Understanding the Immunology of Multiple Sclerosis

Transcription

1 Understanding the Immunology of Multiple Sclerosis Kathleen Costello, MS, ANP-BC, MSCN, and Anne Gocke, PhD Johns Hopkins Multiple Sclerosis Center and Johns Hopkins University School of Medicine, Baltimore, Maryland Abstract A growing body of evidence has accumulated over the past 25 years that multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory and degenerative processes that damage the central nervous system. Knowledge of the immunology of MS has led to the therapeutic arsenal of agents now available to fight the disease, and additional immunopathologic mechanisms currently being elucidated certainly will influence future therapeutic directions. In a course for nurses and other nonimmunologists offered at the joint 28 th Annual Meeting of the Consortium of MS Centers (CMSC) and the 19 th Annual Meeting of the Americas Committee for Treatment and Research in MS (ACTRIMS), speakers described the normal immune response, provided a basic understanding of the immunopathology of MS, discussed the mechanisms of action of current disease-modifying therapies, and delved into more recently discovered inflammatory and degenerative mechanisms involved in relapsing and progressive forms of the disease. M ultiple sclerosis (MS) is an inflammatory-mediated neurodegenerative disease of the central nervous system (CNS). Its etiology is unknown; however, a variety of immune cells including B cells, T cells, monocytes, macrophages, microglia, dendritic cells, and others all play a role in its pathogenesis. The CNS once was considered to be an immune-privileged site. Currently, it is thought that baseline immune surveillance in the CNS is important for maintaining homeostasis and protecting the CNS from opportunistic infection. MS results from an abnormal and dysregulated CNS immune response that causes damage and destruction of myelin, oligodendrocytes, and axons. During a course held at the joint 28 th Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the 19 th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), experts discussed immunology as it relates to MS, medical therapies currently being used and on the horizon, causes of CNS inflammation, and differences between relapsing and progressive forms of the disease. n HOW DOES THE NORMAL IMMUNE SYSTEM WORK? Based on a presentation by Kathleen Costello, MS, ANP-BC, MSCN, Johns Hopkins Multiple Sclerosis Center, Johns Hopkins Medicine, Baltimore, Maryland. The normal immune system protects against infectious threats; responds to active infections; and, through immunologic regulatory mechanisms, prevents development of autoimmune conditions. Specificity, diversity, memory, and the ability to distinguish between the body s own cells ( self ) and foreign cells ( non-self ) are important properties of the immune system. The body has a number of natural defense barriers (skin, body fluids, lung and gut cilia, and mucus) that work to keep infectious threats out of the system. However, a breech in the barrier system provokes the cellular activity of the innate immune system. Through a complex communication system, the innate immune system cells become activated when a threat is identified. Neutrophils, monocytes, macrophages and, natural killer (NK) cells are important members of the innate immune system. These cells can recognize broad classes of pathogens and, in many cases, are able to eradicate them. When an infection requires additional immunologic intervention, the adaptive immune system, staffed by T and B cells, is called to action. Various messengers signal these cells to begin to defend the body (Figure 1). Cell-surface molecules, including the major histocompatibility complex (MHC), are critical to activation of the adaptive immune system, as are co-stimulatory molecules that allow for full activation of adaptive immune cells. Adhesion molecules on blood vessels and cell walls are upregulated, allowing cellular movement from the bloodstream to the site of infection in tissues. Cells That Defend Us Macrophages are the body s sentries, lying in wait for invasion by pathogens. These cells are found under the skin, in the lungs, and in the tissues surrounding the gut. In addition, they collect waste products and minimize cellular debris from Ms. Costello is an Associate Vice President of the Advocacy, Services and Research Department of the National Multiple Sclerosis Society; an Adult Nurse Practitioner in the Johns Hopkins Multiple Sclerosis Center; and Adjunct Assistant Professor of Neurology at Johns Hopkins University School of Medicine, Baltimore, Maryland. Dr. Gocke is Assistant Professor of Neurology at Johns Hopkins University School of Medicine. 6 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 2

