CHAPTER 12: Neuroinflammation

• Immune mechanisms, both intrinsic to the brain and spinal cord and derived from the periphery, are important in fighting central nervous system infections and mediating repair after injury.

• There are two main components of the immune system. The innate immune system is the first line of defense and responds to conserved components of microbes and evidence of tissue injury.

• The adaptive immune system mounts immune responses against specific microbes, which includes humoral immunity (mediated by antibody production by B lymphocytes) and cell-based immunity (mediated by T lymphocytes).

• Such immune responses can damage the nervous system through many mechanisms and contribute to a range of disorders through processes referred to as neuroinflammation.

• Autoimmune diseases are a prominent example of immune-mediated damage of the nervous system, which is mediated by antibodies or T cells reacting against self antigens.

• Many systemic autoimmune disorders can affect the nervous system. Additionally, several autoimmune disorders, such as multiple sclerosis (MS) and myasthenia gravis, selectively target the nervous system.

• MS occurs primarily via cell-mediated destruction of myelin sheaths and consequent damage to underlying axons.

• Myasthenia gravis and the related Lambert–Eaton syndrome occur primarily via antibody-mediated destruction of the neuromuscular junction.

• Treatments for these autoimmune disorders are based largely on targeting specific components of the immune system or the use of general immunosuppressive agents.

• Additionally, myasthenia gravis is treated with agents that promote the function of acetylcholine, the neurotransmitter at the neuromuscular junction.

Under normal conditions the central nervous system (CNS) is immunologically privileged, meaning that immune cells from the periphery cannot penetrate the brain and spinal cord due to the blood–brain barrier (Chapter 1). Nevertheless, immune mechanisms and the inflammatory responses they mediate—generated both by the CNS’s resident immune system and by the recruitment of peripheral immune mechanisms—are important in helping the CNS recover from acute infection or injury. By contrast, chronic autoimmune and inflammatory responses contribute importantly to numerous disease states. Immune-mediated damage to the nervous system can present in diverse ways, reflecting injury to specific neural substrates. In some instances immune damage affects primarily motor function but in other situations can cause selective behavioral abnormalities. Several common systemic autoimmune conditions, such as lupus erythematosus, affect the CNS and indeed often present initially with neurologic and psychiatric symptoms. Certain autoimmune disorders target the CNS selectively; examples include multiple sclerosis (MS) and other demyelinating illnesses (eg, neuromyelitis optica or Devic syndrome), paraneoplastic forms of encephalitis, stiff person syndrome (caused by autoantibodies directed against glutamic acid decarboxylase; Chapter 5), and myasthenia gravis and related conditions (eg, Lambert–Eaton syndrome). Chronic neuroinflammation also plays an important role in several disorders not classically considered neuroimmune, such as neuropathic pain (Chapter 11), Alzheimer disease and Parkinson disease (Chapter 18), and stroke (Chapter 20). Finally, inflammatory processes have been implicated, albeit more speculatively, in several psychiatric disorders as well as in normal aging.

The last decade, taking advantage of the growing understanding of interactions between the nervous and immune systems, has seen great advances in treating immune-based CNS disorders. The reader is referred elsewhere for detailed consideration of basic immunobiology and systemic autoimmune illnesses that can affect the CNS. This chapter briefly reviews the basic principles of neuroimmunology and focuses on the pathogenesis of two of the best studied neuroimmune disorders, MS and myasthenia gravis.

The immune system is designed to protect the host from invading pathogens and to eliminate disease. It responds to invading pathogens and has the capacity to distinguish “self” from “nonself” (foreign) antigens. The immune system is broadly divided into two major components: the innate and the adaptive (acquired) immune systems. The innate immune system includes physical (eg, skin), biochemical (eg, complement, lysozymes, cytokines), and cellular (dendritic cells, macrophages, neutrophils) components. Lysozymes and complement destroy microbial cell walls and membranes. Complement also enhances macrophage and neutrophil phagocytosis and attracts additional immune cells, while large families of cytokines (Chapter 8) exert proinflammatory or anti-inflammatory effects via actions on multiple cellular targets. Over the last decade, several pattern recognition receptors 12–1 have been identified on the surface and endosomal compartment of phagocytic cells. These receptors recognize conserved elements specific for viral, bacterial, and fungal constituents. During the inflammatory response triggered by infection, neutrophils and monocytes enter the affected tissue sites from the peripheral circulation. If these mechanisms are successful, the invading pathogen is eliminated, and illness is either prevented or mitigated.

