Immunology of relapse and remission in multiple sclerosis.

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Further

Annu. Rev. Immunol. 2014.32:257-281. Downloaded from www.annualreviews.org Access provided by INSEAD on 03/06/18. For personal use only.

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Immunology of Relapse and Remission in Multiple Sclerosis Lawrence Steinman Departments of Pediatrics, Neurology and Neurological Sciences, Stanford University, Stanford, California 94305; email: [email protected]

Annu. Rev. Immunol. 2014. 32:257–81

Keywords

First published online as a Review in Advance on January 15, 2014

multiple sclerosis, relapsing-remitting multiple sclerosis, neuromyelitis optica, autoimmune disease

The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev-immunol-032713-120227 c 2014 by Annual Reviews. Copyright All rights reserved

Abstract Eighty percent of individuals with multiple sclerosis (MS) initially develop a clinical pattern with periodic relapses followed by remissions, called relapsing-remitting MS (RRMS). This period of fluctuating disease may last for a decade or more. Clinical relapses reflect acute inflammation in the central nervous system (CNS), composed of the brain and spinal cord. Often, different anatomic areas in the CNS are involved each time a relapse occurs, resulting in varied clinical manifestations in each instance. Relapses are nearly always followed by some degree of remission, though recovery to baseline status before the flare is often incomplete. There are nine approved drugs for treatment of RRMS. The most potent drug for inhibiting relapses, the humanized anti-α4 integrin antibody known as Natalizumab, blocks homing of mononuclear cells to the CNS. The mechanisms of action of the approved drugs for RRMS provide a strong foundation for understanding the pathobiology of the relapse. Despite substantial progress in controlling relapses with the current armamentarium of medications, there is much to learn and ever more effective and safe therapies to develop.

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INTRODUCTION


More than 2.5 million individuals worldwide have multiple sclerosis (MS). Eighty percent have a unique feature of this particular disease characterized by periods of exacerbation followed by substantial remission, termed relapsing-remitting MS (RRMS). Relapses occur once every few years (1). Depending on where the inflammatory attack occurs in the central nervous system (CNS), symptoms may include visual, motor, or sensory disturbances or autonomic disturbances of bowel and bladder. Relapses may last for days or weeks and are followed by remission, often with some residual disability. As the relapsing-remitting disease continues, substantial disability ensues in about one-third of patients and yet the periods of relapse and remission perhaps paradoxically become less frequent. The pathophysiological changes that occur as the disease transforms from relapsing-remitting to progressive are not well understood. At the point where relapse and remission wane, the disease is called secondary-progressive MS (SPMS) (2). There are nine currently approved drugs for RRMS. Another neuroinflammatory disease, neuromyelitis optica (NMO), is characterized by relapses and remissions that are two to four times more frequent than in MS (3). In NMO, the main sites of attack are the optic nerves and spinal cord. There is currently no Food and Drug Administration (FDA)-approved treatment for NMO. NMO is much rarer than RRMS in Northern Europe and North America, although its prevalence is much higher in Asia than is RRMS (4). It is difficult to distinguish what constitutes an immunological trigger for relapse as opposed to some other pathophysiological cause for exacerbation of disease. A relapse is operationally defined as a neurological deficit that lasts for 24 h or more, in contrast to neurophysiological abnormalities that can be elicited transiently by merely elevating temperature, for example (5). Relapses can affect any part of the CNS, and sometimes more than one anatomic area is involved, as inflammation may arise in more than one area of the brain and spinal cord at one time. To describe in more detail the complexity of defining what constitutes an immunological trigger for relapse as opposed to some other pathophysiological mechanism that is nonimmune, let us consider a classic neurological phenomenon seen in patients with RRMS who may overheat during exercise. Uhthoff ’s Phenomenon is an example of an induced, nonimmunological exacerbation (6). In Uhthoff’s, exercise or even placing a warm towel over the ocular orbit of an individual with subclinical optic neuritis can trigger a transient worsening in vision in that eye, an effect that is completely resolved as the retina and optic nerve cool to body temperature. When the eye socket is overheated, conduction in the optic nerve is slowed, colors appear bleached, and visual acuity is impaired. Such a transient phenomenon is not considered a relapse and is solely due to alteration of the biophysics of axonal conduction after there has been demyelination. With demyelination, small increases in temperature lead to slowed conduction along myelinated fibers, where current jumps from one node of Ranvier to the next node. When insulation is damaged in demyelination, the distance from node to node is increased, and current is dispersed given the defective insulation. This may all seem biophysical, and it is! It is not immunological! This type of decline seen in Uhthoff ’s is quite distinct in function from an effect lasting more than 24 h most commonly seen with an immunological trigger. However, these distinctions are blurred when one realizes that one of the hallmarks of inflammation is a small increase in temperature. Prolonged increases in temperature (longer than 24 h), such as during fever in infectious disease, would be considered an immunological trigger for a relapse. Fever—the main reason, besides exercise, that our bodies heat—is a quintessential aspect of innate immunity involving an interaction between cytokines and thermoregulatory neurons in the hypothalamus. When one realizes that increased temperature is a main component of innate immunity, one can understand the complexity of defining what is an immunological trigger. Therefore, the main

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distinction is the temporal duration of the deficit, when we attempt to define a boundary between the purely biophysical and the immunological and inflammatory bases of a relapse. It is difficult to divorce immunology from other aspects of physiology. One must consider immunology in the broad context of physiology when considering complex events such as clinical relapse and remission. I have followed two operational rules for this review: First, I focus on mechanisms that are primarily immunological. Second, I discuss the often described collection of animal models of autoimmune demyelination, grouped under the heading of experimental autoimmune encephalomyelitis (EAE), only when the experiments directly translate to findings that hold true in the human disease counterparts: RRMS, NMO, and acute disseminated encephalomyelitis.


NATURAL HISTORY AND PATHOBIOLOGY OF THE RELAPSE Homing of Immune Cells to the Central Nervous System Is Critical for Relapse A logical strategy for understanding the pathobiology involved in relapse is to examine the mechanism of action of the most potent approved drug for reducing the incidence of relapse, which blocks a decisive event in relapse pathophysiology. We discovered the target for homing to the inflamed CNS in an experiment published in 1992 (7–9). This discovery led to the development of Natalizumab, a monoclonal antibody to α4 integrin. The main implication of the 1992 experiment is that one of the major events leading to a relapse in RRMS is the influx of inflammatory monocytes from the peripheral circulation through venules in the brain into the CNS. Blockade of this influx leads to a dramatic decline in relapses. I describe here details of the critical experiment leading to the development of Natalizumab, for, as the late Ralph Steinman has written, by studying human immunology and successful therapeutic interventions, we gain valuable insight: As scientists, we are accustomed to dissecting and analyzing a system in a reductionist way, often in genetically altered animals, to understand what is going on and in many cases to inspire future treatments. But in human subjects there is often a need to take a more integrative and interventional approach and try to direct physiology in order to understand disease processes and initiate new therapies. . . . The systematic study of a problem by intervention in patients is a powerful form of research, but it is currently a small and relatively neglected part of our profession. . . . The problem has been that most basic science journals simply are not prepared to get excited about the best findings that can be made in human subjects. (10, pp. 1349–50)

In 1992, a detailed analysis was undertaken of lymphocyte adherence to inflamed endothelium in the EAE model. A frozen section binding assay was designed to test the adherence of human or rodent lymphoid cells to the inflamed endothelium from rats with acute EAE. A collection of antibodies to putative adhesion molecules was tested, and only antibodies to α4 integrin or β1 integrin were effective in blocking adhesion to the inflamed endothelium from EAE brain (7). In the frozen section binding assays, antibodies to α4 and β1 integrin completely inhibited the adhesion of either human or rodent lymphocytes to inflamed brain endothelium. Other tested adhesion molecules were completely ineffective. These included antibodies to other integrins, including α3, α5, and α6, as well as to β2 integrin; to LFA-1 (CD18 and CD11a) and Mac-1 (CD18 and CD11b); to L-selectin; to CD2, CD4, and CD45; to OX44; and to Thy1.1. Hence, the binding of lymphocytes to inflamed endothelium in the CNS involved a highly specific interaction between particular integrins on the surface of the lymphocyte and a ligand on the surface of