2 dead cells. Receptors on the surface of macrophages recognize signals from the pathogen that stimulate a seek eat destroy mechanism. When macrophages are stimulated to seek out and destroy an invading pathogen, they send out signals called cytokines to recruit more immune system cells. Macrophages also can engulf an invader and display a piece of it on the cell surface, so it can be recognized by the adaptive immune system. Macrophages provide a strong defense, but bacteria multiply quickly. Rather than acting alone, macrophages send out signals to attract neutrophils and monocytes from the blood to the site of infection. Neutrophils and monocytes are short-lived cells that circulate in the blood. A signal sent from the macrophage allows them to move quickly to the site of infection. Signals from the tissue cause upregulation of surface molecules that allows neutrophil entry into tissue at the infection site. Neutrophils. Along with macrophages, the chemokines interleukin (IL)-1 and tumor necrosis factor (TNF) call neutrophils to action. Complex communication lines cause the neutrophil to slow down, sense the location of infection, adhere to the blood vessel, and migrate from the blood vessel into the tissue. Monocytes circulate for several days and finally leave the blood and enter tissues, where they mature into macrophages. These powerful phagocytes stimulate repair mechanisms and produce IL-1, TNF, and reactive oxygen species (especially hydrogen peroxide) when they are activated. Monocytes also act as antigen-presenting cells (APCs) for lymphocyte functioning in adaptive immunity, and they become further stimulated by the mechanisms of this protective mechanism. NK cells use this same mechanism to exit the circulation and migrate into tissues. Adhesion molecules are key in signaling cells that they have arrived at the correct location. NK cells mostly circulate in the blood; signals from the infection site activate them. Upregulation of adhesion molecules allows NK cells to enter the tissue at Cytokines from activated T cells Clonal expansion of activated T cells Mφ Activation of macrophages Memory T cell Naïve Act T Tcell the infection site and become killers. NK cells deliver powerful enzymes to target cells infected by viruses, which causes the cells to die, thus reducing the number of infected cells. NK cells also secrete cytokines, which help hyperactivate macrophages and prime more macrophages to participate in the killing. Complement is a series of proteins that is activated very rapidly in a coordinated and orderly way by the innate and adaptive immune systems. In innate immunity, proteins in the complement system can become active when they recognize common chemical groups on the infected cell surface. Complement can IL-12 Costimulatory molecules MHC + antigen Antigen presentation and recognition Pathogen Dendritic cells tag an invader for destruction or bore a hole in invading cells to destroy them. Antigens and Antibodies Dendritic cell Dendritic cell encounters pathogen FIGURE 1 Adaptive immunity: T-cell activation. IL-12 = interleukin-12; MHC = major histocompatibility complex; Mφ = macrophage cell. Adapted, with permission, from a slide presented by Kathleen Costello, MS, ANP-BC, MSCN, at the 2014 joint CMSC/ACTRIMS annual meeting. Pathogen Memory Bcell Memory B cell BCR Bcell B cell Activated B cell becomes effector cell (PC) or memory B cell MHC II T h T helper cell PC Antibody produced by PC Activated T helper cell stimulated by B-cell antigen presentation Macrophage Complement stimulated by antibody FIGURE 2 B-cell activation. BCR = B-cell receptor; MHC = major histocompatibility complex; Mφ = macrophage cell. Adapted, with permission, from a slide presented by Kathleen Costello, MS, ANP-BC, MSCN, at the 2014 joint CMSC/ACTRIMS annual meeting. Mφ The adaptive immune system is activated when an additional response is needed to eradicate a pathogen. These actions include cell-mediated activity involving specialized T cells known as T helper (Th) cells, including, Th 1, Th 2, and Th 17 ; and also humoral activity, involving B and T cells, antibodies, and complement. The ability of antibodies to recognize specific antigens is an important characteristic (Figure 2). Antigen recognition and binding allow antibodies to perform T H E N E U R O L O G Y R E P O R T S u m m e r

3 four important effector functions in eliminating invading pathogens: opsonization, complement activation, toxin neutralization, and blocking attachment. T- and B-Cell Interaction T cells are important players in the adaptive immune response, but they are activated only when a recognizable antigen is presented to them by a professional APC, such as a dendritic cell or a macrophage. The naïve T cell is stimulated by antigen presentation and is differentiated into various T-cell subsets, such as Th 1, Th 2, or Th 17. Th 1 differentiation occurs with IL-23 and interferon γ stimulation. Th 2 differentiation occurs with stimulation by IL-4, as with parasitic infections. Th 17 differentiation occurs with stimulation by IL-6, IL-1, and IL-23. T cells become activated and multiply based upon the antigen presented and the cellular environment, and this activation will provoke their immunologic activity. B cells, also important players in adaptive immunity, are able to recognize antigens that are in circulation and do not require the specialized antigen