This author proposes to approach the subject of immunology of multiple sclerosis (MS) from the standpoint of available acute and disease-modifying therapies (DMTs) and currently known immunologic targets for them.

This seems to be a sound approach because historically this vision point has helped to shape and direct our knowledge on MS immunology and has developed and enriched the field over the years.

Another good reason to adopt this approach is its immediate applicability. By engaging this view, we learn not only MS immunology but also how various different medications work. And we not only learn how they work (in other words, mechanism of action or MoA of DMTs) but also come very close to understanding their potential efficacy, risks, and side effects. This strategic approach will serve well in understanding emerging MS therapies.

Unlike many other diseases of the immune system, such as lupus, psoriasis, or rheumatoid arthritis, MS has a single target, and that is myelin. Therefore, we do not expect to see multiple different tissues involved—the
immune system and central nervous system (CNS) are the fields where the events take place.

Contrary to many patients’ beliefs, MS is not a disease of a “weak” immune system; it is a disease of a mistaken immune system. In fact, immune reactions in MS can prove to be very strong, leading to remarkable CNS inflammatory reactions and subsequent damage. But the initial “intentions” of the activated immune system are “good”; it intends to “protect” the human, the host. There is a hypothesis of strong initial inflammatory reaction, which leads to cascades of delayed events in the immune system; for example, one may have had an episode of acute infection, such as, for example, mononucleosis, which made a particularly strong and lasting impression on the immune system, and ever since that episode the immune system gets itself activated trying to find the offending agent, virus or bacteria, for weeks, months, or even years and decades after this particular infection is over. The overzealous protective efforts may get so intense that even mere resemblance to the offending antigen (e.g., the encounter of biochemical structures similar to the structures of relevant viral molecules) may be sufficient to trigger a very strong and destructive immune reaction. The most acute form of inflammation in MS clinically presents itself as a relapse or exacerbation.

Particular environmental factors may predispose to ongoing immune reactions to produce the disease. In addition to the aforementioned infectious exposure, lower levels of vitamin D, increased salt intake, genetic predisposition, obesity, and tobacco exposure seem to contribute to the process.

Initially intended as a protective mechanism, reactive inflammation fails to curb itself to a reasonable or adequate intensity, and chronic progressive disease develops.

As mentioned earlier, the singular target in MS is myelin represented specifically in the CNS, and MS is one of the most prominent CNS demyelinating conditions.

As the term suggests, demyelination is the key component of this disease. As you recall, myelin is a layer of “insulation” surrounding the central nerve fiber or axon. Every fragment of myelin is built by several layers of a single oligodendrocyte, a CNS cell that rolls its own body and membranes around the axon multiple times, thus creating the myelin. It is remarkable that myelin of the CNS is principally different from that of the peripheral nervous system; the latter is built by Schwann cells and the peripheral myelin is not a target for MS. Therefore, peripheral neuropathies are rarely seen in patients with MS, unless those are comorbid or in other words independently developed. As a side note: remember that the only “nerve” directly involved in MS is the optic nerve, but it is not a peripheral nerve per se; it is in fact a “continuation” or “processes” of the brain.

Destruction of myelin is a result of inflammation, which can be acute, subacute, and/or chronic. The three conditions can overlap and coexist. Acute inflammation tends to coincide with the first event of MS or subsequent MS relapses (acute exacerbation) and/or new, active, or enlarged MS lesion formation. Events leading to inflammation targeting myelin usually start outside of the CNS and where the main representation of immune system tends to be, in hematolymphatic system. Mature activated lymphocytes in their search of a potential target encounter the blood-brain barrier (BBB) and gain an increasingly strong ability to cross it; subsequently, they enter the CNS. Activation of the lymphocytes and increased permeability of the BBB result from antigen presentation by the antigen-presenting cells, increased production of proinflammatory cytokines, involvement of the complement cascade, and increased differentiation of activated aggressive lymphocytes.

Thus, the activation of the immune process is initiated systematically, resulting in migration of activated immune cells into the CNS where they get reactivated and their interactions result in parenchymal inflammation; the acute inflammation in MS may be focal, multifocal, or diffuse and is characterized by infiltration of activated lymphocytes, macrophages, and microglia, with involvement of cortex, white matter, and deep gray matter with myelin destruction; axonal, neuronal, and synaptic loss; astroglial reaction; remyelination; and synaptic rearrangement.

Indeed, the experimental studies on the intimate mechanisms of action of the approved or developing drugs for relapsing-remitting MS (RRMS) provide a strong foundation for understanding the immunology of MS. Deregulated immune response, including inflammatory cells (e.g., T cells, B cells, macrophages) and immune mediators (e.g., cytokines, chemokines, matrix metalloproteinases, complement), contributes to the expansion of autoreactive T cells; proinflammatory shifts promote BBB lymphocyte and monocyte extravasation. It was found that activation of B cells of patients with MS may contribute to increased BBB permeability. Regulatory T cells (Tregs) normally control the intensity of an immune response; however, their regulatory function in patients with MS is dramatically impaired. Remarkably, the immunomodulatory role of Tregs and their suppressive capacity are more affected in the early stages of the disease. Consistent with this, there are differences in function and expression of FOXP3 (a master regulator in the development and function of regulatory T cells). Disease exacerbation of MS is also associated with loss of the differentiated autoregulatory CD8+ T cells. The regulatory cell dysfunction in patients with RRMS is especially profound during MS exacerbations as compared with the remission periods or in healthy controls. It was observed that, for example, proinflammatory Th17 cell expansion in patients with MS is counterbalanced by an expanded CD39+ regulatory T cell population during remission but not during relapse. Regulatory B cell (Bregs) subsets were found to be higher during relapse as compared
with patients with non-clinically active MS. There is a growing body of evidence that antibodies play an important role in the pathobiology of MS and MS relapse; IgG antibodies purified from a patient with MS and transferred to mice with experimental autoimmune encephalomyelitis caused a dramatic clinical improvement during relapse after selective IgG removal, whereas passive transfer of patient’s IgG exacerbated motor deficits in animals. These data provide evidence for a previously unknown mechanism involved in immune regulation in acute MS.

