Multiple Sclerosis

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The central nervous system, or CNS, is a network that sends information between nerve cells. This takes the form of electrical signals traveling along nerve fibres. Imagine it like a rail network, but with billions of trains traveling at a hundred meters per second to reach their destinations. On a rail network, when the tracks are damaged, they can be repaired — but only so many times. Eventually, damage can no longer be repaired, and trains are unable to travel on those tracks. This could negatively affect the network,

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but when a track is closed, the signaller can reroute the trains, and services may be able to carry on as normal. Similarly, in MS, inflammation damages the CNS, which can sometimes be repaired by the body — but when it can't, nerve cells and fibres are lost. This permanent loss of nerve cells and fibres is known as disease progression. Disease progression starts at the very beginning of MS, often before diagnosis, and it happens in all forms of MS, regardless of the form a person has or is diagnosed with.

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Like the trains that can be rerouted onto other tracks, those living with MS may not have disability that is visible to others. This may be because MS affects functions that others cannot see, or because their CNS has ways to hide it. At the start of MS, disease progression can be difficult to detect because the CNS can initially compensate for the loss of nerve cells and fibres with what's called neurological reserve. The CNS does this by sending signals through undamaged areas or adapting undamaged areas to take on new functions,

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in addition to repairing damaged areas. On the rail network, it’s only when all remaining tracks are at full capacity and signallers run out of options that the network starts to experience problems and passengers notice. In the case of MS, when the CNS can no longer compensate for damage, this is the point where symptoms become more noticeable or disability worsens. Because disease progression is a steady but permanent process that can go unnoticed for many years, it is important that those living with MS

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speak with a healthcare provider about disease progression and how to identify and delay it. An MRI can measure the loss of brain tissue, especially when images are compared over time. It can be challenging to accurately measure disease progression early in the disease course. Roche is collaborating with research institutes and other companies to develop novel tools and biological markers to identify and potentially predict the progression individuals might experience in the future. Treatment as early as possible

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with a therapy that impacts progression — not just relapses — is important to minimize the permanent loss of nerve cells and the impact that this disease can have on daily life and the years to come.

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[Music] As you saw in the last video, there's a lot going on behind the walls in MS. Disease-modifying therapies can keep this underlying disease activity in check. In this video, we'll explore why acting quickly on MS disease activity is so important. Inflammation is a major part of disease activity in MS. There are two types of inflammation: chronic and acute. Let's think of inflammation like a waterfall — it's always flowing, just like chronic inflammation is always present in MS.
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After a big rain, the waterfall flows even faster, with much more water falling over the edge. This is similar to acute inflammation, which flares up for a short period of time and then goes away. With both types of inflammation, the water breaks down the rocky earth underneath it — one slower or faster than the other. Once the rock is washed away, it will not come back, much like how both types of inflammation lead to irreversible disability and disease progression in MS.
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Let's take a look at how MS disease progression can impact a person's everyday life. Because MS is a disease of the central nervous system, its effects can potentially be felt in almost every part of the body and can lead to difficulties with everyday activities. Driving is one way a person maintains their independence, but many different MS symptoms can affect driving ability, including muscle weakness, spasticity, pain or numbness in hands or feet, impaired coordination, and slower reaction time.
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MS also affects the mind and the person's ability to think, concentrate, organize, and remember things. This, combined with other symptoms like fatigue, speech, and vision problems, can impact a person's ability to work and remain employed without adaptations. Similar muscle problems that can impair driving also impact a person's ability to walk and to do everyday errands like carry bags at the grocery store.
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Many people with MS experience loss of control of the bladder and intestines, leading to increased or urgent use of the toilet. Although MS can impact a person's independence in many ways, it can also affect relationships with loved ones. MS can directly affect sexual arousal and response, and when compounded with other MS symptoms and emotional factors, may lead to less activity in the bedroom.
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Although MS has the potential to impact every aspect of a person's life, disease progression can be slowed or prevented with highly effective medicines. Studies have shown that there is a greater chance of successfully slowing disease progression if effective medicines are given soon after diagnosis. And that means people with MS can live more days with less disruption.
[Music]

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In our last video, we described how the immune system damages the central nervous system in multiple sclerosis. Now, we'll explore how that disease activity can lead to damage and disability progression.