presentation that T cells require. B-cell clonal expansion and the production of plasma and memory cells require the help of T cells and the actions of cytokines. B cells recognize antigen in the circulation and are able to bind to the antigen and internalize it. After internal processing, a small piece or peptide of the antigen is presented on the cell surface in a groove of the MHC molecule, where an activated or memory T cell can can recognize and interact with it. This contact sends signals to the B and T cells to allow the T cells to stimulate production of receptors and cytokines and to provide a second co-stimulatory signal for B cells. Summary The immune system protects the body from pathogens and purges invasive proteins from the circulation. The normal immune system features specificity, diversity, and memory, and it can differentiate the body s own cells from foreign cells. If this system malfunctions, however, an autoimmune response may occur. n WHAT CAUSES INFLAMMATION OF THE CNS IN MS? Based on a presentation and written summary by Anne Gocke, PhD, Assistant Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The most important determinants of permanent neurologic disability in MS are axonal damage and loss. MS is an immune-mediated inflammatory disease characterized by myelin destruction, damage to CNS-resident cells, and loss of mobility and cognition. In acute and chronic active lesions, axons commonly are preserved; macrophages that have taken up myelin debris are evident. In contrast, inactive lesions feature a loss of axons and oligodendrocytes and few macrophages. Cortical plaques, which involve the gray matter, also may be found. The antigens that are targeted in MS likely are not limited to myelin proteins. They also may include neuronal proteins and astrocytic proteins, among other unknown candidates. Genetic predisposition has been linked with mutations in cytokine receptor genes (IL2RA, IL7R) as well as HLA-DR2B. Environmental factors, including vitamin D, Epstein-Barr virus, and gut and lung immunity, also play an important role in MS susceptibility. Gender is another risk factor for development of the disease, since some 66% of affected patients are female. CD4 + T cells of the Th 1 and Th 17 lineages and cytotoxic CD8 + T cells play a pathogenic role in MS, likely due to their ability to secrete proinflammatory cytokines and recruit peripheral monocytes and B cells to MS lesions. B cells may secrete antibodies that can mediate direct damage to axons. The presence of lymphoid follicles in the meninges of some patients points toward a pathogenic role for B cells in MS. B cells also help in repair and remyelination by promoting clearance of myelin debris via opsonization. Microglia sense changes in the CNS and release cytokines and chemokines that pave the way for entry of other immune cells into the lesion site. Peripheral monocytes infiltrate the CNS and secrete proinflammatory cytokines and toxic molecules, such as nitric oxide, IL-1, IL- 6, and matrix metalloproteinases, which can directly damage oligodendrocytes and neurons. CNS Inflammation and Axonal Damage The most important determinants of permanent neurologic disability in MS patients are axonal damage and loss. Axonal damage may occur even early in the course of the disease. Several different hypotheses for a link between an aberrant inflammatory response in the CNS and axonal damage in MS have been put forth. They include: Activation of CD8 + T cells to target neurons directly; Vigorous CD4 + T-cell responses that recruit macrophages, resulting in the release of inflammatory mediators and toxic molecules; Binding of antibodies to neuronal surface antigens, followed by complement fixation or antibody-mediated phagocytosis of axons; Triggering of a program in CNS resident cells by invading immune cells, which results in secondary inflammationindependent neurodegeneration; and Indirect mechanisms, including mitochondrial dysfunction, dysregulation of ion channels, or release of glutamate or nitric oxide as a result of chronic inflammation. Summary The etiology of MS is unknown. However, the immune system is important to the development of the disease, and lesions affect both the gray and white matter. MS may begin with an invasion of the CNS by T and B cells. These events may be secondary to activation of microglia and macrophages and the local release of self or foreign antigens. 8 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 2

