Although the cause of MS is not known, it is generally believed that environmental factors (possibly viral infections) trigger an immunologically mediated process in individuals of a certain genetic background. Genetic factors involved in disease susceptibility probably consist of multiple interacting genes.

Because current theories favour the idea that MS is an immunologic disease, a brief review of the immune system is important. The normal function of the immune system is to recognise and repel foreign invaders, such as bacteria, viruses, and other foreign substances (antigens). Normally, the immune system recognises “self” components and does not destroy them by mistake. An “autoimmune” disease occurs when this system fails to recognise a “self” component as such and attacks it. In the case of MS, strong evidence points to a mistaken attack on the myelin that surrounds most neurons.

Almost 60 years ago it was shown that injections of brain extracts in animals would make some of them develop an inflammatory disease of the central nervous system called experimental allergic encephalomyelitis (EAE). This disease was quite similar to one that was accidentally produced in some humans with an old preparation of rabies vaccine containing fragments of myelin. Post-rabies vaccine encephalomyelitis, in turn, was quite similar pathologically to occasional forms of postinfectious encephalomyelitis appearing in a few unlucky children after naturally occurring measles, rubella, chickenpox, and occasionally other viruses.

Postinfectious encephalomyelitis in humans is not a recurrent disease; it occurs only once. Later it was shown that a chronic relapsing form of EAE could be produced in some genetically susceptible animals. These animals recovered from attacks of paralysis only to develop symptoms weeks or months later in a manner similar to development of MS symptoms. Moreover, pathologic changes in the CNS of such animals are quite similar to those seen in MS.

However, there are important differences between MS and chronic EAE. The antigen is clearly myelin or a myelin component in EAE; the antigen in MS is still unknown. Another important difference is that EAE is easily inhibited and suppressed by a number of drugs that seem to have little impact on MS. A recent observation that the presence of antibodies to myelin antigens at the time of the initial clinical presentation (e.g., in the setting of a “clinically isolated syndrome”) increases the chances of an early conversion to clinically definite MS needs to be validated.

The immune system is complex. Its basic units are two kinds of white blood cells located in the thymus, spleen, and lymph nodes. These cells circulate to all parts of the body by way of the blood and the lymph. The larger cells are macrophages (Greek: “big-eaters”). They function by engulfing and disposing of debris. They also secrete chemicals known as proteases, which are capable of destroying myelin, prostaglandins, and free oxygen radicals, which, in turn, have profound effects on inflammation and immune function. The smaller cells are lymphocytes and they come in several varieties. B lymphocytes are processed in the bone marrow and become antibody-producing cells. The more numerous T lymphocytes are processed mostly in the thymus gland. They become activated when exposed to an antigen to which they are reactive; the cell becomes metabolically more active, enlarges, and secretes a group of chemicals called cytokines. Some of the functions of cytokines are to promote enlargement of lymphocyte populations, activate macrophages, increase blood flow and edema of tissue, and attract other types of white blood cells to the area. Interferon gamma is one such cytokine secreted by activated T cells. This substance facilitates antigen recognition, and its use in the treatment of MS has been associated with an increase in the frequency of exacerbations.

Current evidence suggests that cytokines can basically be divided into pro-inflammatory cytokines, such as tumour necrosis factor (TNF-alpha), and interferon gamma (IFN-gamma), which may be directly responsible for tissue damage in MS, and anti-inflammatory cytokines, such as interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor beta (TGF-beta), which suppress or inhibit disease.

Many B lymphocytes also exist in and around the MS plaques, but they are relatively uncommon in the cerebrospinal fluid (CSF). They are the source of local immunoglobulin production. Immunoglobulins are antibodies, but in the case of MS the target antigen is unknown, and efforts to find the antigen by studying the antibodies have been largely unsuccessful so far.

It has been clearly established from neuropathologic studies of MS lesions that it is against this background of inflammatory cells and cytokines that active demyelination takes place. Traditionally, inflammation and demyelination are considered to be the hallmark of MS lesions (MS is often listed as an “inflammatory demyelinating disease”). Recent studies, however, have reemphasised the importance of damage to the neural cells themselves (“axonal damage”) as a major correlate of permanent clinical deficits.

Therapeutic approaches aim at utilising the increased level of understanding of the immune system; for example, by administering anti-inflammatory cytokines to patients with MS or by developing strategies that inhibit pro-inflammatory cytokines. However, the complex network of the immune system with mutually interdependent factors and mechanisms, which can vary between different phases of the disease, limits the ability to predict the effect of an immune intervention once it is given to a patient. Additional complexity is introduced by the emerging pathologic heterogeneity of MS that apparently encompasses a spectrum from highly destructive cellular lesions and demyelinative processes with or without significant cellular involvement, to primary oligodendrogliopathies.

Given our limited understanding of disease pathogenesis in general, and in a given person with the disease, concrete therapeutic advances in MS are critically dependent on clinical trials. Because of the highly variable and unpredictable course of the disease and the difficulty in precisely measuring neurologic disability, these trials traditionally require large numbers of patients and long periods of follow-up.