When the innate immune response cannot clear an infection, the adaptive immune response is mobilized. Many effector mechanisms of the innate immune response are used to activate the adaptive immune response. The adaptive immune system has several key features that contribute to its ability to combat infections. These include the ability: (1) to recognize a variety of antigens in a specific as opposed to a patterned-recognized manner; (2) to discriminate between nonself and self antigens; and (3) to “remember” previously encountered antigens and respond in a heightened fashion. The adaptive response culminates in humoral immunity via the production of antibodies by B lymphocytes (B cells or plasma cells) and in cell-mediated immunity via activation of T lymphocytes (T cells).

Activation of the numerous cellular constituents of the immune system by cytokines, complement, and many other stimuli is governed by a very large number of intracellular signaling pathways that display complex cross-talk. A detailed discussion of these pathways is beyond the scope of this book, although many of the same intracellular pathways that mediate the actions of neurotransmitters and neurotrophic factors on the CNS (Chapters 4 and 8) are also crucial in the immune system. Likewise, many intracellular pathways first characterized for their important role in the regulation of immune cells, for example, NF-κB signaling (see 4–23) or toll-like receptor signaling 12–1, have more recently been demonstrated to contribute to synaptic transmission and plasticity in the nervous system. In fact, this has contributed to some confusion of what constitutes an “inflammatory response” in the CNS. For instance, if a certain cytokine, NF-κB, or toll-like receptor influences a neural phenomenon—from induction of long-term potentiation in the hippocampus to depression-related behavioral abnormalities (Chapter 15)—it does not automatically mean that a true immune response is involved. This somewhat semantic distinction is an important one to keep in mind as neuroinflammation is implicated in an ever-expanding range of neuropsychiatric disorders.

Autoimmunity arises when the body mounts an immune response against itself due to failure to distinguish self from nonself antigens. This phenomenon derives from multiple potential regulatory failures of the immune system, but results ultimately in the activation of self-reactive T and B lymphocytes that generate, respectively, cell-mediated or humoral immune responses directed against self antigens. Autoimmune reactions might also occur when antibodies are generated against nonself antigens, but cross-react with self antigens, so-called molecular mimicry. One proposed example is Sydenham chorea, which arises as a long-term consequence of infection by group A β-hemolytic streptococci and may be mediated by production of antibacterial antibodies that cross-react with and damage cells in the striatum. A similar mechanism has been implicated in rare psychiatric consequences (tics, obsessive–compulsive symptoms) of streptococcal infection, a process termed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). However, the involvement of molecular mimicry as the major pathogenic mechanism of these conditions remains unproven.

The relative contribution of T and B cells to various organ-specific autoimmune diseases, including neurologic autoimmune disorders such as MS and myasthenia gravis, remains controversial. According to some models, autoimmunity arises from a failure of T-cell tolerance: errors made by T cells in distinguishing nonself from self antigens. However, there is also evidence for a causative role for B cells in presenting self antigens to and consequently activating T cells. In any event, B cells play crucial roles in disease pathophysiology via production of autoantibodies that exert a direct effect on self antigens by functioning as neutralizing antibodies or activating and fixing complement on and thereby damaging the targeted tissues. Activated B cells are also an important source of cytokine secretion, which can lead to further tissue damage. These considerations illustrate that the adaptive immune system (T and B cells) is in a dynamic, constantly changing relationship with cells constituting the innate immune system. Although current therapies are targeted primarily against the adaptive immune system, a better understanding of the innate immune system will likely inform future therapeutic advances.