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Your body is much like a house; many different parts work together to keep the household running. The central nervous system, or CNS, is similar to the electrical wiring in that house. There are about 1,000 kilometers of wiring in your body. Flipping a light switch sends an electrical signal through the wires to turn on the lights, just as your brain sends electrical signals along nerve cells to tell your body what to do.

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The wiring in people with multiple sclerosis, or MS, gets damaged, which can cause it to not work properly. If the wiring continues to be damaged, it can overheat and start to smoke. Sometimes, the effects are noticeable, like flickering lights. Other times, the damage may go undetected, which would be like underlying disease activity in MS, meaning activity that cannot be seen or noticed without an MRI.

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In most people with MS, there are many areas of damage that may grow larger over time. Sometimes, the fire becomes large enough that it can be seen, much like the clinical symptoms people with MS experience during a relapse. Occasionally, the fire burns itself out, and there isn't much damage to the house; this is called remission. Other times, there is permanent damage to the house. In MS, this type of damage usually leads to disease progression and irreversible disability.

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There are multiple ways to help catch ongoing disease activity and protect the CNS in MS. First, let's take a look at one way to monitor disease activity: a brain scan called an MRI, which works much like a smoke detector. It can reveal underlying disease activity that may escape notice.

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Next, let's talk about one way to protect the CNS. Disease-modifying therapies, or DMTs, can act like a fire department that tries to calm the flames and reduce the likelihood of getting worse. The faster the firefighters show up, the less permanent damage there may be to your house.

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Some DMTs are more like electricians. If they're used early enough, they may help protect the wires from damage and reduce the risk of fires from starting in the first place. These high-efficacy medicines may slow disease progression and potentially lessen the risk of a person becoming more disabled.

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Progress in detecting underlying disease activity and protecting against disease progression may lead to better care for people with MS.

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In the first video, we described how multiple sclerosis — or MS — is a disease of the central nervous system. Now, we’ll take a closer look at how the immune system can turn against the central nervous system (CNS) and interrupt communication within the brain and between the CNS and the body.

In healthy people, the immune system is like a team of martial artists that defends the body against enemies such as bacteria, viruses, and even cancer. Much like the different types of martial arts, cells in the immune system

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have different types of defenses.

B cells are one important defender in the immune system. B cells mature, and their jobs change dramatically over time. You can tell what a B cell’s job is by looking at proteins on its outer surface — which are like the differently colored belts worn by martial artists.

B cells begin as stem cells in the bone marrow — like a martial arts training center. Here, they learn how to become defenders and earn their first beginner belts, including CD19 and CD20 proteins. B cells move to different

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training centers like the spleen and lymph nodes to learn to identify the enemy and advance their training. Once they start circulating, B cells are always on the lookout for enemies lurking in the body.

When B cells master their set of maneuvers, some move up the ranks to become plasma cells. Plasma cells have a different uniform — losing their CD19 and CD20 protein belts — much like ninjas. Plasma cells make and use weapons to fight. The weapons plasma cells use are called antibodies, and they always hit their

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intended target.

In MS, two events happen which change how B cells normally work to defend the body against enemy attack.

First, the wall that keeps B cells out of the brain in healthy people breaks down. This allows some B cells to enter the central nervous system.

Second, once inside the CNS, rather than acting as defenders, they — for unknown reasons — begin to attack the body’s own myelin: the supportive insulation around nerve cells.

Plasma cells can use their antibody weapons to attack

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myelin. These antibodies can cause direct damage or act as a homing signal that recruits other defenders in the immune system to attack myelin.

B cells can also inform T cells — another defender — that myelin is the enemy. This type of T cell is like a sensei or trainer that teaches other types of T cells to fight against myelin.

Both B and T cells send signals — called cytokines — to recruit other types of defenders to the fight, which causes inflammation.

B and T cells can also band together to build a training center on the lining of the brain. This allows them

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to continue training and attacking the myelin for a long time.

Scientists discovered that they could target specific B cells that trigger the attack on myelin by making antibody medicines that target the CD20 protein — but not other types of proteins.

Antibodies that target only CD20 do not affect stem cells in the bone marrow, nor the plasma cell "ninjas" that have already been trained to fight specific enemies.