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b Lymphocyte

α4 integrin LUMEN

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Figure 1 Natalizumab blocks lymphocyte homing in MS. (a) α4 integrin binds to vascular cell adhesion molecule 1 (VCAM-1) and to osteopontin (a second binding partner of α4 integrin, not depicted) on inflamed brain endothelium. This interaction gives lymphocytes access to the central nervous system (CNS). The presence of immune cells in the brain is a prominent feature of MS. (b) Natalizumab, a humanized antibody to α4 integrin, blocks binding of lymphocytes to VCAM and osteopontin on inflamed brain endothelium, thereby c 2012 Steinman. Journal of Cell Biology. preventing lymphocyte entry into the CNS. Adapted with permission from Reference 9. 199:413–416. doi: 10.1083/jcb.201207175.

the brain endothelium. The receptors on inflamed endothelium for α4β1 integrin have been demonstrated in both EAE and in MS brain to be primarily comprised of vascular cell adhesion molecule 1 (VCAM-1), although α4β1 integrin also binds to osteopontin (OPN) (11–13). The role of OPN in the induction of relapses in MS and in NMO is described later in this review. In the proof-of-concept experiments leading to the approval of Natalizumab, EAE was induced with T cell lines specific for myelin basic protein (MBP). These T cells home to the brain within 4 to 12 h (7). We had shown earlier that a single injection of T cell clones to a single epitope of MBP, the N-terminal 1–11 amino acids of MBP (MBP1−11 ), could trigger RRMS (14–16). Administration of antibody to α4β1 integrin after intravenous injection of the pathogenic T cells blocked the development of EAE (Figure 1). Even in the animals with paralysis, the severity of neurological impairment was reduced. Inflammation in the brain of these paralyzed animals was far less severe, indicating a concordance between clinical improvement and the extent of histopathology. Confirmation of these results was published soon thereafter by Janeway’s group, who showed that α4 integrins on cloned T cells were critical for the induction of EAE (17). Janeway, Baron, and colleagues (18) showed that α4 integrins on pathogenic T cells interacted with VCAM-1. It is pertinent to note that Janeway’s group was independently heading to the same conclusion as our group in 1992. It is remarkable how often in science we see multiple groups arriving at the same conclusion at about the same time. Phase 1, 2, and 3 clinical trials were performed in RRMS for the next ten years. The results showed that Natalizumab reduced the incidence of clinical relapses by over two-thirds and halted progression of disease compared with placebo. There was a large reduction in the extent of inflammation in the CNS as measured by the number of gadolinium-enhancing lesions; gadolinium lesions were reduced by 92%, and the number of new enlarging T2 hyperintense lesions was reduced by 83%. FDA approved Natalizumab in 2004 after an accelerated review indicated that the antibody was superior to other available therapies for RRMS (10, 19, 20). The mechanism of action of this antibody to α4 integrin has given us major insights into the critical event in a relapse: an influx of immune cells from outside the CNS (Figure 1). 260

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There are four implications of these results for our understanding of relapse pathophysiology: First, the brain does not have its own adaptive immune system. The composition of cells in inflammatory lesions in MS consists of endogenous microglia and astrocytes, along with exogenous immune cells from outside the CNS, including T cells, B cells, natural killer T (NKT) cells, and macrophages. Second, it is possible to detect the presence of a single clone within this diverse inflammatory infiltrate. This single T cell clone specific to a single epitope on a myelin antigen can itself trigger relapsing-remitting disease (21, 22). We still lack strong evidence of a dominant T cell clone that can trigger RRMS, although we can find clonal expansions of T cells in lesions as well as their clonal descendants in the peripheral circulation outside the CNS (23–25). Third, the main conduit of passage of immune cells into the brain is via the venules. Fourth, the most important molecules involved in homing are α4 integrin and its primary binding partner VCAM-1 (11, 13, 18). Blockade of lymphocyte homing to the brain is not without risk. Individuals who take monthly injections of Natalizumab beyond 24 months risk contracting a rare and devastating viral disease of the brain, progressive multifocal leukoencephalopathy (PML). This disease is triggered by a polyoma virus, known as the John Cunningham ( JC) virus. PML is usually seen only in immune-suppressed patients with HIV or in those individuals receiving potent drugs to block organ transplant rejection. Fortunately, the likelihood of developing PML can be determined by a simple antibody test in the blood. If an individual is negative for JC antibodies, the risk is essentially zero (26, 27). If JC antibody is present, however, then the risk is greater than 1 in 100 for those who have taken Natalizumab for more than 24 months and are also on immunosuppressive therapy before starting Natalizumab (26, 27). The implications of this complication of anti-integrin therapy are important: normal immune surveillance is crucial to protecting the brain from opportunistic infection. The physiological processes that allow immune cells to enter the brain with the potential to trigger relapse in MS are also vital components of a normal physiological process—the homing of α4 integrin–positive lymphoid cells—to protect against infection. One exciting aspect of these studies is that antibody JC is now approved by FDA as a biomarker to mitigate PML risk. More than 100,000 patients with MS have taken Natalizumab. So far, all patients with PML for whom samples were available before the diagnosis were positive for antiJC virus antibodies (9, 10, 26, 27). Other aspects of lymphocyte homing to the brain may influence relapses in MS. One major question is whether T helper 1 (Th1) and Th17 cells home to the brain via different mechanisms or even by different routes. Experimental animal studies have shown that CCR6+ Th17 cells may migrate to the brain via the choroid plexus (28). In defining the molecules involved in the homing of Th17 cells to the brain, Flanagan, Yednock, and colleagues applied a strategy similar to what we had tried together in 1992 (7). Yednock et al. (7) used a modified frozen section binding assay first described by Stamper & Woodruff (29). Flanagan and colleagues (30) showed that melanoma cell adhesion molecule (MCAM) expressed on Th17 cells binds to laminin-411 on inflamed endothelium. Blockade of MCAM with a monoclonal antibody suppresses EAE. Whether this discovery will lead to yet another therapy directed to the specific homing of Th17 cells remains to be seen. However, a link to human Th17 cells was shown in human memory T cells, with potent IL-17-secreting capacity shown in a population of cells expressing MCAM (30). Furthermore, MCAM is expressed on human endothelial cells at the blood-brain barrier (31). Prat and colleagues (31) showed that MCAM-positive CD4 T cells are increased in the circulation and within the CNS of MS patients as well as animals with EAE. A fascinating study of immune traffic to the brain in MS and EAE comes from investigations of the role of CXCL12 on brain endothelial barriers. Loss of CXCL12 from the abluminal surfaces of endothelium and redistribution to the luminal surface in regions of pathologic activity occurs www.annualreviews.org • Immunology of Relapse and Remission in MS

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in MS (32, 33). Activation of CXCR7, a receptor for CXCL12, occurs in EAE, and treatment with a CXCR7 antagonist reduces EAE disease severity even when clinical paralysis is ongoing. Applying this approach in the clinic could determine whether there are other modalities for interfering with leukocyte traffic—in addition to integrin blockade—that might effectively treat various forms of MS without the potential for the devastating consequences of opportunistic infections like PML. The barriers to testing such innovative approaches are steep, however. Many attractive strategies such as CXCL12 modulation have been shelved due to the high costs and long timelines for testing new RRMS medications. There has been an explosion in our understanding of various anatomic pathways of lymphocyte traffic to the brain. Flugel and colleagues (34) showed that, in EAE, immune cells must first pass ¨ through the lungs. There, these cells are licensed with various homing molecules, including integrins like β1 integrin and chemokines including CCL19 and CCL21, before they are competent to traffic to the brain (34, 35). Sphingolipids are critical in the migration of leukocytes away from the lungs to the brain (34–36). The molecule Fingolimod—an FDA-approved drug for treatment of RRMS—can trap lymphocytes in the lungs, thus impeding the cells’ ability to continue to the brain (34, 35). By modulating sphingolipid receptors, Fingolimod reduces the relapse rate in MS and impedes lymphocyte migration to the CNS. Fingolimod is a sphingosine phosphate analog that has agonist activity at a variety of sphingosine receptors, including S1P1, S1P4, and S1P5 receptors. The drug is effective at trapping lymphocytes in lymph nodes and impeding their egress. Treatment with Fingolimod leads to lymphopenia, and there is a risk of opportunistic infections, particularly with herpes viruses, as well as a risk of cancer from diminished immune surveillance (36). The physiological processes that are critical in protection from herpes virus may be somewhat different from those involved in protection from JC virus. As we learn more about the nature of homing mechanisms, including the characteristics of transit through the choroid plexus and brain venules, and about the requirement for passage of both monocytic and polymorphonuclear leukocytes that are particularly elicited by Th17 cytokines, we shall develop a more detailed picture of immune cell traffic to the brain in health and disease (8–10, 28, 30–35).


