tolerate these treatments. Others may not have adequate insurance coverage needed to afford these treatments. Additionally, newer drugs used as DMTs have severe adverse events associated with them, and patients must be closely monitored.
Despite any limitations of the presently approved long-term treatments for MS, they still hold great value for many members of the MS community in delaying or preventing disease activity. Most of the DMTs have an excellent safety profile after many years of use, which is reassuring for those on long-term therapies. And the good news for everyone is the fact that research continues at an exciting pace. New details about the disease are constantly being discovered, which provide new targets for treatment.
Dozens of experimental drugs and treatments are under development, with several in later-stage clinical trials. While the presently approved DMTs are given via self-injection at one’s home, or through infusions at medical facilities, several oral medications are now being studied. Gilenia (FTY720) and oral Cladribine are two drugs presently being reviewed by the United States’ Food and Drug Administration (FDA), while other oral drugs are in late-stage clinical trials.
The Immune System and MS
The Body’s Defense
The body’s defense against disease and infection is the immune system. It is incredibly complex, and using an analogy, it may be thought of as an army of soldiers who are ready at a moment’s notice to defend against any invader that may pose a threat to the body’s good health. This army has many members who play different roles.
Of course, the system includes plenty of disease-fighting warriors who attack invading viruses, bacteria, other foreign bodies, or malignant cells involved in cancer (all of which are known as “antigens”). It also has cells that act like generals to instruct the soldiers when to go to battle, as well as those that act like military police, or “MPs,” who tell the warriors when to settle down and when to retreat. The body’s defense system even has “detectives” which circulate throughout the body, searching for any invaders that do not belong there. This wonderful policing system helps to keep people healthy throughout their lives. Without the immune system, a person would not survive a simple infection.
The members of the defense system’s army are constantly aware of what they recognize as “self,” and what they recognize as “non-self.” This system is designed to protect the tissues and organs which are a natural part of the body – and are recognized as “self.” Its army of soldiers circulates through the blood system in a peaceful manner, and the soldiers are kept away from vulnerable areas of the brain and spinal fluid by the blood-brain barrier, which lines the walls of the blood vessels.
When a non-self entity is spotted, such as a virus, bacteria, or foreign tissue from a transplanted organ, the army is called to action. When this happens, many types of cells, molecules, chemicals, and proteins are produced – all in an effort to rid the body of the foreign invader. The fighters rush to the area of infection, causing inflammation and swelling at the site of attack.
This is where the system becomes quite complex and specialized, as messages are passed from cell to cell. Adhesion molecules work like a key to open the blood-brain barrier (BBB) and allow the disease-fighting soldiers into the fragile CNS, giving them access to the brain and spinal fluid. Chemicals bind to the foreign antigen through matching receptors, and these foreign antigens are then presented by “antigen presenting cells,” or “APCs,” to the immune system cells, or soldiers, so they may recognize and destroy them.
Macrophages are cells that are constantly on “KP duty,” and they are sent in to clean up what is left of the destroyed enemies. And while this war is being waged on the invading entity, tissues recognized as “self” are normally protected and remain untouched. Confusion arises if a foreign antigen looks too much like “self” tissue.
With autoimmune disorders, the body’s defending army malfunctions and perceives certain “self” tissue as the enemy. It may be a case of mistaken identity, or molecular mimicry, where the cells of the immune system initially locate an antigen (foreign invader) which happens to have a similar molecular structure to a part of the body’s own tissue.
If not mistaken identity, the attack could be a result of overly aggressive soldiers (immune system cells), or perhaps those cells designed to suppress the aggressiveness of the fighter cells are short in supply, or not doing their job. Genetic factors are thought to be involved with the malfunction, and other causes such as a defect in the myelin, could also play a role.
Another area of interest concerns astrocytes, which are star-shaped cells found in the nervous system. These are believed to be involved with different functions, including the conduction of nerve impulses and response to injury. The potentially changing role of astrocytes and MS is being researched intensely by some scientists.
A great deal is known about the immune system, but researchers do not know if the immune system’s initial attack is the “cause” or a secondary “effect.” All agree that the immune system plays an important role in MS and current FDA-approved treatments are advantageous in most patients.
Features of the Immune System
The immune system is extremely complex and includes far too many components to mention all of them in this article, so to follow are some important features of the immune response. Many of these terms are identified in articles on the approved disease-modifying therapies for MS, as well as emerging therapies in clinical trials.
The defense system is set up to respond to a foreign entity (or antigen) in two different ways. The first type of reaction is the innate immune response, and the second type of reaction is the adaptive immune response. The actions of both responses are needed to work together for the best protection against foreign entities and disease.
The “innate” or “natural” immune response is nonspecific. It does not have any type of memory, and reacts in the same way each time it encounters a foreign entity, such as a virus or bacteria. Even if the exposure is to the same germ, the innate response has no memory and its reaction will not change. This type of immune response is quick to react to a foreign invader and is first on the scene to protect the body.
Several types of “soldiers” take part in this initial attack. They include neutrophils, monocytes, and macrophages. They work by engulfing and digesting foreign invaders (a process known as “phagocytosis”), and they also clear up dead cells and debris. Natural killer (NK) cells destroy the enemy by rupturing the plasma membrane. This destruction is known as “cell lysis.”