While the CNS is an immune-privileged site, shielded from the peripheral immune system under normal conditions as stated earlier, it contains its own resident innate immune system mediated via microglia and astrocytes. Microglia are macrophage-like cells that reside in the CNS and are crucial for recognizing nonself antigens and neutralizing them through phagocytosis. They are also an important source of cytokines. Activated astrocytes contribute to innate CNS immunity through the release of cytokines and neurotrophic factors and the formation of glial scars. Infection or traumatic brain injury can disrupt the blood–brain barrier and allow entry of cells of the peripheral immune system into the CNS, leading to further immune reactions. For example, the CNS innate immune system interacts with infiltrating monocytes and dendritic cells from the blood, which can result in peripheral blood-derived antigen-presenting cells leaving the CNS and traveling to cervical lymph nodes where they encounter cells of the adaptive immune system. Activated T cells may then emigrate from the lymph nodes and travel to the CNS, while activated B cells may generate antibodies that target antigens within the CNS. Migration of neutrophils into the CNS may also occur through a tightly regulated process involving cellular activation and migration of activated cells through vascular junctions and the basement membrane into CNS tissue, where they contribute further to inflammatory responses. These various processes can help resolve the acute infection or injury, but can also trigger downstream deleterious consequences including autoimmune diseases and frank neural injury. An improved understanding of the steps and specific molecules involved in the trafficking of peripheral immune cells into the CNS has played a major role in the development of current drug therapies for disorders such as MS.

The large majority of mechanisms established in neuroimmunology have come from the study of MS and myasthenia gravis, which are discussed in greater detail in the sections that follow. Lessons learned from these two disorders highlight the two main disease pathogenesis pathways described earlier. In the case of MS, the primary defect centers around loss of T-cell tolerance. In contrast, myasthenia gravis is an example of an antibody-mediated disorder.

MS is a common cause of neurologic disability in young adults. It is roughly three times more common in women. Clinically it is marked by periods of disease activity and relative quiescence termed relapses and remissions manifesting as neurologic deficits lasting at least 24 hours and supported by objective findings.

The pathologic hallmark of MS is multiple focal areas of myelin loss and associated axonal damage within the CNS called plaques or lesions 12–1. Demyelination is accompanied by variable inflammation and gliosis with increasingly recognized damage to axons as well. Lesions are disseminated throughout the CNS but are most frequently observed involving optic nerves, subpial spinal cord, brainstem, cerebellum, and juxtacortical and periventricular white matter regions. MS is diagnosed based on clinical evidence of neurologic deficits combined with the presence of characteristic MS plaques or lesions by magnetic resonance imaging (MRI) 12–2. Cerebrospinal fluid shows evidence of inflammatory responses in a majority of patients, including characteristic oligoclonal bands of immunoglobulins revealed with electrophoretic methods.

The pathogenesis of MS is incompletely understood. The animal models of experimental autoimmune encephalitis (generated by injection of brain extracts or myelin proteins into animals) and experimental viral encephalitis (infecting animals with any of several encephalitic viruses) have shed insight into the immunbiology of CNS inflammation, but have not replicated key aspects of the human disease process. A widely held view is that MS occurs when certain environmental exposures trigger the activation of CNS autoreactive T cells in genetically susceptible individuals leading to a CNS autoimmune disease. The estimated lifetime risk of an individual in northern North America or northern Europe is approximately 0.1% to 0.2%. Nieces and nephews (~25% genetic similarity) of an MS proband have a 5- to 10-fold increase in risk; siblings (50% similarity) have a 20- to 30-fold increase, while monozygotic twins (100% similarity) have 200 to 300 times greater risk compared with the general population. Still, the concordance rate between proband monozygotic twins from northern Europe is reported to be only on the order of 20% to 30%, indicating large nongenetic contributions to MS pathogenesis. The single largest genetic risk for developing MS relates to human leukocyte antigen (HLA) haplotypes. HLA-DR2 alleles are estimated to account for ~20% of the total genetic risk for MS. Roughly 5% of the risk appears to be composed of immune regulatory genes, with ~75% of genetic risk remaining unidentified. A curious finding in MS is that its incidence increases significantly in individuals who live farther from the equator. There is also some evidence that season of birth affects the incidence of MS. The mechanisms responsible for this geographical and seasonal pattern of MS remain unknown, although there is increasing evidence for the involvement of epigenetic factors in controlling oligodendrocyte survival and axonal degeneration.