This means that the immune system should still be able to defend the body against harm. Clinical studies have shown that

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antibodies that target the CD20 protein slow disease progression in people with MS — and may potentially become a new treatment approach for people with MS.

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Multiple sclerosis or MS is one of the leading causes of neurological disability, affecting approximately 2.3 million people worldwide. In MS, the peak age of onset is around 30 years, and diagnosis is about two times more likely in women than in men. The symptoms of MS may include weakness in an arm or leg, sensory disturbances such as numbness, tingling, and pain, problems with balance and lack of coordination, fatigue, cognitive impairment, and problems with vision such as blurred or double vision.
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Most patients experience these symptoms as an initial series of recurrent deficits and remissions, which may be followed by progressive and worsening disability. In some patients, disability is continuously progressive from the onset of disease. The symptoms of MS are believed to result from underlying processes of inflammation and neurodegeneration. In particular, the inflammatory process causes destruction of myelin sheaths and axons, leading in turn to disruptions of neurotransmission.
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MS is characterized by increased permeability of the blood-brain barrier, allowing immune cells such as macrophages, T cells, and B cells to infiltrate into the CNS. The traditional view of MS pathophysiology holds that CD4-positive T helper cells react with components of myelin and trigger an inflammatory cascade in the CNS, resulting in demyelination and axonal loss. However, B cells, plasma cells, and excess immunoglobulins are known to be present in both lesions and cerebrospinal fluid of patients with MS. This long-standing recognition has suggested that B cells may also play key roles in the pathophysiology of MS.
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In humans, the bone marrow functions as a primary lymphoid tissue. B cells arise from stem cells in the bone marrow, where they develop to form immature naïve B cells. Further development occurs in the spleen or lymph nodes. At these sites, continuing maturation ultimately gives rise to either memory B cells or plasma cells. Some B cells, said to be autoactive, have the capacity to recognize self-antigens. In healthy individuals, the developmental process includes checkpoints to limit the production of autoactive B cells.
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In MS, some autoactive B cells are able to bypass these checkpoints and grow to maturity. Following chemical signals, it has been shown that autoreactive B cells breach the blood-brain barrier and traffic into the CNS, where they may contribute to MS pathobiology through different mechanisms that initiate and propagate inflammation. Four possible mechanisms of B cell-associated pathophysiology in MS can be described: antigen presentation, antibody production, cytokine regulation, and the formation of new lymphoid structures in the meninges.
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Antigen presentation may play an important role in the immune response. B cells can recognize and internalize specific antigens. Intracellular processing generates fragments of antigen, which are subsequently displayed on the B cell surface. Preclinical models suggest that through antigen presentation and co-stimulation, autoreactive B cells in the CNS may activate T cells for a pro-inflammatory response. B cells also receive activation and proliferation signals from T cells during such interactions.
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Antibodies may be considered key effectors of humoral immunity. Preclinical data indicate that B cells, including autoactive B cells, can differentiate into plasma cells producing antibodies which may bind to myelin sheaths and oligodendrocytes. Bound antibodies can induce the deposition of complement proteins on tissue surfaces, promoting injury. Antibodies may also activate other immune cells, such as macrophages or natural killer cells, to destroy tissue.
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Immune cells coordinate their activity through the release of signaling molecules known as cytokines. B cells release a variety of cytokines, some of which promote inflammation while others may be protective. It has been reported that B cells in patients with MS tend to produce more pro-inflammatory cytokines and less protective cytokines compared with healthy controls.
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In the meninges of patients with progressive MS, B cells may form ectopic lymphoid structures or germinal centers through the process of neo-lymphogenesis. These structures contain activated B cells and follicular dendritic cells in addition to T cells, and may promote ongoing T cell activation within the brain. Ectopic lymphoid structures may be linked to microglial activation, local inflammation, and neuronal loss in the nearby cortex.
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In summary, B cells that target neural structures undergo abnormal development, bypass immune tolerance checkpoints, and may play multiple roles in the pathophysiology of MS. B cells express various surface receptors at different stages of their development. In MS, certain stages of B cell maturation may be crucial to determining the pathogenic activity of B cells.
Current research is investigating whether the selective targeting of receptors expressed at specific stages of B cell maturation may potentially help to eliminate specific B cell subsets, including autoreactive B cell subsets that are pathogenic in MS.
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