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Varied Role of Microbial Infection in Relapse There is an increasing awareness of how the microbiome influences the immune response, including its impact on EAE (37–39). After T cell clones that trigger EAE with relapses and remissions were first demonstrated in the mid-1980s (14–16), mice transgenic for T cell receptors that recognized epitopes on myelin proteins were developed. In one classic experiment, TCR transgenic mice for myelin basic protein elicited paralysis in a non-sterile facility, while the same mice housed in a sterile, specific pathogen–free facility did not exhibit paralysis (39). This experiment provided one of the first opportunities to study the role of the microbiome on autoimmunity. But clinical neurologists were well aware of the influence of infection on relapses and remissions in MS long before these revelations in mouse models. Paying attention to what happens in the clinic and what is known from clinical medicine would certainly benefit those of us in immunology who pay rapt attention to studies in experimental animals. Sibley and colleagues (40) analyzed the role of infection in relapses and MS progression in a prospective longitudinal study of 304 patients assessed monthly over an 8-year period. The study illuminated an interesting association with infection. During the two weeks before infection, exacerbation rates increased almost threefold (40). Similar results were seen by Correale and colleagues (41), who showed a strong correlation between infection and MS relapse. They demonstrated that there was increased activity on magnetic resonance imaging with an increased

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frequency of gadolinium-enhancing lesions with concomitant increases in T cell activity following infection and a subsequent clinical relapse of MS (41). Not all infections are deleterious. Helminth infections, which are notorious for eliciting a Th2 response, are associated with a lower relapse rate and decreased inflammatory activity on magnetic resonance imaging (42, 43). Correale & Farez (42, 43) showed that treating helminth infections with anti-helminth drugs actually worsened disease. These experiments implied that the Th2 milieu with helminth infections might be beneficial in reducing relapses in RRMS, demonstrating how the microbiome can protect against autoimmunity.


Role of Immunization in Relapse The possibility that routine immunizations may trigger relapses in RRMS has been studied extensively. One possible explanation for this is based on the concept of molecular mimicry, in which a vaccine component shares structural homologies with a component of myelin. There is strong evidence of molecular mimicry between various components of vaccines approved for human use—including seasonal influenza, hepatitis B, and human papilloma virus (HPV) vaccines—and myelin proteins (44–46). However, there is no epidemiological evidence linking these vaccines to flares of MS or to relapses of NMO. Earlier experience has shown that some vaccines, such as the 1976 swine flu vaccine, can be linked epidemiologically to neuroinflammation, with an increase in inflammatory neuropathy (Guillain-Barré Syndrome) evident between 1 and 12 weeks after immunization (47, 48). However, case reports and circumstantial evidence link other immunizations with individuals who have had relapses of MS and exacerbations of NMO. A report of four cases of NMO linked to the HPV vaccine showed molecular mimicry between HPV16 and 18 and regions of aquaporin-4 (AQP4) (49). Reports of five cases of MS followed immunization with HPV vaccine (50). Molecular mimicry has been reported between various HPVs (as well as components of hepatitis B vaccines) and epitopes of MBP (51). Further evidence supports a plausible mechanism for how a vaccine component that is a molecular mimic of a myelin protein could trigger relapse in the EAE model of MS. In the EAE model, Brocke and colleagues (52) immunized with a peptide from HPV that had homology to MBP. The HPV peptide—a molecular mimic of this region of HPV—was highly pathogenic and caused EAE with paralytic disease (52). Interestingly, other molecular mimics of bacterial and viral components can also suppress EAE (53). Thus, molecular mimics contained in the viral proteome may be potent modulators of both relapse and remission in RRMS. These experiments emphasize that microbial infections have “Janus faces” and can trigger or suppress neuroinflammation via shared structural homologies that lead to triggering or inhibition of the adaptive immune system. The role of infection in triggering innate immunity is described below as we consider the roles of Th1, Th17, and other inflammatory molecules in triggering relapses.

Role of Microbial Superantigens in Relapse At the intersection of innate and adaptive immunity are microbial superantigens that can bind to T cell receptors (TCRs) outside the traditional major histocompatibility complex (MHC) groove. Bacterial superantigens were shown to trigger exacerbations of EAE (54, 55). We reported that in various strains of mice, T lymphocytes expressing the Vβ 8 TCR bind the N-terminal epitope Ac1-11 of MBP, leading to EAE. The bacterial superantigen staphylococcal enterotoxin B (SEB) activates Vβ 8–expressing T cells. After immunization with Ac1-11, or after transfer of


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encephalitogenic T cell lines or clones reactive to Ac1-11, SEB induces exacerbation or relapses of paralytic disease in mice that are in clinical remission following an initial episode of paralysis, and it triggers paralysis in mice with subclinical disease (54). Whether relapses are triggered by superantigens in humans remains an open question.

Role of Adaptive Immunity to Myelin Antigens in RRMS and NMO


A popular idea to explain relapses in RRMS is that, following the initial adaptive immune response to a myelin antigen or mimic, intramolecular spreading to other epitopes on the same protein and to other antigens ensues (intermolecular spreading). Each time there is spreading to a new antigen without appropriate regulatory responses, a relapse might occur. However, evidence for this attractive idea is scant in RRMS. We do not know the dominant antigen or epitope that triggers RRMS, and there has not been a detailed study of epitope spreading at the T cell level, although autoantibody arrays have been used to track epitope spreading at the B cell level in RRMS (56). In NMO, the dominant immune response is to AQP-4 (57). No studies have been published on epitope spreading in NMO. The concept of epitope spreading was first described in 1992 by Lehmann and colleagues (58). It remains an attractive potential mechanism to explain relapses in RRMS. However, almost all the data relate to EAE, with only a few studies on the specifics of the adaptive immune response in RRMS. In EAE, there is abundant evidence of epitope spreading of the immune response to myelin antigens at both the T cell and antibody levels (58–61) (Figure 2). It is much more tractable to study epitope spreading to antibody determinants. The use of large-scale arrays can accommodate a design that measures the two-body interaction between antibody and antigen much more easily than is afforded with a measurement of a trimolecular interaction between the TCR, antigen epitope, and MHC protein (59). We designed autoantibody planar arrays in which all the major epitopes of the major myelin proteins were arrayed along with the parent recombinant myelin proteins. Using these arrays, we learned that the degree of epitope spreading of the antibodies to various myelin antigens correlated with relapse rates in three different models of relapsing-remitting EAE (59). Some epitopes of certain antigens also assume dominance, or a higher importance relative to others (59). In a study using an altered peptide ligand of a critical epitope of myelin basic protein, we observed that the massive inflammatory infiltrate representing diverse TCRs reactive to diverse epitopes could largely be attenuated after the peptide was delivered to paralyzed mice. The degree of paralysis was reduced and the extent of the inflammatory infiltrates regressed. The effect could be reversed with antibodies to IL-4, indicating that Th2 cytokines might be critical for controlling the spread of the immune response to multiple epitopes (21). Figure 2 illustrates this phenomenon (62). Relapsing-remitting EAE can be initially triggered with a T cell clone specific for one epitope on one myelin antigen, but this adaptive response can spread to other epitopes on that antigen— known as intramolecular spreading—or to new epitopes on other myelin antigens (14–16, 21, 59–62). Epitope spreading is quite complex, with spreading to different epitopes on one molecule having distinct MHC class II restriction elements. Thus, MBP1−11 is restricted by I-A, whereas MBP35−47 is restricted by I-E (60). Other epitopes are nested within a larger peptide and are recognized by distinct TCRs. MBP89−101 is recognized by a different TCR than MBP89−100 (61). Evidence in EAE suggests an ordered progression of epitope spreading in models of RRMS (21, 62) (Figure 2). Attempts to tolerize in RRMS to multiple epitopes on different myelin proteins—myelin basic protein, proteolipid protein, myelin-associated glycoprotein, myelin oligodendrocyte glycoprotein—have been undertaken with DNA vaccination (56, 63, 64), with peptides covalently coupled to lymphocytes (65), and with a transdermal peptide (63, 66). All trials 264