Several clinical subtypes of MS have been described based on varying courses of the disorder 12–3. In some patients, the course is relatively benign and individuals can lead largely normal lives for many years before significant disability occurs. By contrast, individuals with more aggressive forms of the disorder can become disabled within several years of the initial diagnosis. The mechanisms responsible for these very different courses are poorly understood.

The target of the immune-mediated response is believed to be components of the CNS typically shielded from the peripheral immune response. Antigen-presenting cells—both native to the CNS and those in the periphery (blood-derived monocytes/macrophage and dendritic cells)—presumably present CNS self antigen fragments to CNS-reactive T cells in cervical lymph nodes that drain the brain or may present foreign antigens with characteristics similar to CNS self antigens (molecular mimicry). Activated T cells may then exit the lymph nodes and secrete molecules that facilitate migration across the blood–brain barrier. Once within the CNS, autoreactive immune cells participate in a proinflammatory-mediated process that leads to demyelination and eventual axonal injury.

Current treatments of MS focus on the immune processes that contribute to its pathogenesis, as will be presented in the last section of this chapter. Important directions for future research include establishing a better understanding of the factors that trigger MS in the first place with the goal of preventing subsequent illness. There is also considerable interest in developing ways to promote the regeneration of lost myelin as well as the repair of damaged axons through the stimulation of oligodendrocytes that are responsible for all myelin production in the CNS.

Myasthenia gravis is an example of a disorder that is mediated via an antireceptor antibody, in this case an antibody directed against protein constituents of the neuromuscular junction. The study of myasthenia gravis has not only provided insight into its biology but also contributed importantly to the understanding of other autoimmune disorders. Indeed, the pathogenesis and pathophysiology of myasthenia gravis are understood better than virtually any other autoimmune illness.

As discussed in Chapter 3, the neuromuscular junction is the synapse between a motor nerve terminal and a muscle fiber. The motor nerve terminal contains acetylcholine (ACh)-filled synaptic vesicles that collect at active zones to ready the vesicles for exocytotic release. These active zones are also enriched in P/Q-type voltage-gated Ca²⁺ channels (VGCCs). With the arrival of an action potential at the nerve terminal, the VGCCs open, resulting in the entry of Ca²⁺ into the nerve terminal. The ACh-containing vesicles then fuse with the nerve terminal plasma membrane leading to the release of ACh into the synaptic space. The synaptic space between the presynaptic and postsynaptic sites of the neuromuscular junction is composed of a basal lamina that is enriched in acetylcholinesterase, the enzyme that catabolizes the released ACh (Chapter 6). Choline, a product of this reaction, is then pumped back into the nerve terminal by a choline transporter.

The released ACh molecules diffuse across the synaptic space and bind to the multimeric nicotinic ACh receptors (nAChRs) located on the postsynaptic membrane of the muscle cell surface. This postsynaptic membrane, termed the end plate, is composed of many folds that are especially rich in nAChRs. The binding of ACh to nAChRs results in the opening of cation channels intrinsic to the receptors and the consequent propagation of an action potential in the muscle cell that induces muscle cell contraction.

Myasthenia gravis can be caused by antibodies directed against several components of the nAChR complex, which impair neuromuscular transmission in distinct ways 12–4. First, the binding of the antibody to the receptor can directly block binding of ACh and thereby impede neuromuscular transmission. Second, antibody binding to the nAChR can recruit components of the innate immune system, such as complement, and cause damage and eventually destruction of the postsynaptic membrane. Third, antibody binding to the nAChR can stimulate enhanced physiologic turnover of the receptors, which results in their increased internalization and further reductions in neuromuscular transmission. Finally, antibody binding can interfere with the molecular interactions between various components of the neuromuscular junction, causing failed assembly of new junctions or loss of existing ones. Thus, in aggregate, although the amount of ACh released by motor nerve terminals in response to an action potential is normal in myasthenia gravis, the reduced binding of ACh to a damaged postsynaptic membrane results eventually in failure of neuromuscular junction transmission and muscle weakness.

