The Pathogenesis of MS
RRMS is a singular disease, characterized by relapsing episodes — at least through the early years — and moving into a progressive form. A small number of MS cases are progressive from the onset. Neurologists now accept the theory that MS involves a faulty autoimmune process that affects the nervous system.
In MS, the body launches an abnormal attack against its own central nervous system, (the brain and the spinal cord). During this assault, myelin — the protective sheath that surrounds and protects the nerve fibers — is damaged. This destruction is termed demyelination. Demyelination is the single most characteristic feature of MS. In this chapter we will discuss:
- Autoimmune Response
- Demyelination
- Distribution of Lesions in the CNS
- Immunopathology of Inflammation
- Remyelination
- Virus Antigen
Autoimmune Response
Scientists now believe that myelin damage most likely results when white blood cells known as T cells launch an attack on protein that makes up myelin. This is called an autoimmune response. For reasons that are not yet fully understood, the body mistakes myelin for foreign (enemy) tissue and attempts to destroy it. In effect, the body is attacking and destroying itself. This damage causes inflammation to the myelin sheath, and sclerotic lesions develop. As mentioned earlier, this process is termed demyelination. Let's talk about it a little more.
Demyelination
The body’s immune system is a built-in defense system that is programmed to protect itself and repair damage that may occur as a result of disease or injury. After myelin damage occurs, oligodendrocytes (cells that synthesize and maintain myelin) and astrocytes (star-shaped cells that define anatomical boundaries, stimulate growth, participate in conduction of nerve impulse, and respond to injury) are dispatched to the scene, and rebuilding begins. This process leaves scar tissue known as gliotic plaques. The resulting lesions, or plaques, thicken and become hard, causing interference with nerve impulses that travel along the nerve cell. This interruption of normal nerve impulses leads to the symptoms that characterize MS.
The type and severity of symptoms are determined by the following:
- Location of sclerotic (hard) lesions
- Size of the lesions
- Number of plaques that are present at any given time
Lesions that are located in the optic (eye) nerve will interrupt messages to the brain and result in blurred vision, while lesions in the brain or spinal cord may cause problems with movement, coordination, or balance. A review of symptoms will follow later in this course.
Let's take a closer look at what happens to oligodendrocytes during demyelination. Oligodendrocytes are cells of the central nervous system (CNS) that synthesize and maintain myelin. In early stages of MS, high numbers of these cells are present and are probably not a target in the demyelination process. In fact, oligodendrocytes that remain after demyelination are thought to be responsible for remyelination, which will be discussed later in this chapter. Loss of oligodendrocytes is a characteristic of chronic (long-term) MS, however, and may be a result of demyelination. Scientists believe the role of oligodendrocytes in remyelination will be a key factor in controlling MS.
Distribution of Lesions in the CNS
It is important to understand that it is possible to have many lesions located throughout the central nervous system at one time, thus the term multiple sclerosis. Plaques are most often found on the outer surface of the brain and spinal cord. These round or oval lesions may have finger-like extensions that grow along vessels in the brain. The largest lesions and the greatest number of lesions are typically located in the forebrain, but the lesion load (the number of lesions per tissue weight) is the highest in the brainstem, the part of the CNS that controls respiration, blood pressure, and heart rate. Spinal cord lesions may be located anywhere throughout the cord, but the highest concentration of these seems to be in the cervical spine.
Immunopathology of Inflammation
Demyelination is accompanied by inflammation throughout the CNS. However, inflammation in the brains of people affected with MS is not limited to areas of demyelination, though it is usually more dense there. Some inflammation is also found in normal gray and white matter.
There has been much disagreement through the years about whether inflammation occurs as a result of demyelination, or rather, as a cause of it. Scientists now believe that inflammation most often is the instigating (starting) component leading to demyelination. In primary progressive MS, the reverse is true: the injury of myelin and the loss of oligodendrocytes is believed to promote subsequent inflammation.
MS experts know that when myelin is damaged, inflammation occurs around the area. Inflammation is the body’s natural response to tissue injury, usually helping to protect the body and promote healing. Inflammation associated with MS, however, is out of proportion to the tissue damage, so this "bad" kind of inflammation associated with MS can cause more harm than the initial autoimmune response that caused it.
Recently, a new theory has emerged that suggests some inflammation may actually protect the myelin from further damage. Researchers have identified what they are calling "good" inflammation in MS. Although inflammation is a complex process, it appears that “good” inflammation can protect myelin from further damage and may even promote remyelination.
The blood-brain barrier is a membrane between circulating blood and the brain that prevents harmful substances from reaching the brain. New MRI studies have demonstrated evidence of a breakdown and inflammation of theblood-brain barrier in patients with MS, thus leading to new insights into the mechanism of inflammation associated with demyelination.
Remyelination
Studies suggest that complete remyelination of MS lesions can, in fact, occur. Unfortunately, studies indicate that it is possible for remyelinated lesions to undergo new attacks of demyelination. Scientists are hopeful that a deeper understanding of remyelination will lead to the development of effective strategies for the treatment of MS.
Virus Antigen
Though a direct role of viruses has not been identified, much speculation exists that viruses may be responsible for triggering the inflammatory response that begins the attack on myelin. Two virus species were isolated in MS patients in studies in 1992 suggesting that no single virus is responsible for MS, but may be a contributing factor in some cases. It is important to be aware that whether the immune response is reactive to a virus antigen or an autoantigen, the pathological outcome of demyelination is likely to be the same.