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Figure 2 Mechanism for intra- and intermolecular epitope spreading in autoimmunity. After the initial encounter with a virus mimicking an epitope on a myelin protein, immunity to various myelin components arises. During the initial phase of the disease, first responses are often directed to a proteolipid protein (PLP) such as PLP peptide 210–244. As the disease recurs or progresses, T cell responses spread to other determinants (indicated by the letter D) on PLPs, such as PLP peptide 50–59 (labeled as protein 1, D2 , in the figure). As intramolecular spreading occurs, the residual response to protein 1, D1 , wanes and becomes undetectable. The immune response spreads to other determinants on other proteins, a process called intermolecular epitope spreading. T cells can be detected that are reactive to myelin basic protein, protein 2, D3 , and D4 ; or to myelin oligodendrocyte glycoprotein, protein 3, D5 , and D6 . The spreading response can be suppressed by applying a soluble fragment of a protein that elicits Th2 cell responses involving cytokines such as IL-4, which subverts spreading. The yellow arrows indicate that IL-4 turns each Th response from a Th1 to a Th2 response (lower bars). Although the decreasing heights of the bars indicate that the sequential Th1 responses are reduced, they may be increased upon stimulation during relapses of disease. The yellow thunderbolt indicates that the initiating autoimmune response wanes and may become undetectable as the disease progresses. In this way, an entire inflammatory infiltrate can be cleared using one suppressive peptide fragment (62). The magenta cones on the right indicate the size of an inflammatory infiltrate, composed largely of bystander T cells, at the site of disease. Treatment with altered peptide ligands can reduce the size c 1999. Rockefeller of these inflammatory infiltrates (62). Reproduced with permission from Reference 62. University Press. Journal of Experimental Medicine. 189:1021–24. doi: 10.1084/jem.189.7.1021.

reported some positive results. With DNA vaccination to myelin basic protein in a 267-patient analysis, the median 4-week rate of new enhancing lesions during weeks 28 to 48 was 50% lower with 0.5 mg BHT-3009 ( p < 0.07) and, during weeks 8 to 48, was 61% lower with 0.5 mg BHT-3009 ( p < 0.05). The mean volume of enhancing lesions at week 48 was 51% lower on 0.5 mg BHT-3009 compared with placebo ( p < 0.02) (56). Dramatic reductions in levels of antibody in the cerebrospinal fluid (CSF) to 23 myelin-specific antigens were seen in the 0.5 mg arm. There was no change in the annualized relapse rate at one year, however, though the annualized relapse rate was substantially lower—0.4 relapses per year—than in other trials (56). In a study with transdermal applications of three myelin peptides, 30 patients entered a placebo-controlled trial (66). Twenty treated patients had transdermal applications of three myelin peptides: MBP85−99 , MOG35−55 , and PLP139−155 . There was a significant reduction in both gadolinium lesions and in relapse rate, and safety was excellent (66). In a study of antigen-coupled www.annualreviews.org • Immunology of Relapse and Remission in MS

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peripheral blood monocytes, seven RRMS and two SPMS patients were treated with peripheral blood mononuclear cells chemically coupled with seven myelin peptides (MOG1−20 , MOG35−55 , MBP13−32 , MBP83−99 , MBP111−129 , MBP146−170 , and PLP139−154 ). In this trial, patients given higher doses of peptide-coupled spleen cells (>1 × 109 ) had a decrease in myelin-specific T cell responses not seen at lower doses (65). In RRMS, autoantibody arrays have been used to measure the extent of epitope spreading at the B cell level. Spreading to a wide range of myelin antigens, including both proteins and lipids, is extensive (67, 68). Longitudinal studies correlating the spread to periods before, during, and after relapse have not been published.

Role of Pregnancy in Relapses of MS Annu. Rev. Immunol. 2014.32:257-281. Downloaded from www.annualreviews.org Access provided by INSEAD on 03/06/18. For personal use only.

Pregnancy has a profound effect on relapses, with a reduction in relapse rate during the third trimester of pregnancy. After delivery, there is a rebound increase in relapse rate (69). Concordant results have been seen in EAE (70). Pregnancy protected against EAE in mice, protecting against the induction of relapses and even the initiation of new relapses. A serum factor modulated the proliferative response and the production of IL-2 in T cells sensitized to PLP139−151 , the antigen that triggers the relapsing-remitting model of EAE in SJL/J mice. In studies of MS brain lesions, pregnancy-related proteins such as pregnancy-associated plasma protein A (PAPPA) were present in acute and chronic lesions. PAPPA is a large zinc glycoprotein whose function is not fully known. Its sequence shows conserved motifs resembling the short consensus repeats of complement control proteins. Pregnancy-specific β1 glycoprotein mRNA was elevated in acute lesions (71). Studies have not supported a possible increase in relapse rate postpartum with breastfeeding (72, 73). There is an interesting association of HLA class I histocompatibility antigen, alpha chain G (HLA-G), a molecule that may play a role in pregnancy and fetal tolerance, as it is expressed by the placenta. HLA-G is associated with modulation of susceptibility to MS (74); it may help resolve neuroinflammation and is found in the cerebrospinal fluid in RRMS patients (75).

Role of Type 1 and Type 2 Interferons in Relapses of MS and NMO In one of the first publications on large-scale transcriptional profiling of MS lesions, the authors observed increases in IL-6, interferon (IFN)-γ, and IL-17 in lesions of patients with MS (71). The roles of type 1 and type 2 IFNs and of IL-17 in RRMS have some remarkable intersections with classical Th1 and Th17 pathways. Panitch, Johnson, and colleagues (76, 77) performed one of the classic human MS experiments in the 1980s when they administered recombinant IFN-γ to 18 individuals with RRMS. Recombinant IFN-γ induced relapses in seven of these patients. This experiment is one of the strongest arguments that relapses may be due to increased Th1 activity (76–78). The implications of this study in RRMS led many to conclude that EAE was also a Th1 disease. But in EAE, the story is more complex. Instead of worsening EAE, administration of IFN-γ ameliorated disease, whereas antibody to IFN-γ worsened disease; mice lacking the IFNγ gene had worsened disease. The same paradoxical results were seen in loss-of-function mice when TNF-α was genetically deleted (78–83). These results called for a major revision in our understanding of EAE as an interaction between two antagonistic pathways (Th1 and Th2) and helped pave the way for the emergence and elucidation of the Th17 pathway (see Table 1). To begin to study how the Th1 and Th17 pathways contribute to the induction of relapses, we first examined the effect of type 1 IFN on clinical disease in different forms of EAE. In EAE, it is possible to polarize disease into a Th1 and a Th17 form by adoptively transferring myelin-reactive T cells polarized in vitro to Th1 with IL-12 or to Th17 with IL-23 (84). In these 266

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Table 1 Predictions and outcomes in experimental autoimmune encephalomyelitis (EAE): flaws in the Th1/Th2 hypothesisa Prediction Administration of IFN-γ would worsen EAE IFN-γ knockouts would be resistant to EAE

EAE was worse in IFN-γ knockouts

Antibody to IFN-γ would protect in EAE

Antibody to IFN-γ worsened EAE

TNF knockouts would be resistant to EAE

EAE was worse in TNF knockouts

Administration of TNF would worsen EAE

Administration of TNF protected from EAE

a


Outcome Administration of IFN-γ protected from EAE

Source: Reference 78.

