Principles and Guidelines of Immunotherapy in Neuromuscular Disorders


Among the variety of diseases seen by neuromuscular specialists, immune-mediated disorders generate tremendous interest. These disorders are relatively common and often respond favorably to treatment. The field has become more exciting but has also become more complicated due to the many treatments available as well due to the side effects that can arise from manipulation of the immune system. However, the timely and accurate diagnosis and management of these entities can still be a gratifying experience for both patient and physician. This chapter provides a general overview of the components and function of the immune system and discusses the use of individual therapies aimed at altering the immune response to treat these disorders. Lastly, the available evidence for the use of these drugs in the treatment of select neuromuscular disorders is summarized.

Basics of the Immune Response

The principal function of the immune system is the differentiation between self and non-self and resultant rejection of the latter. When infection with bacterial, viral, fungal, or parasitic organisms occurs, components of the pathogen are recognized by specialized immune cells. The first such cells to come into contact with the invading organism are macrophages and dendritic cells. These cells are able to recognize pathogens using a small number of constitutively expressed receptors called pattern-recognition receptors , such as the Toll-like receptors. Such receptors bind common elements of microorganisms that cause disease (e.g., endotoxin of gram-negative bacteria or lipoteichoic acid of group B Streptococcus ) and help to provide a quick response to a threat but lack the exquisite specificity and plasticity of the adaptive immune system. The role of the innate immune response in human disease, particularly in the development of autoimmunity, is only beginning to be understood ( ; ).

Adaptive immunity refers to the ability of lymphocytes to respond to a specific threat, to amplify the response to that threat, and to retain memory of the threat to quickly respond when reexposure occurs. Antigens, which are molecules that are capable of inducing an immune response, are presented to T lymphocytes via major histocompatibility complex (MHC) molecules. Class I MHC molecules present endogenous antigens, such as those present intracellularly during a viral infection. In contrast, class II MHC molecules are present on antigen-presenting cells, such as macrophages and dendritic cells, and present exogenous (i.e., extracellular) antigens to lymphocytes. In each case, recognition and response occur by binding of the antigen with the lymphocyte’s T cell receptor (TCR) along with the interaction of appropriate costimulatory molecules (e.g., CD28 with CD80). The specificity of the adaptive immune response is due in large part to the vast repertoire of TCRs available. This enormous variety is generated through random rearrangement of the genes encoding for TCRs during lymphocyte development. The result is a unique TCR for each lymphocyte that binds with high affinity to a single antigen.

Once a pathogen is encountered and its antigens are presented to and recognized by a T lymphocyte, an intracellular signaling cascade is initiated that leads to an effective T cell response. The initial events in this signaling cascade consist of hydrolysis of components of the T cell’s lipid bilayer to form inositol triphosphate and diacylglycerol. Diacylglycerol activates protein kinase C, and inositol triphosphate facilitates the entry of calcium into the cytosol. Calcium in turn activates numerous proteins, including calcineurin and several DNA-binding proteins. Calcineurin facilitates the release of interleukin-2 (IL-2), a powerful stimulator of T cell proliferation (discussed later), whereas DNA-binding proteins alter gene transcription. The end result of these changes is T cell proliferation and differentiation. Thus, stimulated, T cells are ready to respond to the threat.

T lymphocytes bearing the cluster of differentiation marker 8 (i.e., CD8+ lymphocytes) respond by engaging in cell-mediated cytotoxicity and act most effectively against viruses by destroying host cells that have been invaded. The response of CD4+ T lymphocytes usually involves the secretion of substances, such as cytokines, that modify the cell-mediated or humoral immune response. T helper type 1 (Th1) cells are CD4+ lymphocytes that release cytokines that strengthen the cell-mediated, cytotoxic response to an antigen. Th2 cells, in contrast, release cytokines that may be anti-inflammatory or that favor the production of antibodies by B cells.

Immunoglobulins are also produced in a large variety and contribute to the specificity of the immune system. Like the TCRs, the genes for immunoglobulin heavy and light chains undergo random genetic rearrangement during B cell development, resulting in a complement of lymphocytes that each bear a unique receptor and respond to a particular antigen. In addition, mature B lymphocytes can alter immunoglobulin production from one immunoglobulin class to another when stimulated. Immunoglobulin A (IgA) is secreted at mucosal surfaces and is most useful in repelling pathogens in the gastrointestinal tract and respiratory tree. IgE mediates the release of cytotoxic substances from eosinophils, mast cells, and basophils and is most effective against parasitic organisms, but it also plays an important role in allergic reactions. IgM is the first subtype produced in response to a threat and is most effective at activating complement. IgG can also effectively activate complement and is able to coat, or opsonize, a pathogen for effective clearance by phagocytes. In addition to immunoglobulins, mature B lymphocytes are distinguished by their expression of cell markers CD19 and CD20.