Destruction of myelin leads to exposure and increased vulnerability of the axons. According to the data by Bruce Trapp, the number of transected axons increases with the level of activity in MS lesions, and in active MS lesions can be more than 11,000. Transected axons indicate permanent damage. Conglomerates of transected axons form permanent CNS lesions, which subsequently advance the brain tissue volume loss.

Brain tissue loss is the strongest morphologic correlate with MS disability progression. Therefore, the famous sentence “time is brain” so actively and successfully used in stroke neurology has its specific relevance to MS as well, with the only difference that, in stroke, time means minutes and hours and in MS, time means weeks and months. The sentiment, however, is the same: Do not delay the start of treatment.

As mentioned earlier, the knowledge on MS immunology grew together with the continuous and ongoing introduction of different DMTs for MS treatment. The mechanism of action of different treatments for MS targets specific “key players” as discussed earlier.

Let us review the targets.

As we remember, increased permeability of the BBB allows activated aggressive lymphocytes to travel from the bloodstream and into the CNS (brain, spinal cord, or optic nerves).

High-dose systemic steroids and adrenocorticotrophic hormone, two Food and Drug Administration (FDA)-approved options for immediate treatment of MS relapse, are known to dramatically reduce the BBB permeability among their other direct and indirect anti-inflammatory functions, helping them to significantly shorten prolongation of disturbing symptoms associated with MS exacerbation.

While we are on this relevant subject, let us discuss specifically the specifics of MS relapse treatment.

Relapses (exacerbations, attacks, or flares) are a hallmark of MS and are often associated with significant functional impairment and decreased health-related quality of life. For the vast majority of patients with MS, relapses are the central concern and provoke most of the fears and uncertainty associated with the disease. The unpredictability of MS exacerbations only adds to the notoriety of this entity.

The generally accepted definition of an MS exacerbation is a new or worsening neurologic deficit lasting 24 hours or more, in the absence of fever or infection.

The symptoms associated with MS relapse represent activation of any demyelinating lesion or lesions located in any segment of the CNS; therefore, there may be a broad variety of different signs (which may or may not replicate previously experienced episodes).

In general, the most commonly seen symptom complexes are related to new or worsened inflammatory processes involving the optic nerves, spinal cord, cerebellum, and/or cerebrum. Thus, the symptoms may present alone or as a combination of visual disturbances, motor and sensory impairments, balance issues, and cognitive deficits.

It is important to rule out symptoms that mimic exacerbations but that do not represent new damage to the nervous system. These pseudoexacerbations are caused by an uncovering of older symptoms due to Uhthoff phenomenon (overheating shortens the duration of action potentials, leading to electrochemical transmission failure along demyelinated axons); common causes include fever, infections (most commonly seen urinary tract and upper respiratory infections), and exposure to significant temperature extremes.

Usually the natural course of most of MS exacerbations completes itself with a period of repair leading to clinical remission and, sometimes, especially early in the disease course, to a complete recovery; however, the residual deficit after an MS relapse may persist and contribute to the stepwise progression of disability.

There are many reasons to treat an MS relapse:

1. Treatment of MS relapses is important because it may help to shorten and lessen the disability associated with it.

2. Successful treatment of MS relapse has another important psychological aspect: it helps to establish good physician-patient relationship and to develop in patients with MS a feeling of trust that they may be able to take control over their disease.

The history of acute relapse treatment in MS reflects well the history of what we know about MS and how the knowledge evolved. In the early 20th century, the treatment of choice for an acute MS relapse was bed rest. In 1978, the first medication for MS relapse treatment was approved—adrenocorticotropic hormone, or ACTH.

The presumption that the efficacy of ACTH gel results solely from its corticotropic effects later led to the acceptance of high-dose corticosteroids for MS exacerbation treatment. However, more recent data in other disease states (e.g., nephrotic syndrome, opsoclonus-myoclonus, and infantile spasms) provide clinical evidence that steroidogenic actions fail to fully explain the efficacy of ACTH gel in these conditions. In addition, research into melanocortin peptides and their receptors argues against the
long-standing belief that the beneficial effect of ACTH depends solely on its ability to stimulate the release of endogenous corticosteroids and suggests that further exploration of how best to use ACTH in MS should be considered. The melanocortin system has many diverse functions in the human body, including melanogenesis, glucocorticoid production, control of food intake and energy expenditure, control of sexual function, behavioral effects, attention, memory, learning, and, important for MS, neuroprotection, immune modulation, and anti-inflammatory effects. The description of the melanocortin system and the recognition of the other proposed mechanisms of action of ACTH may help to explain the renewed interest in ACTH.

As mentioned previously, in the 1980s focus shifted to intravenous methylprednisolone (IVMP) as the preferred treatment option for MS relapse.

Low dosages of systemic steroids were found to be ineffective in MS, and the dosages from 500 mg to 1 g of IVMP per day became widely accepted and the preferred regimen.

Ever since ACTH and corticosteroids have been used to treat MS relapses, it was observed that some cases may not respond to these treatment options.

Several alternatives, including plasmapheresis, cyclophosphamide, or intravenous immunoglobulin were attempted, but it seems that only the plasmapheresis option is supported by strong evidence. In 2011, American Academy of Neurology guidelines recommended plasmapheresis for severe MS exacerbations not responding to the first-line treatments.