As with other autoimmune diseases, HLA loci are implicated in susceptibility to myasthenia gravis. HLA-A, -DQ, and -DR alleles have been identified in different at-risk populations. As well, non-HLA loci, including polymorphisms in the interferon-γ, cytotoxic lymphocyte–associated protein-4 (CTLA-4), and protein tyrosine phosphatase nonreceptor-22 (PTPN22) genes, have been offered as contributing to myasthenia gravis risk. How these various genetic factors summate to induce specific immunity toward nAChR complexes is uncertain. However, persistent inflammation of the thymus, in response to otherwise common viral infections, has been implicated in precipitating myasthenia gravis in at-risk individuals through mechanisms not yet understood.

The most common presentation of myasthenia gravis involves weakness of ocular, bulbar, and limb muscles 12–5. Fifty percent to sixty percent of patients present with ocular muscle weakness manifesting as ptosis and diplopia. Many individuals with myasthenic gravis progress eventually toward exhibiting more generalized disease, involving bulbar, limb, and respiratory weakness. Bulbar symptoms such as dysarthria and dysphagia can result in weight loss and aspiration pneumonia. A myasthenic crisis can be a neurologic emergency when respiratory muscle weakness leads to respiratory failure, requiring mechanical ventilation. Myasthenia gravis typically affects adults, although a neonatal form of the illness can occur when a mother with myasthenia gravis passes anti-nAChR antibodies across the placenta to affect neuromuscular junctions in the child. A congenital form of myasthenia gravis also has been described, which is caused by mutations in several genes that encode proteins of the neuromuscular junction.

Lambert–Eaton (also called Eaton–Lambert) syndrome is considered a variant of myasthenia gravis. Much less common than myasthenia gravis, Lambert–Eaton syndrome is caused by autoantibodies directed against VGCCs and likely other protein components of nerve terminals at the neuromuscular junction. Interestingly, this syndrome typically presents initially with limb weakness followed by bulbar and ocular weakness as the disorder progresses. It is not known why antibodies directed against presynaptic components (Lambert–Eaton syndrome) favor limb weakness, while those directed against postsynaptic components (myasthenia gravis) favor ocular and bulbar weakness. Most cases of Lambert–Eaton syndrome are associated with an underlying malignancy and are therefore considered examples of a paraneoplastic syndrome (Chapter 9).

In addition to physical examination, myasthenia gravis is diagnosed in several ways: by the identification of anti-nAChR antibodies in the patient’s blood, by electromyography that reveals muscles that are easily fatigued on repeated stimulation, and by rapid improvement in clinical symptoms seen on the intravenous administration of edrophonium, a rapidly acting and rapidly degraded acetylcholinesterase inhibitor. Muscle biopsies are used rarely when the diagnosis is uncertain. Lambert–Eaton syndrome is diagnosed with similar approaches, plus additional measures to search for an underlying malignancy (eg, small cell carcinoma of the lung).

Strategies used to treat myasthenia gravis and Lambert–Eaton syndrome are a direct consequence of our understanding of the organization of the neuromuscular junction and the role of autoantibodies in mediating these illnesses. The treatment of Lambert–Eaton syndrome involves, in addition, addressing the underlying malignancy found in most cases.

The major goal of disease-modifying therapies for MS and myasthenia gravis, and for related neuroinflammatory disorders, is to reduce the severity and frequency of relapses, thus changing the trajectory of the disease process. However, comparing the efficacy of the various drug therapies available is challenging because the clinical trials that led to the drugs’ approval often do not match the clinical scenarios in which the drugs are used today. A major limitation of many available therapies for neuroinflammatory conditions is that they must be given parenterally, by either intravenous or intramuscular injection. More recently approved drugs, which are effective by oral administration, have begun to mitigate this challenge.