The “adaptive” or “active” immune response is specific. While this type of defense initially responds slowly, it has a memory, and with each repeated exposure, the reactions become faster and stronger. The adaptive immune response reacts with both T-cell and B-cell lymphocytes, also referred to as T cells and B cells.
The different classes of T cells secrete chemicals or mature into cells that regulate other cells, helping to either increase or decrease inflammation. To become activated, T cells require an antigen-presenting cell (APC) to present the foreign antigen; otherwise, the T cell cannot recognize it. The APCs must break the antigens down into smaller pieces, and some of these smaller pieces are associated with genetically determined major histocompatibility complex (MHC) proteins in the APC. T cells are only able to recognize foreign antigens when they are with MHC proteins on the surface of APCs.
CD4+ and CD8+ cells are the two main types of T cells. Here is where the recognition of the MHC proteins on antigen-presenting cells (APCs) comes into play. CD8+ T cells only recognize class I MHC proteins (expressed on almost all nucleated cells). The CD8+ cells can then implement the direct destruction of the foreign antigen. CD4+ T cells only recognize class II MHC proteins (expressed on specific APCs, such as macrophages, dendritic cells, and B cells).
When activated, the CD4+ cells differentiate, or mature into four different subsets of T cells: (1) Th1 cells are pro-inflammatory and secrete cytokines IL-1, IL-2, interferon (IFN) gamma, IL-15, tumor necrosis factor alpha (TNFA), and other elements; (2) Th3 cells are anti-inflammatory and secrete cytokines IL-4, IL-5, IL-6, IL-10, and IL-13; (3) Th17 cells are pro-inflammatory and produce the cytokine IL-17 and other elements; (4) T-regs are regulatory; they are able to suppress the function of pro-inflammatory T cells; In this manner, T-regs help to protect against autoimmune disorders.
Many immune-system cells secrete cytokines and chemokines. Cytokines are small proteins that may stimulate or inhibit the function of other cells. They connect to specific receptors found on the surface of cells, and send messages from one cell to another. More than 100 cytokines have been discovered within the past decade; they include interleukins (IL); interferons (INF); tumor necrosis factor alpha (TNFA), transforming growth factor (TGF), and more.
Chemokines are very small cytokines that direct the T and B cells to areas where inflammation or injury is taking place. Scientists have found more than 50 chemokines, and these are categorized into families, identified as C, CC, CXC, and CX3C.
The complement system is another important part of the immune response. This system has many proteins which circulate as inactive molecules, and become activated once the immune system’s antibodies have joined up with invading antigens (foreign bodies). From here, the “complement cascade” begins, increasing inflammation. Normally, this mechanism is helpful in eliminating foreign antigens. In MS, they can be misdirected to damage normal “self” brain tissue.
B cells produce immunoglobulins (Ig), which are usually antibodies aimed at fighting disease and infection. Immature B cells interact with T-helper cells to mature into memory B cells (where Ig is expressed only on the surface), or plasma cells (which secrete large amounts of Ig). This ensures a rapid response to recurrent foreign antigens. Recently, the role of B cells has been recognized as a major factor in the formation of MS lesions.
An Overview of the MS Process
Much MS research has focused on the development of the MS lesion. The process is believed to originate from activation of CD4+ cells specific for myelin antigens in genetically susceptible individuals. This activation enables these cells to enter the CNS through changes in the BBB. Activated T cells migrate into the CNS across the BBB through a step-by-step process, which includes binding to the vascular cell adhesion molecule-1 (VCAM1).
Once in the CNS, the T cells are then reactivated when they recognize myelin antigens on the surface of local APCs. This triggers pro-inflammatory cytokine release and a cascade of events leading to the formation of an inflammatory, demyelinating lesion. Many other cell types are included in the process, such as CD8+ cells, B cells, activated macrophages, microglial cells, complement, immunoglobulin antibodies, and more. A lack of sufficient T-reg cells, which usually keep the immune system from over-reacting, also contributes to lesion development. In active MS lesions, a perivascular infiltration of CD4+ cells, CD8+ cells, monocytes, and B cells occurs, with the eventual appearance of macrophages. Both Th1 cells and Th17 cells promote inflammation, while Th3 cells reduce inflammation.
MS Targets and Treatments
Targets for MS treatments include the many components and functions of the immune system response. In general, treatments have been developed to reduce or deplete those cells and other agents that promote inflammation and/ or damage the CNS. Examples of these include T cells, B cells, monocytes, macrophages, dendritic cells, leukocytes, chemokines, cytokines, complement, and others. Specific targets for reducing inflammation include shifting the response from Th1 (pro-inflammatory) to Th3 (anti-inflammatory) as well as the enhancement of T-regulatory cell function.
Interrupting this chain of events also includes preventing the damaging cells from entering the CNS through the BBB. Researchers approach this by developing methods to limit the number of T cells circulating in the blood system, so they do not cross the BBB. Another approach is to interfere with the recognition of the adhesion molecules, so T cells cannot bind to them and subsequently pass through to the CNS.
In addition to the treatments which are FDA approved or in development to limit or stop the MS process, treatments are also being developed for neuroprotection and remyelination. Such strategies would protect the axons and myelin from further damage, and could potentially return lost function for individuals with MS. The future looks bright as science continues to discover more about the immune system and MS.