4 A small number of antigens presented in the CNS may drive the highly focused, persistent acquired immune response in MS. Possible candidates include myelin or neuronal antigens and antigens from infectious agents epidemiologically associated with the disease. n HOW DISEASE-MODIFYING THERAPIES (DMTs) AFFECT THE ALTERED IMMUNE RESPONSE Based on a presentation by Scott Newsome, DO, Assistant Professor of Neurology and Director, Neurology Outpatient Services, Johns Hopkins University School of Medicine, Baltimore, Maryland. The subtypes of MS are based upon the clinical behavior of the disease over time. They include relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), primary-progressive MS (PPMS), and progressive-relapsing MS (PRMS). In untreated individuals who initially have a relapsing-remitting course to their MS, approximately 50% will develop more progressive symptoms (SPMS) after about 15 years. Over the past 25 years, increasing knowledge of the immunopathology of MS has led to the development of several different DMTs that can reduce the frequency of relapses; reduce new inflammatory activity in the CNS; and, to varying degrees, delay the accumulation of disability (Table 1). Examination of how these drugs affect patients with RRMS reflects a greater understanding of the pathways of the disease. Interferon β-1a and β-1b Interferon β-1a and β-1b are proteins that have powerful anti-inflammatory effects. Interferons reduce T-cell activation and proliferation, reduce secretion of matrix metalloproteinases that disrupt the blood-brain barrier (and thus allow fewer immune cells entry into the CNS), inhibit interferon γ release (reduces antigen presentation to T cells), and limits T-cell migration across the blood-brain barrier. In addition, recent findings suggest that interferons reduce antigen processing and antigen presentation to T cells. At low doses, these drugs may cause minor side effects, such as flu-like symptoms, TABLE 1 Currently Approved Disease-Modifying Therapies for Patients with Relapsing-Remitting Multiple Sclerosis Year Generic name (trade name) Route and frequency of administration 1993 Interferon β-1b (Betaseron) Subcutaneous injection every other day 1996 Interferon β-1a (Avonex) Intramuscular injection once a week 1996 Glatiramer acetate (Copaxone) Subcutaneous injection once a day 2000 Mitoxantrone (Novantrone) Intravenous infusion every 3 months 2002 Interferon β-1a (Rebif) Subcutaneous injection 3 times a week 2004 Natalizumab (Tysabri) Intravenous infusion once a month 2009 Interferon β-1b (Extavia) Subcutaneous injection every other day 2010 Fingolimod (Gilenya) Orally once a day 2012 Teriflunomide (Aubagio) Orally once a day 2013 Dimethyl fumarate (Tecfidera) Orally twice a day 2014 Glatiramer acetate (Copaxone) Subcutaneous injection 3 times a week 2014 Peginterferon β-1a (Plegridy) Subcutaneous injection every 14 days headache, transaminitis, and depression; major side effects include suicidal ideation, anaphylaxis, hepatic injury, blood dyscrasias, seizures, and autoimmune hepatitis. At high doses, all of these effects may be seen, although injection-site reactions and skin necrosis also may occur. Patients should be followed with complete blood cell counts with differential, liver and thyroid function tests, and interferon-neutralizing antibodies, if clinically warranted. Glatiramer Acetate Originally, the mechanism of action of glatiramer acetate was believed to involve a shift from Th 1 to Th 2 cells and a blocking of the MHC peptide antigen. More recently, treatment with glatiramer acetate has been shown to cause migration of Th 2 cells into the CNS, modification of antibody production by plasma cells, and regulation of B-cell properties. In addition, recent evidence suggest that glatiramer acetate may produce cytokine modulation, inhibition of antigen presentation to T cells, and effects on oligodendrocyte precursor cells (myelin repair). Minor side effects of glatiramer acetate include injection-site reactions and postinjection vasodilatory reactions; major side effects include lipoatrophy, skin necrosis, and anaphylaxis. No particular patient monitoring is needed. Mitoxantrone Mitoxantrone mainly is used to treat leukemia and prostate cancer. This DNA topoisomerase II inhibitor suppresses the proliferation of T and B cells and macrophages. The lifetime dose of this drug is 140 mg/m 2. Owing to its high-risk profile and the availability of other effective DMTs with fewer risks, mitoxantrone currently is used infrequently for the treatment of patients with RRMS. Use of mitoxantrone is related to nausea, vomiting, hair thinning, infections, liver dysfunction, and menstrual irregularities. Significant reported risks include cardiotoxicity, acute myelogenous leukemia, serious infections, and infertility. Patients should undergo a complete blood cell count with differential, liver function tests, echocardiography, or an echo/multigated acquisition scan while receiving mitoxantrone and even after therapy ends. Natalizumab Natalizumab, the first selective adhesion molecule inhibitor developed, is a humanized monoclonal antibody that targets the α4-integrin on the surface of lymphocytes, which facilitates the movement of white blood cells into organs. Natalizumab blocks the expression of this adhesion molecule, thus limiting the number of lymphocytes that enter the CNS. Treatment with natalizumab may cause headaches; joint pain; fatigue; and a wearing-off phenomenon, wherein patients feel a temporary recrudescence of their MS symptoms just prior to each infusion. T H E N E U R O L O G Y R E P O R T S u m m e r