adoptive transfer models, administration of IFN-β leads to amelioration of Th1 EAE and to worsening of Th17 EAE. IFN-β induces the often suppressive cytokines IL-10 and IL-27 under Th1 polarizing conditions but not under Th17 conditions (84). In RRMS, high levels of IFN-β and high levels of IL-17F (above 200 pg/ml) are correlated with an increase in relapses (84–86). A type 1 IFN gene signature in peripheral blood monocytes is also associated with an increase in relapses in RRMS (87, 88). The concept that type 1 IFNs worsen Th17 neuroinflammatory disease received further support from studies of relapses in the related disease NMO (84, 89–93). NMO has the hallmarks of a Th17 inflammatory disease (89, 94, 95). Th17 inflammation is characterized in part by an altogether different pathology than Th1 inflammation and can be distinguished from Th1 inflammation by the presence of polymorphonuclear cells. Additionally, IL-17 is concomitantly expressed at the sites of disease in Th17 pathology but not Th1. The poles of Th1 versus Th17 pathology are even more evident in a comparison of pathology in RRMS and NMO (94, 95). In NMO, the adaptive immune system targets the water channel AQP-4, which is heavily expressed at the blood-brain barrier; this leads to inflammation in the CNS, with particularly heightened inflammation in the optic nerve and in longitudinally extensive regions of the spinal cord (57, 96). Areas of the brain around the area postrema associated with hiccups and vomiting are also prime targets of the immune system, and NMO sometimes presents with intractable vomiting or hiccups. More often, presentation and relapses involve recurrent spinal cord deficits or visual disturbances. The relapse rate in NMO is two to four times higher than in MS, and the progression of disability is often more rapid than in RRMS. In NMO, administration of type 1 IFN increases the relapse rate and increases antibody responses to AQP-4. So great is the evidence that IFN-β worsens NMO that it is medically contraindicated to administer type 1 IFN once a diagnosis of NMO is made (84, 89–93). In NMO, relapses worsen in the second trimester of pregnancy, when type 1 IFN levels are high (97–100). One of the critical neuropathological features of NMO—a feature that is characteristic of Th17 inflammation and distinguishes NMO from RRMS—is the presence of polymorphonuclear leukocytes (granulocytes) in lesions (84, 89, 95) (Figure 3). In experimental Th17 autoimmune neuroinflammation, relapses can be prevented by administering neutrophil elastase inhibitors (101, 102). Clinical trials of such inhibitors in NMO are under way. Many other intersections likely exist between other cytokines and Th1 and Th17. But the type 1 IFN response common to so many microbial infections may provide mechanistic insight into how infection triggers a relapse, particularly in individuals with a Th17 version of RRMS or with NMO. EAE studies have indicated that T cells with varied ratios of Th1 compared to Th17 characterize the infiltrate in the spinal cord, whereas T cell infiltration of the brain occurs when Th17 cells outnumber Th1 cells (103). It appears that Th1 T cells enter the brain first and that Th1, not Th17, cells drive spontaneous MS-like disease despite a functional regulatory T cell www.annualreviews.org • Immunology of Relapse and Remission in MS

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Predominantly Th17 Antigen

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Figure 3 Autoimmune diseases with a predominately IL-23−Th17 response secrete high levels of IL-17A and IL-17F, which signal to the surrounding tissue to upregulate granulocyte recruitment and activation factors such as G-CSF, CXCL1, and CXCL8. Through a currently unknown mechanism, endogenous expression of IFN-β by plasmacytoid dendritic cells or the therapeutic administration of IFN-β worsens Th17 disease. Conversely, predominantly Th1-mediated diseases are characterized by high levels of IFN-γ and have a lymphocytic and macrophage infiltrate. In Th1 disease, IFN-β, in concert with IFN-γ, drives anti-inflammatory responses such as upregulation of IL-27 or IL-10 or inhibits chemokine expression by macrophages. Adapted with permission from Reference 89.

response (104, 105). From recent studies on adoptively transferred MOG35−55 T cells polarized to Th17, we see longitudinally extensive lesions in the spinal cord and optic neuritis (101). However, it is paramount to avoid overreliance on conclusions from studies in mice.

Role of CD4+ T Cells, CD52+ T and B Cells, and CD20+ B Cells in RRMS and NMO In both RRMS and NMO, reductions in relapse rate are seen following administration of antiCD20 antibody (106, 107). In a recent Phase 2 trial of Ocrelizumab, gadolinium-enhancing lesions were reduced in frequency (lesions per patient) by 89% in the 600 mg dose group and 96% in the 2,000 mg dose group at 24 weeks. Annualized relapse rates were 80% and 73% lower in frequency (number of relapses) per patient, respectively, compared with placebo in these two groups. There was a concomitant reduction in new gadolinium-enhancing lesions in these clinical trials (107). Although anti-CD20 is not an FDA-approved therapy for NMO, open label trials indicate that there is a decline in the rate of relapse following administration of anti-CD20 (108). In NMO, anti-CD20 treatment was effective in reducing number of relapses, but paradoxically there was an increase in anti-AQP-4 antibody with a concomitant elevation in BAFF (B cell–activating factor) after initial treatment (109). Although many investigators state that RRMS is a T cell–mediated disease, results with depletion of CD20 B cells are far more impressive than what was seen in clinical trials with a CD4 268

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T cell–depleting chimeric antibody (110, 111). In a Phase 2 trial with a chimeric antibody that depleted CD4 T cells in RRMS, the degree of depletion of CD4-positive cells was important with regard to treatment efficacy; using CD4 counts as a covariate there was a statistically significant effect on the number of active lesions over 18 months ( p = 0.04). There was a statistically significant reduction of 41% in the number of


clinical relapses (a secondary efficacy parameter) after 9 months ( p = 0.02), which was still present after 18 months, but this finding may be partly due to physician unblinding. (111, p. 351)

The role of CD8+ T cells in both demyelination and in relapses and remissions is a subject ripe for further study. Goverman and colleagues (112, 113) have shown that CD4-induced EAE triggers spreading to epitopes on myelin proteins that are recognized via CD8+ T cells. Other treatments for NMO involve targeting plasmablasts with anti-IL-6R. Early studies indicate that even in treatment failures with anti-CD20, anti-IL-6R (tocilizumab) may be effective (114). A marked reduction in relapses is seen in treatment of RRMS with anti-CD52 (115). A remarkable side effect of this therapy is the emergence of new autoimmune diseases in the RRMS patient, most commonly Graves’ disease, Hashimoto’s thyroiditis, or, rarely, idiopathic thrombocytopenic purpura or Goodpasture’s syndrome. CD52 may have regulatory capacities in blocking autoreactivity. Treatment with anti-CD52 removes CD52+ cells expressing this regulatory break (116). This may explain the high incidence of new autoimmune disease with this experimental treatment of RRMS. A biomarker study has shown elevated levels of IL-21 in patients receiving anti-CD52 therapy who developed a new autoimmune condition (117).

Role of Osteopontin in Relapses of MS and NMO In 2001, we discovered that there were copious amounts of OPN transcribed in MS lesions (118). Investigators later showed that OPN is also highly expressed in lesions in NMO (119). Though OPN is not a cytokine, it is a key inflammatory molecule and a member of the family of small integrin binding proteins, termed SIBLING proteins (13). OPN’s role in relapses and its relationship to the most efficacious therapy for RRMS—treatment with antibody to α4 integrin— are now well understood. OPN binds α4 integrin (13). Injection of OPN into mice with EAE induces relapses (120). Measurements of OPN levels in blood in RRMS correlate with relapse and thus may be an effective biomarker for prediction of impending relapse (121–124). The mechanistic understanding that T cell signaling is modulated through OPN illuminates this molecule’s critical role in triggering relapses. In various models of EAE, injection of recombinant OPN (rOPN) induced relapse. In the SJL/J model of relapsing-remitting EAE induced by PLP peptide 139–151, administration of rOPN during a period of remission after an initial relapse resulted in a relapse within 24–36 h and the appearance of paralysis. In the C57Bl/6 model of SPMS, EAE is induced with MOG35−55 . In this model, OPN inhibited spontaneous recovery, and its daily administration resulted in disease exacerbation characteristic of a relapse with further disease progression (120). For TCR transgenic mice, in which all TCRs recognize MOG35−55 , EAE occurs spontaneously. Injection of rOPN into these mice induced relapses characteristic of NMO, with the development of heightened paralysis and with the rapid onset of optic neuritis. Furthermore, optic neuritis developed rapidly in these mice (120). The mechanism of relapse induction involves two major pathways: OPN stimulates expression of proinflammatory mediators, including Th1 (120) and Th17 (13, 125, 126) cytokines in myelin-specific T cells. OPN also inhibits FOXO3a-dependent apoptosis of autoreactive immune www.annualreviews.org • Immunology of Relapse and Remission in MS