There are multiple ways that current drug therapies can be categorized. One approach is to group drugs by their presumed mechanism of action. Over the past decade several monoclonal antibodies originally approved for treatment of myeloid malignancies or small-molecule drugs originally used to prevent organ transplant rejection have been brought to bear in the treatment of MS. Another grouping strategy is by molecular class in which treatments affect a particular aspect of the immune response. The agents described below are grouped as those that: (1) impair antigen presentation, (2) alter lymphocyte function, (3) alter cellular proliferation, and (4) alter the functioning of the neuromuscular junction 12–6. As the newer therapies enter wider clinical use, undoubtedly our understanding of the complex interactions between components of the immune system and functioning of the nervous system will grow.

Drugs With Specific Immune-Directed Mechanisms

Glatiramer acetate is a first-line disease-modifying drug to treat MS. It is a random polymer of glutamate, lysine, alanine, and tyrosine, with a structure similar to myelin basic protein. Glatiramer acetate, which must be given intravenously, was shown to significantly lower the number of lesions and exacerbations compared with patients who received placebo. The mechanism of action of glatiramer acetate is not completely understood. The results of in vitro and in vivo systems suggest that glatiramer acetate has multiple effects on the host’s innate and adaptive immune system. By binding to MHC class II molecules, glatiramer acetate can prevent the presentation of other antigens and stop subsequent T-cell activation. Glatiramer acetate also appears to have other effects on T cells, B cells, and monocytes: it promotes the production of anti-inflammatory cytokines, as well as increases the number of certain regulatory T cells while decreasing the number of proinflammatory T cells (ie, Th17 lineage cells). Furthermore, it has been demonstrated that glatiramer acetate treatment promotes remyelination and axonal repair in MS lesions by inducing secretion of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3 and -4. Response to glatiramer acetate varies, with approximately 50% of patients not responding to therapy.

Interferons (IFNs) are a family of pleiotropic cytokines produced by immune cells in response to viral infections. IFNs exhibit antiviral, immunomodulatory, and antitumor properties by regulating the expression of hundreds of genes involved in crucial biological processes such as cell cycle progression, cell proliferation, and apoptosis. While the exact mode of action of IFN-β in MS is complex, and not yet fully understood, the effects in the periphery include inhibition of antigen presentation, and at the blood–brain barrier there is downregulation of adhesion molecules and decreased production of matrix metalloproteinases. This limits the entry of T cells into the CNS. Furthermore, IFN-β is linked with alterations in the generation of specific T-cell subtypes, causing a shift from T helper 1 to T helper 2 cells, creating an anti-inflammatory milieu. More recently, IFN-β has been shown to downregulate the T helper 17 cell subset, also an anti-inflammatory action. Several IFN-β products are available (all given by intramuscular injection) for treating relapsing-remitting MS, and clinical trials have shown that they reduce the rate of relapse, slow the appearance of new and enhancing lesions on MRI, and delay progression of disability.

Fingolimod is a once-daily oral medication that was approved by the US Food and Drug Administration (FDA) in 2010 for the treatment of relapsing forms of MS. It is derived from myriocin, a metabolite of the fungus Isaria sinclairii. Fingolimod is believed to work by sequestering autoreactive T and B cells within lymph nodes, preventing their release into the bloodstream and subsequent migration into the CNS. Fingolimod, a structural analogue of sphingosine, is a negative modulator of the sphingosine-1-phosphate receptor, by inducing receptor internalization and degradation. The sphingosine-1-phosphate receptor is a member of the lysophospholipid receptor family, a group of G protein–coupled receptors important for lipid signaling. Lymphocytes migrate along a sphingosine-1-phosphate gradient to egress from lymph nodes. Blockade of the sphingosine receptor blocks this migration and the egress of the cells from lymph nodes.

Rituximab is a monoclonal antibody, given intravenously, that targets the B-cell surface molecule CD20. This chimeric mouse/human IgG antibody binds CD20 and lyses B cells, primarily via complement-dependent mechanisms. Rituximab has been shown in phase 2 trials to reduce MRI contrast-enhancing lesions and to reduce frequency of relapses in MS. Despite encouraging clinical trials, the drug is not yet approved by the FDA in part because of ongoing development of fully humanized monoclonal anti-B-cell antibodies that are in development and are expected to have fewer side effects.