Complement refers to a group of proteins that are produced in the liver and participate in humoral immune responses in association with antibodies, particularly IgM and most classes of IgG. Complement can be activated by immunoglobulin binding to an antigen or deposited through less specific mechanisms. The term complement refers to the ability of these proteins to supplement antibodies and phagocytes in destroying bacteria and damaged host cells. The deposition of complement on a foreign substance, allowing for its recognition by other immune components and subsequent clearance, is called opsonization. In addition, serum complement proteins C5b, C6, C7, C8, and C9 associate to form a cytolytic structure called the membrane attack complex . Some products of complement activation (e.g., C5a) may also serve as chemotactic factors, drawing immune cells to the area for a more robust response.

A key feature of the immune system is the communication between cell types, allowing for the coordination of humoral and cellular responses. This communication is mediated in large part by proteins called cytokines that are secreted by many different types of cells, including antigen-presenting cells and lymphocytes. The interferons and interleukins are considered cytokines, as are tumor necrosis factor (TNF) and the chemokines, or chemotactic cytokines.

Interferons were first noted to be produced in the setting of viral infection, where they effectively interfered with viral replication. Interferons, which are generated by a wide variety of cell types, are also produced in response to other microorganisms as well as neoplasms. Once interferons bind to their receptors, they initiate a broad alteration of gene expression, ultimately leading to multiple antiviral and antioncogenic actions, including apoptosis ( ; ).

Interleukins are a large group of small polypeptide molecules that, in general, have pleiotropic effects on lymphocytes as well as many other cell types. This feature, combined with the baffling array of interactions among the different cytokines, makes the understanding of individual interleukins difficult. Still, some of these molecules have roles that are predictable enough to bear mentioning. IL-1 augments lymphocyte production of other cytokines, notably IL-2. It is also partly responsible for many of the symptoms of severe systemic illness, including fever, anorexia, myalgias, and decreased production of so-called housekeeping proteins, such as albumin. IL-2 primarily stimulates T lymphocyte proliferation. IL-10, in contrast, has a predominantly anti-inflammatory action and appears to help induce tolerance ( ).

Tumor necrosis factor is a proinflammatory cytokine that was initially named for its antioncogenic actions. Its effects are similar to those of IL-1, as discussed earlier. Both TNF and IL-1 can act on endothelium to increase intercellular and vascular adhesion molecules, facilitating egress of inflammatory cells into the tissues. In addition, TNF causes the cachexia seen in some patients with cancer.

Chemokines are named for their ability to draw inflammatory cells to an area along a chemical gradient and, like interleukins, have diverse functions. Chemokines can be subdivided based on the amino acid sequence on the N -terminal portion of the molecule. One group has two adjacent cysteine residues (i.e., the CC family of chemokines), whereas another has two cysteine residues separated by some other amino acid (i.e., the CXC family). It is believed that CC chemokines are more effective in attracting macrophages, eosinophils, and basophils, whereas CXC chemokines attract polymorphonuclear granulocytes.

Autoimmunity

The elements of the immune system described earlier usually work together in the differentiation of self from non-self with amazing fidelity. The importance of this system in fighting infection is highlighted by the various inherited immunodeficiency states as well as by the more recent HIV/AIDS epidemic. However, when the line between self and non-self becomes blurred in autoimmune disorders, these mechanisms, which are so effective in the destruction of invading pathogens, can be unleashed on the host, with devastating consequences.

Because of the random nature of recombination of genes involved in T and B cell receptor formation, there are always some lymphocytes that have an affinity for self-antigens. Thankfully, many of these are eliminated during their development. In the bone marrow and thymus, primitive B and T lymphocytes are exposed to numerous self-proteins bound to MHC molecules. Those lymphocytes whose receptors have little or no affinity for the MHC molecule are unable to participate effectively in an appropriate immune response and are allowed to die. Lymphocytes with receptors that bind with very high affinity to the MHC molecule are likely to initiate autoimmunity and are actively targeted for destruction. Both groups undergo apoptosis, or programmed cell death. This process has been termed clonal deletion ( ).

Although many self-antigens are present in the bone marrow or thymus, not all are. Therefore, a peripheral mechanism for inducing tolerance must also be in operation. Some lymphocytes possess receptors that recognize antigens that are sequestered in immunologically privileged sites. Anatomic barriers, such as the blood-brain and blood-nerve barriers, prevent these lymphocytes from encountering their antigens under normal circumstances. Such T and B cells are said to be in a state of ignorance ( ). If there is a breakdown of the barrier or if the antigens are released through injury or infection, then an autoimmune response may occur.

Some autoreactive lymphocytes are held in check by regulatory T cells. These unique CD4+ T cells act through membrane-bound or soluble molecules, such as cytokines, to suppress immune responses. The absence of these cells promotes the development of numerous autoimmune diseases in mice ( ).