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Osteopontin α4β1 integrin

CYTOPLASM p50 p65 IκBα

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P

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IκBα Ub Ub Ub

BIM

BAK BAX Mitochondrion Cytochrome c

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Degradation NF-κB NUCLEUS

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Enhanced expression of prosurvival genes

Prosurvival genes and Th1- and Th17type cytokines

Active FOXO3A

Antisurvival genes such as BIM, BAK, and BAX

Decreased expression of antisurvival genes

Figure 4 Induction of relapses by osteopontin (OPN). OPN binds to its receptor α4β1 integrin (also known as VLA-4), leading to increased phosphorylation of IκB kinase-β (IKKβ). Subsequent phosphorylation of the inhibitor of the NF-κB α-subunit (IκBα) releases the NF-κB subunits p50 and p65, which then translocate to the nucleus. NF-κB upregulates the expression of prosurvival genes and T helper 1 (Th1)- and Th17-type cytokines. OPN engagement by α4β1 integrin also provides prosurvival signals by blocking apoptosis as a result of increased phosphorylation of the transcription factor forkhead box O3A (FOXO3A). This prevents the translocation of FOXO3A to the nucleus, blocking the transcription of antisurvival genes such as BCL-2-interacting mediator of cell death (BIM), BCL-2-associated X protein (BAX), and BCL-2 antagonist/killer (BAK). Ub, ubiquitin. Adapted with permission from Reference 13.

cells (13, 120). A balance is in play between the transcription factors FOXO3a and NF-κB, which have opposing effects on the apoptotic death of activated T cells (Figure 4). OPN signaling promotes survival of autoreactive T cells: Following OPN engagement of α4 integrin, phosphorylated FOXO3a is excluded from the nucleus. When FOXO3a translocates to the nucleus, it promotes apoptosis. Thus, exclusion promotes survival of autoreactive T cells. OPN signals increase IκBα degradation, leading to nuclear translocation of NF-κB. OPN signals activate IκB kinase-β (IKKβ), adding to nuclear translocation of NF-κB. OPN thus inversely impacts FOXO3a and NF-κB, leading overall to the survival, rather than the apoptotic death, of activated autoreactive T cells (13, 120) (Figure 4). OPN is also a durable biomarker for relapse in RRMS. We know that OPN is produced by macrophages, microglia, and astrocytes as well as CCR2+ CCR5+ T cells (127). CCR2+ CCR5+ T cells are found in the CSF of patients with RRMS during relapse. These T cells have a higher capacity to cross the blood-brain barrier than do T cells devoid of these chemokine receptors. Numerous studies indicate that OPN is a reliable measure of disease activity before and during relapse: Bornsen and colleagues (121) demonstrated increased OPN in CSF during MS relapses, but ¨ OPN levels fell after successful treatment with Natalizumab (128). Vogt and colleagues (122, 123) had previously demonstrated increased OPN levels in plasma in RRMS patients. In a longitudinal study, these investigators showed that OPN levels were elevated even one month before the appearance of new gadolinium-enhancing lesions, indicative of new inflammatory activity in the brain 270

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(123). Comabella et al. (124) studied 221 MS patients and 36 healthy controls. OPN levels were elevated in clinical relapse compared with remission. OPN levels also rise during flares of NMO (129).


NATURAL HISTORY AND PATHOBIOLOGY OF REMISSION One remarkable aspect of relapse in RRMS is the strong natural remission that occurs following the nadir in neurological symptoms. Most deficits are alleviated, and the patient’s neurological status returns to normal after full-blown relapses. This is true for recovery from some of the more devastating attacks of optic neuritis or transverse myelitis in both RRMS and NMO. Recovery— often full recovery—evolves over days to weeks. What do we know about this phenomenon? What molecules are involved in the recovery, and could they be developed as part of a therapeutic strategy? As a clinician, I often tell my patients after an attack that if we could only understand which molecules are involved in the induction of their likely remission, then we would have some good leads for new therapies!

Role of Regulatory T Cells in Remission in MS There is some evidence that regulatory T cells (Tregs) are themselves dysregulated in RRMS and that they contribute both to increased relapse and to incomplete recovery during the remission phase (130, 131). There is an increase in Tregs with increased Foxp3 expression in circulating CD4+ CD25+ T cells in the remission phase of MS (132). Other studies point to a failure of Tregs to modulate T effector cells in RRMS. The basis for the resistance of T effectors to Tregs is due to an increase in IL-6 receptor α (IL-6Rα) expression and elevated IL-6 signaling as measured by pSTAT3 in CD4+ T cells in RRMS subjects (133). A major role for Tregs in relapse or remission in RRMS has yet to be defined, although some form of Treg—not necessarily of the Foxp3+ variety (130–132) but perhaps a CD52+ regulatory T cell (116)—likely plays a major role.

Role of Neurotrophins in Remission in MS In a study of complete remission following relapse in RRMS, investigators analyzed peripheral blood mononuclear cells and observed increases in brain-derived neurotrophic factor (BDNF), during the relapse, followed by increased expression of nerve growth factor, glial cell line–derived neurotrophic factor, neurotrophin 3, and neurotrophin 4 (134). The most widely used medicine for RRMS, glatiramer acetate, was shown to increase BDNF in peripheral blood mononuclear cells (134). An increase in BDNF plausibly underlies its benefit in reducing relapse and disease progression in RRMS (135, 136).

Role of Vitamin D in Relapses of MS Vitamin D is a potent immune modulator. Lower levels of vitamin D are correlated with higher rates of relapse (137). Vitamin D3 has a direct suppressive effect on transcription and production of IL-17A from human CD4 T cells. The downregulation of 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ] on IL-17A involves the blocking of nuclear factor for activated T cells, the recruitment of histone deacetylase, the sequestration of Runt-related transcription factor 1 by 1,25(OH)2 D3 /VDR, and the direct effect of 1,25(OH)2 D3 in inducing Foxp3. These results have been seen in both human CD4 T cells and in mice (138). In EAE, administration of vitamin D3 inhibits disease progression (138). Over the past 20 years, there has been a general decrease in the relapse rate in the placebo arm of clinical trials based on data from 12 published trials (139). One www.annualreviews.org • Immunology of Relapse and Remission in MS

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potential reason is the increasing awareness of the potential benefits of vitamin D3. Many RRMS patients self-medicate with vitamin D3, and it is common practice for physicians to prescribe vitamin D3 to their patients.