5 The major risk of taking natalizumab is a severe and potentially fatal infection known as progressive multifocal leukoencephalopathy (PML), caused by reactivation of the otherwise dormant John Cunningham virus (JCV). In addition, infusion reactions, hypersensitivity reactions, and other serious infections, such as herpes zoster virus and other infections, may occur. Patients should have a complete blood cell count with differential, liver function tests, and serum JCV antibody measurements every 6 months, as well as periodic magnetic resonance imaging (MRI), and measurement of natalizumab antibodies if clinically indicated. Should PML be suspected, an MRI should be obtained to identify any new CNS activity. If it is present, a lumbar puncture may be needed to search for JCV in the cerebrospinal fluid. Fingolimod This oral medication is given daily. It is a sphingosine 1-phosphate receptor (S1PR) modulator that affects the receptors S1P1, S1P3, S1P4, and S1P5. Fingolimod functionally antagonizes S1PR blocking lymphocyte egress from secondary lymphoid organs to the peripheral blood circulation. Minor side effects include lymphopenia (lymphocyte count > 200 cells/mm 3 ) and transaminitis; major side effects include bradycardia, heart block, hypertension, risk of herpetic infections, lymphopenia (lymphocyte count < 200 cells/mm 3 ), macular edema, skin cancer, reactive airway, and posterior reversible encephalopathy syndrome. Patients should undergo cardiac monitoring with the first dose, an eye and skin examination, a complete blood cell count with differential, liver function tests, measurement of varicella IgG titers before starting the medication, and pulmonary function tests if indicated. Teriflunomide This oral medication is an active metabolite of leflunomide. It mimics pyrimidine as a DNA building block, interferes with DNA synthesis, and inhibits dihydro-orotate dehydrogenase. Use of the drug is cytostatic to proliferating B and T cells. Teriflunomide reduces T-cell proliferation and activation and production of cytokines, and it interferes with the interaction between cells and APCs. Teriflunomide may cause diarrhea, nausea, and thinning of the hair; more severe effects include transaminitis, lymphopenia, teratogenicity, latent tuberculosis, neuropathy, and hypertension. A complete blood cell count with differential and liver function tests should be done monthly for the first 6 months of therapy. In addition, patients should undergo tuberculosis screening before starting treatment with teriflunomide and a wash-out if indicated. Dimethyl Fumarate Dimethyl fumarate changes the balance of Th 1 to Th 2 cells and activates the transcription factor Nrf2 transcriptional pathway, which can reduce oxidative stress. Patients using dimethyl fumarate have experienced flushing and GI distress; in more severe cases, transaminitis and leukopenia may occur. Monitoring should include a periodic complete blood cell count with differential and liver function tests. Peginterferon β-1a Peginterferon β-1a is a chemically modified version of interferon β-1a, where polyethylene glycol has been attached to the interferon molecule, thus allowing it to remain active in the circulation for 2 4 weeks after a single subcutaneous (SC) injection. Adverse effects include injection-site reactions and flu-like symptoms. Laboratory monitoring of MS patients receiving this drug is similar to that of other interferons. Emerging Therapies Several drugs are in late stages of clinical development to treat patients with relapsing MS. Alemtuzumab targets CD52 + cells present on mature lymphocytes and depletes B and T cells. Used off-label to treat MS, it is administered over several days once a year. Side effects of alemtuzumab can be serious and may include infusion reactions, autoimmune thyroid disease, idiopathic thrombocytopenic purpura, Goodpasture s syndrome, and herpes simplex and varicella virus infections. Patients receiving alemtuzumab should undergo monthly complete blood cell counts with differential, liver function tests, and thyroid function tests. Daclizumab high-yield process targets the α subunit of the IL-2 receptor on T cells, reduces activation and proliferation of T cells, and expands CD56-bright cells that inhibit T-cell survival. It is administered monthly by SC injection. Side effects include transaminitis, autoimmune hepatitis, lymphadenopathy, rash, and alopecia universalis. Although exact monitoring still must be determined, patients should undergo liver function tests and complete blood cell counts with a differential. Ocrelizumab is a fully humanized monoclonal antibody that targets CD20 + B cells. It is given as an intravenous infusion every 6 months. Adverse effects include infusion reactions, lymphopenia, and infections. Patients should be monitored with CD19/CD20 B-cell counts. n HOW DOES PROGRESSIVE MS DIFFER FROM RELAPSING MS? Based on a presentation and written summary by Anne Gocke, PhD. Most MS patients will experience progression at some stage of their disease (Figure 3). RRMS involves unpredictable attacks that may involve permanent deficits and periods of remission. Patients with PPMS exhibit a steady increase in disability without attacks, whereas those with SPMS experience initial RRMS that suddenly is related to declines in function, although periods of remission occur. Finally, those with PRMS experience a steady decline in function and exhibit superimposed attacks. A definitive disease mechanism for progressive and relapsing MS has not been identified, although the role of environmental triggers, genetics, and other factors has been scrutinized. However, a number of interlinked pathways may contribute to the pathogenesis of the disease. PPMS Men are more likely to be affected by PPMS than by any other form of the 10 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 2