Even when an autoreactive T cell encounters its antigen, activation and an immune response do not always occur. In addition to TCR binding to the protein-MHC complex, costimulatory molecules such as CD28 must bind to their respective receptors on the antigen-presenting cell if activation is to take place. If such costimulatory molecules are not present, the lymphocyte undergoes apoptosis. The presence of Fas ligand, which is constitutively expressed in some tissues, and its interaction with its receptor CD95 can also directly trigger cell death of autoreactive T lymphocytes ( ). In addition, a proper balance of Th1 and Th2 cytokines (e.g., IL-2 and IL-10, respectively) helps to keep autoreactive lymphocytes in check.

To better explain how the cellular constituents and soluble factors of the immune system can damage the peripheral nervous system, the following is a brief review of their role in the development and maintenance of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

The initial trigger that leads to immune attack of the peripheral nerves in CIDP remains obscure, as in most autoimmune disorders. The most popular notion, for which there is some existing evidence, is molecular mimicry. Approximately one third of patients with CIDP report a preceding illness or vaccination within 6 months before the development of symptoms ( ). In axonal forms of Guillain-Barré syndrome (GBS), certain infectious organisms, such as Campylobacter jejuni, are likely to cause a cross-reaction against nerve ganglioside antigens, such as GM1, and trigger the autoimmune cascade ( ). In rare cases, CIDP and malignant melanoma may coexist ( ), suggesting some molecular mimicry between epitopes on melanoma cells and Schwann cells, both of which develop from the neural crest.

Regardless of the inciting event, once autoreactive T cells or immunoglobulins against nerve antigens appear, the immune system’s property of biologic amplification takes over ( Fig. 7.1 ). Circulating immunoglobulins bind to their antigens and can be recognized by patrolling monocytes that then become activated to begin phagocytosis. Once nerve antigens are digested, they are presented via MHC II molecules to T cells. T cells that recognize these antigens become activated in the presence of appropriate costimulatory molecules. Th1 cells generate IL-2, which further activates these self-reactive T cells. In addition, both T cells and phagocytes produce TNF, which increases vascular permeability and increases endothelial intercellular and vascular adhesion molecules. These substances allow for adhesion to the vascular wall and transmigration of inflammatory cells into the area. Chemokines secreted by many different cell types in the immune response also ensure that lymphocytes and macrophages are drawn to the region. Th2 cells in the area are stimulated to release interleukins, such as IL-4 and IL-6, which promote immunoglobulin production by B cells. Immunoglobulins that recognize nerve antigens not only facilitate phagocytosis but also can activate complement, resulting in membrane attack complex formation and cell lysis as well as the production of chemotactic factors ( ). In addition, immunoglobulins against certain myelin proteins, such as P 0 , may be partially responsible for the development of conduction block seen on nerve conduction studies ( ). A more comprehensive review of the proposed pathophysiology of CIDP is provided by .

Fig. 7.1, Immunopathogenesis of chronic inflammatory demyelinating neuropathy. A schematic illustration of the basic principles of the cellular and humoral immune responses shows that autoreactive T cells recognize a specific autoantigen in the context of major histocompatibility complex class II and costimulatory molecules on the surface of antigen-presenting cells (macrophages) in the systemic immune compartment. An infection might trigger this event through molecular mimicry, a cross-reaction toward epitopes shared between the microbial agent and nerve antigens. These activated T lymphocytes can cross the blood-nerve barrier in a process involving cellular adhesion molecules, matrix metalloproteinases, and chemokines. Within the peripheral nervous system, T cells activate macrophages that enhance phagocytic activity, the production of cytokines, and the release of toxic mediators, including nitric oxide reactive oxygen intermediates, matrix metalloproteinases, and proinflammatory cytokines, including tumor necrosis factor α and interferon γ. Autoantibodies crossing the blood-nerve barrier or locally produced by plasma cells contribute to demyelination and axonal damage. Autoantibodies can mediate demyelination by antibody-dependent cellular cytotoxicity, potentially block epitopes that are functionally relevant for nerve conduction, and activate the complement system by the classic pathway, yielding proinflammatory mediators and the lytic membrane-attack complex C5b-9. Termination of the inflammatory response occurs through the induction of T cell apoptosis and the release of anti-inflammatory cytokines, including interleukin-10 and transforming growth factor β. The myelin sheath ( insets ) is composed of various proteins, such as myelin protein zero, that account for more than 50% of the total membrane protein in human peripheral nervous system myelin, myelin protein 22, myelin basic protein, myelin-associated glycoprotein, connexin 32, and gangliosides and related glycolipids. These molecules have been identified as target antigens for antibody responses with varying frequencies in patients with this disease. IL , Interleukin; MAG , myelin-associated glycoprotein; PMP , peripheral myelin protein; TN , tumor necrosis.