Role of Small Heat Shock Proteins and Other Amyloids in Remissions of MS


In 2001, large-scale sequencing of cDNA libraries derived from plaques dissected from brains of patients with MS revealed that αB-crystallin was the most abundant transcript unique to MS lesions (13, 118). αB-crystallin is a member of the small heat shock protein (sHSP) superfamily, the most widespread set of molecular chaperones, which are expressed by organisms in all three kingdoms. Members of this superfamily are diverse in sequence and size but are characterized by their conserved 90–amino acid heat shock protein 20 (HSP20) domain (13, 118). Members of the sHSP family form amyloid aggregates, albeit slowly compared with proteins such as amyloid beta (Aβ) or tau. In the past decade, the role of amyloid-forming proteins in MS lesions has become more apparent (13, 140–148). The surprising lesson is that these amyloid-forming proteins may provide benefit and account for remission in RRMS (146). In fact, hexapeptide domains from these proteins—ranging from αB-crystallin to Aβ to tau, all found in MS lesions—can reverse paralysis and prevent relapses in the EAE model (142, 146). Genetic deletion of the parent amyloid proteins, whether αB-crystallin, tau, Aβ, or serum amyloid P (SAP), all exacerbate EAE (140, 145, 147, 149–151). Thus, these proteins found in MS lesions are protective—reducing paralysis and preventing relapses in EAE—in gain-of-function experiments but worsen neuroinflammation in loss-of-function experiments (147, 149–151). αB-crystallin is part of a functional trimolecular complex in astrocytes and microglia at the blood-brain barrier, where it potentially interacts with the OPN–α4 integrin complex. With its strategic presence at the blood-brain barrier in astrocytes, αB-crystallin is positioned to dampen and reverse damage that occurs following the α4 integrin–mediated homing of immune cells to the brain (13). αB-crystallin can protect the brain both when it is an intracellular sHSP and when it is administered as an extracellular molecule. In its intracellular role, αB-crystallin decreases the activation of NF-κB and p38 mitogen-associated protein kinase (MAPK, also known as MAPK14) in T cells, macrophages, dendritic cells, and glial cells (Figure 5). Adaptive Th1 and Th17 cell responses directed to myelin are accentuated in αB-crystallin-deficient mice when various forms of EAE are induced. αB-crystallin also reduces the cleavage of pro-caspase 3 to active caspase 3 and thus attenuates apoptosis (13, 140). Administration of recombinant αB-crystallin resolved ongoing paralysis in various models of relapsing-remitting and progressive EAE (140). The amelioration of disease by such administration in mice with EAE was in part due to the decreased infiltration of immune cells into the brain and spinal cord and the suppression of immune cell function. Furthermore, we observed decreased proliferation and diminished production of IL-2, IL-12p40, TNF, IFN-γ, and IL-17 by splenocytes from mice treated with recombinant αB-crystallin. In human CD4 T cells from RRMS patients, the secretion of proinflammatory cytokines was decreased in the presence of CRYAB in RRMS participants with mild disease severity, whereas no changes were observed in healthy controls (148). Furthermore, higher levels of miR181a microRNA, a marker upregulated in tolerant CD8+ T cells, were also correlated with suppressed cytokine production in CD4+ T cells of MS patients (148). αB-crystallin opposes many of the deleterious effects of OPN, which include the production of Th1- and Th17-type cytokines and the activation of proinflammatory p38 MAPK pathways. Remissions of EAE can be induced by the administration of αB-crystallin alone (13, 140). 272

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Figure 5 Mechanism of remission induced by αB-crystallin. αB-crystallin inhibits apoptosis of neurons and glial cells by blocking the cleavage of pro-caspase 3. αB-crystallin also inhibits the phosphorylation of p38 mitogenactivated protein kinase (MAPK, also known as MAPK14) and of the NF-κB subunits p50 and p65 by inhibitor of NF-κB α-subunit (IκBα), thereby inhibiting NF-κB-mediated transcription of proinflammatory cytokines. Consequently, the production of both Th1- and Th17-type cytokines is reduced. There is considerable crosstalk between the p38 MAPK and NF-κB pathways in inflammatory responses, as indicated by an arrow connecting these two key pathways. Ub, ubiquitin. Adapted with permission from Reference 13.

In a proteomic study of MS lesions, other proteins that form amyloid in addition to αB-crystallin were detected, including Aβ, tau, and SAP (141). Although amyloid proteins are often associated with neuropathology, their roles in MS have never received much attention. As we have shown, genetic deletion of αB-crystallin, also known as HspB5 (140), and of amyloid precursor protein, the parent protein of Aβ A4 (145), increased paralysis and inflammation in the EAE animal model of MS. Deletion of αB-crystallin also worsened outcome in stroke, with bigger lesions, whereas administration of αB-crystallin led to amelioration of stroke pathology, even when given as long as 48 h after onset (152). Deletion of amyloid precursor protein (APP) worsened outcome in brain trauma models, whereas overexpressing APP ameliorated the neurological effects of trauma (153). This property of exacerbating EAE has been reported with genetic deletion of other amyloidforming proteins, including major prion protein, SAP, and tau (147, 149–151). αB-crystallin, tau, APP, and SAP precursor protein are all found in MS lesions (141). When this evidence is taken together, one might conclude that loss of expression of amyloid-forming proteins is associated with a worsening of the spectrum of inflammatory, ischemic, and traumatic brain injuries. This, of course, runs counter to the amyloid hypothesis in Alzheimer’s disease, which holds that amyloid deposits of Aβ and tau are deleterious and lead to dementia (147, 154). Following the biophysical models developed by Eisenberg & Jucker (155), we took fibrilforming hexapeptide motifs from αB-crystallin, tau, and SAP protein and examined what would happen if we gave these hexapeptides to a mouse with an acute attack of EAE (147). To our surprise, these amyloid hexapeptides reversed paralysis, often within 24 h, and diminished the number and extent of inflammatory lesions in the CNS. Hexapeptides were therapeutic when they had chaperone function and when they formed amyloid fibrils. The mechanism of action involves www.annualreviews.org • Immunology of Relapse and Remission in MS

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binding and precipitation of proinflammatory molecules found at the site of neuroinflammation (147). The paradoxical implication of these studies is that amyloid-forming proteins may be involved in the remissions seen regularly in RRMS. Of note, amyloid proteins including Aβ and tau are modulated during relapse and therapy in MS. After successful treatment with Natalizumab, levels of APP and Aβ in the CSF actually increase, implying that lower levels of these molecules are associated with inflammatory states (156).

CONCLUDING REMARKS


The clinical course of MS and NMO is marked by periods of intense worsening called relapses, followed by impressive remissions. Understanding the molecular foundations of both the attack and the recovery may provide new targets for therapy. If we could harness the physiology of remission, we might discover an effective cure for RRMS. Why not induce permanent remission by bolstering the mechanisms in play during natural remission? Studies on relapse and remission will undoubtedly uncover predictive biomarkers that will inform treatment before the attack occurs and that may help us decide which medication to choose from the growing armamentarium of approved pharmaceuticals.

DISCLOSURE STATEMENT The author has received consulting fees from Tolerion, Cardinal Therapeutics, Atreca, Biogen IDEC, MedImmune, Receptos, Sanofi, Teva, Pfizer, and Novartis. LITERATURE CITED 1. Steinman L, Martin R, Bernard CCA, Conlon P, Oksenberg JR. 2002. Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy. Annu. Rev. Neurosci. 25:491–505 2. Steinman L. 2013. Weighing in on autoimmune disease: ‘hub and spoke’ T cell traffic in autoimmunity. Nat. Med. 19:139–41 3. Mealy MA, Wingerchuk DM, Greenberg BM, Levy M. 2012. Epidemiology of neuromyelitis optica in the United States: a multicenter analysis. Arch. Neurol. 69(9):1176–80 4. Jacob A, McKeon A, Nakashima I, Sato DK, Elsone L, et al. 2013. Current concept of neuromyelitis optica (NMO) and NMO spectrum disorders. J. Neurol. Neurosurg. Psychiatry 84(8):922–30 5. Multiple Sclerosis Society. 2012. Relapsing Remitting (RRMS). London: MS Natl. Cent. (MSNC). http://www.mssociety.org.uk/what-is-ms/types-of-ms/relapsing-remitting-rrms 6. Frohman TC, Davis SL, Beh S, Greenberg BM, Remington G, Frohman EM. 2013. Uhthoff ’s phenomena in MS-clinical features and pathophysiology. Nat. Rev. Neurol. 9:535–40 7. Yednock T, Cannon C, Fritz L, Sanchez-Madrid F, Steinman L, Karin N. 1992. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 356:63–66 8. Steinman L. 2005. Blocking adhesion molecules as therapy for multiple sclerosis: Natalizumab. Nat. Rev. Drug Discov. 4:510–19 9. Steinman L. 2012. The discovery of natalizumab, a potent therapeutic for multiple sclerosis. J. Cell Biol. 199(3):413–16 10. Steinman RM. 2005. Research on human subjects in the JEM. J. Exp. Med. 201(9):1349–50 11. Verbeek MM, Westphal JR, Ruiter DJ, de Waal RM. 1995. T lymphocyte adhesion to human brain pericytes is mediated via very late antigen-4/vascular cell adhesion molecule-1 interactions. J. Immunol. 154(11):5876–84 12. Osborn L, Hession C, Tizard R, Vassallo C, Luhowskyj S, et al. 1989. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 59(6):1203–11 274