6 disease. This form of disease progression typically begins about 10 years after the onset of RRMS. Genetic susceptibility and pathology of this disorder are similar to those of other forms of MS, and an underlying neurodegenerative problem could be involved. Meningeal infiltrates of B and T cells are particularly prominent in patients with PPMS, and lymphoid follicles associated with underlying microglia activation and cortical plaques may be evident. White-matter plaques often are neuroinflammatory at their center, but microglia, macrophages, and ongoing simmering and possibly concentrically expanding axonopathy may be found. In addition, diffuse, low-grade parenchymal inflammation has been reported. Therapeutic failures could be explained by perivascular inflammation, which often occurs without associated disruption of the blood-brain barrier. Axonal and neuronal death may result from glutamate-mediated excitotoxicity, oxidative injury, iron accumulation, and/or mitochondrial failure. Currently, a lack of full understanding about the biology of MS impedes the development of effective treatments. Clinical investigators have questions about mechanisms driving progressive disease, therapeutic options currently are limited to symptomatic treatments and physical therapy, and no animal model that accurately models this disease stage is available. Further, an important question remains is the evolution from relapsing MS to progressive MS different from that of PPMS? Pathogenesis. In progressive MS, brain damage is driven by inflammation similar to that of RRMS but with an intact blood-brain barrier. This condition starts as an inflammatory disease. However, chronic inflammation leads to neurodegeneration or disease progression independent of inflammation. This neurodegeneration might cause intact neurons to lose control over microglial activation. In the early stages of the disease, inflammation amplifies progression of primarily neurodegenerative disease. In general, PPMS is characterized by diffuse, rather than focal, inflammation and involves more prominent cortical Increasing disability demyelination, diffuse axonal injury, and, frequently, the presence of microglial nodules in the brain. RRMS Time RRMS is characterized by acute focal inflammatory lesions in the white matter. Pathologically, RRMS is associated with inflammatory demyelinating lesions in the brain and spinal cord, which herald axonal damage and loss related to the foci of inflammation. The gray matter is involved less prominently in RRMS than it is in progressive MS. Pathologic Changes Inflammation occurs at all stages of MS and consists of perivascular and parenchymal infiltrates of lymphocytes and macrophages. The initial inflammatory response in patients with RRMS mainly involves the proliferation of CD8 + T cells in active lesions, as abundant macrophages are Progressive-relapsing multiple sclerosis Steady decline in function since onset, with superimposed attacks Secondary progressive multiple sclerosis Initial relapsing-remitting multiple sclerosis followed by a sudden decline in function, with periods of remission Primary progressive multiple sclerosis Steady increase in disability without attacks Relapsing-remitting multiple sclerosis Unpredictable attacks, which may or may not leave permanent deficits, followed by periods of remission FIGURE 3 Types of multiple sclerosis. Adapted, with permission, from a slide presented by Anne Gocke, PhD, at the 2014 joint CMSC/ACTRIMS annual meeting. recruited and activated. In the secondary response, T and B cells and macrophages are recruited as a result of myelin destruction. Profound damage to the blood-brain barrier, as evidenced by the presence of gadolinium-enhancing lesions on MRI, results from infiltration of inflammatory cells into the CNS. The relationship between inflammation and damage to the blood-brain barrier is less obvious in SPMS and PPMS, because impairment can occur with or without inflammatory infiltrates. Features of lymphoid follicle are found in large aggregates of inflammatory cells observed in the meninges. As the disease progresses, inflammation becomes compartmentalized behind the intact blood-brain barrier. Demyelination. During all stages of MS, plaques may be found in the gray and white matter. In progressive MS, slow expansion of preexisting lesions results in pronounced cortical demyelination associated with extensive diffuse injury T H E N E U R O L O G Y R E P O R T S u m m e r