Immunotherapy

After a review of the components of the immune system and the problem of autoimmunity, the next topic is the available medications and treatments that can alter the immune response for those affected by autoimmune neuromuscular conditions. As with all drugs, these medications have potential side effects, some modest and some considerable. The first agents discussed are those used most frequently.

Corticosteroids

All corticosteroids bind to the glucocorticoid receptor, which then enters the nucleus and binds to glucocorticoid-responsive elements within the chromosomal DNA. This results in alteration of the chromatin structure and subsequent up- or down-regulation of gene transcription. As expected, the consequences of this shift in gene expression are varied. Corticosteroids are known to increase apoptosis, or programmed cell death, of autoreactive T cells as well as to inhibit T cell proliferation and shift cytokine profiles ( ).

Many corticosteroids are available, all with varying anti-inflammatory and mineralocorticoid actions. The most commonly used drug is prednisone. It is actually a prodrug and is converted by the liver to the active drug prednisolone. Although very low doses can be helpful for certain conditions, such as polymyalgia rheumatica ( ), most disorders require a more aggressive approach referred to as slam and taper. A high dose of 0.5 to 2.0 mg/kg is prescribed for daily use and after 1 month is tapered to alternate-day dosing. The dose can then be further tapered to reach the lowest dose that controls symptoms. At alternate-day or daily doses of less than 20 mg, the rate of tapering may need to be very slow, perhaps no more than 10% per month, to avoid disease recurrence or adrenal insufficiency.

Corticosteroids are also used in focal neuropathies that are of autoimmune etiology, such as Bell palsy. In this disease, the combination of corticosteroids and antiviral agents was considered beneficial. However, in two new controlled studies, the addition of antivirals was not superior to prednisolone alone. Prednisolone was given in doses of 50 mg ( ) to 60 mg ( ) daily.

Other regimens for corticosteroids have been proposed. Some experts favor a gradual introduction of steroids with a 5- to 10-mg daily dose that is increased by 5-mg increments every few days until the 0.5- to 2.0-mg/kg dose is achieved. This is primarily used for patients with myasthenia gravis in whom there is a risk of disease exacerbation by sudden, high doses of steroids. suggested a unique corticosteroid regimen for patients with CIDP. They performed a retrospective study of patients with CIDP who were treated with intravenous immunoglobulin (IVIg), oral corticosteroids or cyclosporine, or intermittent intravenous methylprednisolone. They found no difference in improvement in muscle strength between groups over an average of 4.5 years of follow-up; however, weight gain and cushingoid features were much less frequent in those treated with intermittent intravenous steroids ( ). Intravenous methylprednisolone is also sometimes used in the management of myasthenia gravis in crisis. A recent study also suggested that weekly pulses of oral methylprednisolone may be effective in the treatment of CIDP ( ).

The side effects of corticosteroids are well known ( Box 7.1 ) and often limit treatment. Acutely, most patients tolerate steroids well, but some experience insomnia or depression. Rarely, acute psychosis may occur ( ). Hyperglycemia and hypertension can develop quickly as well. A low-calorie, low-carbohydrate, low-sodium diet may help to lessen these problems as well as later weight gain. Gastric ulceration is also a concern, and patients may need to take proton pump inhibitors prophylactically. Late effects of steroids include the development of type II muscle fiber atrophy, glaucoma, cataracts, acne, avascular necrosis, and osteoporosis ( ). Both calcium and vitamin D supplementation (with daily doses of 1000 mg and 800 IU, respectively) have been found to be effective in helping to prevent loss of bone mineral density in patients taking chronic glucocorticoids, and their use is strongly recommended ( ). More active forms of vitamin D, such as calcitriol, can also be used, but patients must be monitored for the development of hypercalcemia and hypercalciuria. Several randomized clinical trials have found bisphosphonates to be effective for the prevention and treatment of glucocorticoid-induced osteoporosis ( ; ; ; ; ). One study showed that human recombinant parathyroid hormone or teriparatide provided greater improvement in bone mineral density and fewer fractures than daily alendronate ( ). Bone densitometry is recommended at the initiation of corticosteroid therapy as well as yearly thereafter ( ).

Box 7.1
Complications of Systemic Corticosteroids

Central Nervous System

  • Psychosis

  • Mania

  • Depression

  • Insomnia

  • Epidural lipomatosis

Ophthalmologic

  • Cataracts

  • Glaucoma

  • Corneal ulceration/perforation in those with herpes simplex virus (HSV) infection

Ear/Nose/Throat

  • Epistaxis

Cardiovascular

  • Sodium and water retention

  • Peripheral edema

  • Worsening of congestive heart failure

Pulmonary

  • Reactivation of tuberculosis

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