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148. Quach QL, Metz LM, Thomas JC, Rothbard JB, Steinman L, et al. 2013. CRYAB modulates the activation of CD4+ T cells from relapsing-remitting multiple sclerosis patients. Mult. Scler. J. 19:1867– 77 149. Gourdain P, Ballerini C, Nicot AB, Carnaud C. 2012. Exacerbation of experimental autoimmune encephalomyelitis in prion protein (PrPc)-null mice: evidence for a critical role of the central nervous system. J. Neuroinflamm. 9:25 150. Ji Z, Ke J, Geng JG. 2012. SAP suppresses the development of experimental autoimmune encephalomyelitis in C57BL/6 mice. Immunol. Cell Biol. 90:388–95 151. Weinger JG, Davies P, Acker CM, Brosnan CF, Tsiperson V, et al. 2012. Mice devoid of Tau have increased susceptibility to neuronal damage in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. J. Neuropathol. Exp. Neurol. 71:422–33 152. Arac A, Brownell SE, Rothbard JB, Chen C, Ko RM, et al. 2011. Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation. Proc. Natl. Acad. Sci. USA 108(32):13287–92 153. Corrigan F, Vink R, Blumbergs PC, Masters CL, Cappai R, et al. 2012. sAPPαrescues deficits in amyloid precursor protein knockout mice following focal traumatic brain injury. J. Neurochem. 122:208–20 154. Flatow I. 2013. Amyloid proteins help paralyzed mice walk again. Talk of the Nation. Apr. 5. http://www.npr.org/2013/04/05/176339692/amyloid-proteins-help-paralyzed-mice-walk-again 155. Eisenberg D, Jucker M. 2012. The amyloid state of proteins in human diseases. Cell 148:1188–203 156. Augutis K, Axelsson M, Portelius E, Brinkmalm G, Andreasson U, et al. 2013. Cerebrospinal fluid biomarkers of β-amyloid metabolism in multiple sclerosis. Mult. Scler. 19(5):543–52


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Contents

Annual Review of Immunology Volume 33, 2015


Remembrance of Immunology Past: Conversations with Herman Eisen Herman N. Eisen and Sondra Schlesinger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 HLA-B27 Paul Bowness p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p29 Inflammasome-Independent Regulation of IL-1-Family Cytokines Mihai G. Netea, Frank L. van de Veerdonk, Jos W.M. van der Meer, Charles A. Dinarello, and Leo A.B. Joosten p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p49 Programmed Necrosis in the Cross Talk of Cell Death and Inflammation Francis Ka-Ming Chan, Nivea Farias Luz, and Kenta Moriwaki p p p p p p p p p p p p p p p p p p p p p p p p p79 Endoplasmic Reticulum Stress in Immunity Sarah E. Bettigole and Laurie H. Glimcher p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 107 Insights into Cytokine–Receptor Interactions from Cytokine Engineering Jamie B. Spangler, Ignacio Moraga, Juan L. Mendoza, and K. Christopher Garcia p p p 139 T Cell Antigen Receptor Recognition of Antigen-Presenting Molecules Jamie Rossjohn, Stephanie Gras, John J. Miles, Stephen J. Turner, Dale I. Godfrey, and James McCluskey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 169 Immunity to Helminths: Resistance, Regulation, and Susceptibility to Gastrointestinal Nematodes Richard K. Grencis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 201 Microbiota-Mediated Inflammation and Antimicrobial Defense in the Intestine Silvia Caballero and Eric G. Pamer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 227 Innate Immune Pattern Recognition: A Cell Biological Perspective Sky W. Brubaker, Kevin S. Bonham, Ivan Zanoni, and Jonathan C. Kagan p p p p p p p p p p p 257 Ion Channels in Innate and Adaptive Immunity Stefan Feske, Heike Wulff, and Edward Y. Skolnik p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 291 TAM Receptor Signaling in Immune Homeostasis Carla V. Rothlin, Eugenio A. Carrera-Silva, Lidia Bosurgi, and Sourav Ghosh p p p p p p p 355 Structural Biology of Innate Immunity Qian Yin, Tian-Min Fu, Jixi Li, and Hao Wu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 393

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The Immunobiology of Interleukin-27 Hiroki Yoshida and Christopher A. Hunter p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 417 Innate Immune Recognition of Cancer Seng-Ryong Woo, Leticia Corrales, and Thomas F. Gajewski p p p p p p p p p p p p p p p p p p p p p p p p p p p p 445 Natural Antibody Repertoires: Development and Functional Role in Inhibiting Allergic Airway Disease John F. Kearney, Preeyam Patel, Emily K. Stefanov, and R. Glenn King p p p p p p p p p p p p p p p 475 Transcription Factor Networks Directing the Development, Function, and Evolution of Innate Lymphoid Effectors Joonsoo Kang and Nidhi Malhotra p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 505 Annu. Rev. Immunol. 2014.32:257-281. Downloaded from www.annualreviews.org Access provided by INSEAD on 03/06/18. For personal use only.

Early T Cell Activation: Integrating Biochemical, Structural, and Biophysical Cues Bernard Malissen and Pierre Bongrand p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 539 The Varieties of Immunological Experience: Of Pathogens, Stress, and Dendritic Cells Bali Pulendran p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 563 Transcriptional Regulation of Innate and Adaptive Lymphocyte Lineages Maria Elena De Obaldia and Avinash Bhandoola p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 607 Macrophages: Development and Tissue Specialization Chen Varol, Alexander Mildner, and Steffen Jung p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 643 Dynamic Tuning of Lymphocytes: Physiological Basis, Mechanisms, and Function Zvi Grossman and William E. Paul p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 677 Stromal Cells in Chronic Inflammation and Tertiary Lymphoid Organ Formation Christopher D. Buckley, Francesca Barone, Saba Nayar, Cecile Bénézech, and Jorge Caamano ˜ p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 715 Interleukin-22: Immunobiology and Pathology Jarrod A. Dudakov, Alan M. Hanash, and Marcel R.M. van den Brink p p p p p p p p p p p p p p p 747 The Immunology of Epstein-Barr Virus–Induced Disease Graham S. Taylor, Heather M. Long, Jill M. Brooks, Alan B. Rickinson, and Andrew D. Hislop p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 787 Molecular Mechanisms in Genetically Defined Autoinflammatory Diseases: Disorders of Amplified Danger Signaling Adriana Almeida de Jesus, Scott W. Canna, Yin Liu, and Raphaela Goldbach-Mansky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 823

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Contents

Relapse in multiple sclerosis.

Headache in relapse and remission phases of multiple sclerosis: A case-control study.

Multiple sclerosis: Atacicept increases relapse rates in multiple sclerosis.

The complex immunology of multiple sclerosis.

Seasonal variation in multiple sclerosis relapse.

Multiple sclerosis: recent advances in diagnosis clinical immunology and virology.

Characterizing cognitive function during relapse in multiple sclerosis.

Emerging Approaches for Validating and Managing Multiple Sclerosis Relapse.

The Lived Experience of Multiple Sclerosis Relapse: How Adults with Multiple Sclerosis Processed Their Relapse Experience and Evaluated Their Need for Postrelapse Care.

How to run a multiple sclerosis relapse clinic.

miR-326 and miR-26a, two potential markers for diagnosis of relapse and remission phases in patient with relapsing-remitting multiple sclerosis.

Regulation of Treg-associated CD39 in multiple sclerosis and effects of corticotherapy during relapse.

Remission of seizures and relapse in patients with epilepsy.

Improving remission and preventing relapse in youths with major depression.

Platform Therapy Compared with Natalizumab for Multiple Sclerosis: Relapse Rates and Time to Relapse Among Propensity Score-Matched US Patients.

Long-term effect of ACTH treatment of relapse in multiple sclerosis.

Sex as a determinant of relapse incidence and progressive course of multiple sclerosis.

Severe relapse in a multiple sclerosis patient associated with ipilimumab treatment of melanoma.

Seasonal variation of relapse rate in multiple sclerosis is latitude dependent.

Atorvastatin calcium in combination with methylprednisolone for the treatment of multiple sclerosis relapse.

Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood.

The UK patient experience of relapse in Multiple Sclerosis treated with first disease modifying therapies.

Poor early relapse recovery affects onset of progressive disease course in multiple sclerosis.

Increased anti-KIR4.1 antibodies in multiple sclerosis: could it be a marker of disease relapse?