Natalizumab is a humanized monoclonal antibody, given intravenously, which acts as an α4 integrin antagonist. α4β1 integrin, a protein on the surface of lymphocytes, interacts with vascular cell adhesion molecule 1 (VCAM1), which is expressed on the surface of vascular endothelial cells in the brain and spinal cord, mediating the adhesion and migration of lymphocytes as they cross the blood–brain barrier. Natalizumab thus blocks the binding of lymphocytes to endothelial receptors. It was approved by the FDA in 2004 for the treatment of relapsing forms of MS based on trials that showed reduced clinical relapses and decreased lesions by MRI. Natalizumab acts rapidly, and its benefits appear to persist. After its approval, however, the incidence of progressive multifocal encephalopathy (PML), caused by reactivation of latent JC virus infection, resulted in the drug’s voluntary removal from the market in 2005. Although natalizumab has since been reintroduced to the market given its strong efficacy and safety in most patients, a major focus of research has centered around monitoring JC virus reemergence and identifying patient attributes that put them at risk for this serious side effect.

Alemtuzumab is a humanized monoclonal antibody against CD52, an antigen found on the surface of most B and T cells and monocytes. The antibody, administered intravenously, causes rapid complement-mediated lysis of almost all circulating lymphocytes by targeting this antigen. The impact is long-lasting, with time to recovery to the lower limit of normal circulating lymphocytes averaging 35 months. Alemtuzumab was first approved for treatment of B-cell chronic lymphocytic leukemia in 2001. Since that time it has been studied in a variety of autoimmune conditions. Numerous studies supporting the efficacy of alemtuzumab in MS have been published over the past few years, and studies comparing its efficacy with that of IFN are ongoing. However, there have been multiple reports of serious side effects as might be expected when depleting major components of the immune system.

Daclizumab is a humanized monoclonal antibody, requiring intravenous administration, being evaluated for MS. Daclizumab targets the α subunit (CD25) of the interleukin-2 receptor found on regulatory and antigen-activated T cells. By targeting CD25, daclizumab interferes with expansion of activated T cells. It was introduced originally for prevention of rejection after organ transplantation.

General Immunosuppressive Agents

Teriflunomide is a once-daily oral medication that was approved by the FDA in 2012 for the treatment of relapsing forms of MS. It is the active metabolite of leflunomide, a previously released medication used to treat rheumatoid arthritis. Teriflunomide reversibly inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in pyrimidine synthesis required for DNA replication. The drug limits stimulated T- and B-cell activation, proliferation, and function in response to autoantigens. Slowly dividing or resting cells, which rely on the salvage pathway for pyrimidine synthesis, are relatively unaffected by teriflunomide.

Azathioprine is a prodrug that generates mercaptopurine, which inhibits the amidophosphoribosyltransferase enzyme that is required for the synthesis of purines required for DNA synthesis. It most strongly affects proliferating cells, such as T and B cells, and thus exerts broad immunosuppressive effects. Azathioprine is effective in the treatment of several autoimmune disorders. Its full clinical effects occur after several months of administration, and, once improvement begins, it is maintained for as long as the drug is given, but symptoms often recur within a few months after the drug is discontinued. Azathioprine is often used in conjunction with corticosteroids (see below). Approximately one third of patients have mild dose-dependent side effects that may require dose reductions. The main side effect of azathioprine is bone marrow suppression, usually manifested as leukopenia, but anemia, thrombocytopenia, and bleeding may also occur.

Dimethyl fumarate was first described in 1959 for the use in psoriasis. It was found subsequently to be effective for the treatment of several other immune-mediated dermatologic conditions. Dimethyl fumarate was approved in 2013 as a twice-daily oral medication for use in relapsing forms of MS. It is thought to activate the nuclear factor–like 2 (NFR2) antioxidant response pathway, the primary cellular defense against the cytotoxic effects of oxidative stress. Fumaric acid esters may decrease leukocyte passage through the blood–brain barrier and exert neuroprotective properties via the activation of antioxidative pathways. It may also suppress proinflammatory cytokine production or signaling pathways.