7 in white and gray matter that appears to be normal. Cortical lesions occur most abundantly during the progressive stage of MS; these lesions are most prominent in subpial cortical layers, and they can be linked to local meningeal inflammation. Finally, activated microglia are associated with active lesions. The pathology of acute and relapsing MS is dominated by focal inflammatory demyelinated plaques in the white matter. Tissue injury. The brains of patients with MS exhibit widespread inflammation, microglial activation, astrogliosis, and mild demyelination and axonal loss in normal-appearing white matter. The extent and severity of these changes increase with disease duration and most closely are asociated with progressive MS; small-caliber axons are most affected. However, the extent of diffuse injury does not correlate with the number, size, or destructiveness of focal lesions. Instead, it correlates moderately with the extent of cortical demyelination. RRMS is related to distinct patterns of demyelination and tissue injury, probably because of distinct immune processes of inflammatory lesions. In contrast, patterns of tissue injury largely are homogeneous in SPMS and PPMS, probably because of the slow expansion of existing lesions with sparse remyelination. Disease Mechanisms Microglial activation. In both RRMS and progressive MS, active tissue injury is associated with microglial activation. In addition, microglial nodules are seen in progressive MS. Oxidative bursts by activated microglia my help to induce demyelination and progressive axonal injury. Microglia may be neuroprotective and could promote remyelination after debris is removed and neurotrophic molecules are secreted. Mitochondrial injury. The pathogenesis of MS may be related to energy deficiency or virtual hypoxia. Impaired NADH dehydrogenase activity and increases in complex IV activity have been noted in the mitochondria of MS lesions. Mitochondrial injury may reflex oxidative damage noted in areas of initial tissue injury. The increased susceptibility to neurodegeneration seen in patients with SPMS and PPMS may be explained partially by an accumulation of mitochondrial DNA deletions. Oxidative stress encourages mitochondrial dysfunction in a number of ways. Free radicals disrupt mitochondrial enzyme function. Oxidative stress modifies mitochondrial proteins and accelerates their degeneration. Further, it interferes with de novo synthesis of respiratory chain components and induces mitochondrial DNA damage. Oxidative injury is pronounced in progressive MS lesions, even though inflammation is low; therefore, it may be driven by factors other than inflammatory processes. Iron accumulation. Iron accumulates in the aging brain and is stored in oligodendrocytes; subsequently, it is detoxified when it binds to ferritin. Intracytoplasmic iron accumulation may explain why these cells are so susceptible to degeneration during oxidative stress. In MS lesions, activated macrophages and microglia take up iron, leading to dystrophy, fragmentation, and cellular degeneration. The process depends upon patient age and may be more pronounced among patients with progressive MS than among those with RRMS. Summary More information is needed about the disease mechanisms of RRMS and progressive MS. A number of interlinked pathways contribute to the development of the disease, and inflammation mediated by T and B cells and macrophages orchestrate demyelination and degeneration in patients with all forms of MS. In progressive forms of the disease, inflammation is noted by lymphoid follicles in meninges becoming trapped behind an intact blood-brain barrier, making use of anti-inflammatory agents ineffectual. Tissue injury may be affected by microglia activation, oxidative injury, and damage to mitochondria. In progressive MS, liberation of iron may enhance oxidative damage and result in increased neurodegeneration. Accumulated tissue damage exhausts the functional reserve capacity of the brain and may accelerate clinical deterioration, with slow, progressive tissue injury. Better models of progressive MS are needed to develop effective DMTs for it. SUGGESTED READINGS Abbas A, Lichtman A (eds). Basic Immunology, Functions and Disorders of the Immune System. 3rd ed. Philadelphia PA: Saunders Elsevier; Calabresi PA, Kieseier B, Arnold D, et al; ADVANCE Study Investigators. Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014;13: Clinical Immunology Society. Basic immunology. educational-resources/basic-immunology. Accessed July 17, Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380: Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380: Dhib-Jalbut S. Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis. Neurology. 2002;58(suppl 4):S3 S9. Giovannoni G, Gold R, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial. Lancet Neurol. 2014;13: Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo controlled trial. Lancet. 2013;381: Heath G. Basic immunology. ec6326f4b524b41c_heath pdf. 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