Mitoxantrone is a synthetic antineoplastic anthracenedione approved in 1987 as a treatment for acute myeloid leukemia and in 1996 for hormone-refractory prostate cancer. Mitoxantrone, a topoisomerase II inhibitor, prevents the unwinding of DNA and thereby inhibits cell proliferation. Although it must be given intravenously, it is a small molecule able to cross the blood–brain barrier, where it inhibits dividing cells in the CNS and suppresses T-cell, B-cell, and monocyte proliferation and function. Its use is limited by cardiac toxicity.

Methotrexate was developed in 1950 initially as a treatment for lymphoblastic leukemia. It is an antimetabolite and acts by inhibiting the metabolism of folic acid by binding to the active catalytic site of dihydrofolate reductase. Methotrexate interrupts the synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine, thereby interfering with DNA, RNA, and protein synthesis. Methotrexate has been studied as single drug and combination treatment for both MS and myasthenia gravis. Side effects are usually observed in the bone marrow and to a lesser extent in the skin and gastrointestinal mucosa.

Mycophenolate is a semisynthetic molecule derived from the mold Penicillium glaucum. It is an immunosuppressive agent that acts by inhibiting purine synthesis and thereby antagonizes T- and B-cell responses. It is used as an adjunct in the treatment of MS for patients with breakthrough relapses while on injectable therapies.

Cyclosporine, isolated from the fungus Tolypocladium inflatum, inhibits predominantly T-cell-dependent immune responses. It binds to the cytosolic protein, cyclophilin. The complex of cyclosporine and cyclophilin inhibits calcineurin (also known as protein phosphatase 3; Chapter 4), which is required for normal T-cell function. Cyclosporine is a general immunosuppressive agent. Most patients with myasthenia gravis improve several months after starting cyclosporine, and improvement is maintained as long as therapeutic doses are given. There is evidence that cyclosporine is also useful in the treatment of MS. In addition, cyclosporine has been investigated as a possible neuroprotective agent in conditions such as traumatic brain injury, and has been shown in animal experiments to reduce brain damage associated with injury. Renal toxicity and hypertension are important adverse reactions to cyclosporine.

Corticosteroids were the first class of hormonal agents recognized to have immunosuppressive properties. These steroids are thought to interfere with the cell cycle of activated lymphocytes. In myasthenia gravis, marked improvement or complete relief of symptoms occurs in the vast majority of patients treated with prednisone, a synthetic corticosteroid, and some improvement occurs in most of the rest. The best responses occur in patients with recent onset of symptoms, but patients with chronic disease may also respond. The major disadvantages of chronic corticosteroid therapy are the side effects of weight gain, osteoporosis, diabetes, hair loss, and skin fragility (Chapter 10).

Drugs Acting at the Neuromuscular Junction

Pyridostigmine’s use in myasthenia gravis began in the 1930s. It acts as an acetylcholinesterase inhibitor, blocking the catabolism of ACh at the neuromuscular junction and thereby enhancing cholinergic transmission. Acetylcholinesterase inhibitors can result in dramatic improvement in some patients and certain muscle groups and little to none in others. Use of pyridostigmine alone rarely results in return to normal strength. Neostigmine is another acetylcholinesterase inhibitor often used in the treatment of myasthenia gravis. The doses of acetylcholinesterase inhibitors vary from day to day and even during the same day in response to infection, antibiotic use, menstruation, or emotional stress. Use of acetylcholinesterase inhibitors is associated with numerous prominent adverse effects based on the enhancement of cholinergic function in the autonomic nervous system and CNS (Chapter 9).

Active research into the pathogenesis of MS and myasthenia gravis, coupled with expanded understanding of the components and functioning of the immune system, has resulted in a vastly expanded range of therapeutic options for autoimmune neurologic disorders. At present drug therapies are primarily based on the wholesale alteration of entire components of the immune system. Although these therapies are powerful and may be effective disease-modifying agents, they are accompanied by risks associated with drug side effects and long-term imbalances to the immune system. The goal of future immunotherapies will be to directly target the specific clonally expanded cells responsible for a given autoimmune disease, while leaving the remainder of the immune system intact to ward off infections and malignancy.