Innate Adaptive Cns

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Review Innate and Adaptive Autoimmunity Directed to the Central Nervous System Roopa Bhat1 and Lawrence Steinman1,* 1Beckman Center for Molecular Medicine, B002, Stanford University, Stanford, CA 94305, USA *Correspondence: [email protected] DOI 10.1016/j.neuron.2009.09.015

The immune system has two major components, an innate arm and an adaptive arm. Certain autoimmune diseases of the brain represent examples of disorders where one of these constituents plays a major role. Some rare autoimmune diseases involve activation of the innate arm and include chronic infantile neurologic, cutaneous, articular (CINCA) syndrome. In contrast, adaptive immunity is prominent in multiple sclerosis, neuromyelitis optica, and the paraneoplastic syndromes where highly specific T cell responses and antibodies mediate these diseases. Studies of autoimmune brain disorders have aided in the elucidation of distinct neuronal roles played by key molecules already well known to immunologists (e.g., complement and components of the major histocompatibility complex). In parallel, molecules known to neurobiology and sensory physiology, including toll-like receptors, gamma amino butyric acid and the lens protein alpha B crystallin, have intriguing and distinct functions in the immune system, where they modulate autoimmunity directed to the brain. There are extensive interactions between the brain and the immune system in human autoimmune diseases. This review focuses on the autoimmune diseases where the brain and spinal cord itself are attacked. In certain very rare autoimmune diseases of the nervous system, the more primitive form of immunity, known as innate immunity, drives the pathology of autoimmunity. Innate immunity is characterized by a more rapid response to danger and does not involve antibodies or antigenspecific receptors on T lymphocytes. Diseases driven through innate immunity are often triggered in a subcellular compartment known as the inflammosome, where IL-1 is the main pathological mediator. These IL-1-mediated autoimmune diseases are epitomized by a rare condition called NOMID-CINCA (neonatal onset multisystem inflammatory disease [NOMID]; chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) (Church et al., 2008). However more common conditions, including Alzheimer’s disease, are likely to involve these same aspects of innate immunity (Steinman, 2008a). Conversely, a group of autoimmune diseases of the brain and spinal cord, including multiple sclerosis, represent situations where adaptive immunity predominates. Adaptive immunity involves an antigen-specific T cell and an orchestrated antibody response to a component of the brain or spinal cord. The major disease in this category is, first and foremost, multiple sclerosis, where the brain’s white matter is attacked, and as we are now learning, neurons and axons are also involved. A rarer form of demyelinating disease, neuromyelitis optica, where an adaptive immune response is directed to a water channel, also falls into this category, as do the paraneoplastic syndromes. In the case of paraneoplastic syndromes, the adaptive immune responses target cancer antigens that are shared with structures in the nervous system, resulting in some characteristic neurological conditions that often appear before the clinical presentation of the cancer itself. This review discusses what is known about interactions between

the immune and nervous system in both innate and adaptive autoimmune brain diseases and highlights how such interactions inform our understanding about these diseases and their treatment. Dual Roles of Molecules in Autoimmunity and in Normal Brain Physiology The innate and adaptive immune systems involve many molecules that are now known to have dual roles in the immune system and in normal brain physiology. The ‘‘toll-like’’ receptors are one of the key families of molecules that convey information about an impending danger from microbes. They were first discovered while studying the embryogenesis of Drosophila (Anderson et al., 1985). Flies that lacked the Toll gene could not achieve dorsal ventral polarity. A decade later, it was observed that this same family of genes encoded a product that conferred resistance to tobacco mosaic virus in plants and bore resemblance to the cytoplasmic domain of Toll-like receptors in Drosophila and interleukin 1 receptor in mammals (Whitham et al., 1994). This same family of genes turned out to have a fundamental role in activating what we now know as the innate immune system (Medzhitov et al., 1997). It is one of many remarkable examples of how molecules play a key role in one context, in this case development, and then play an entirely different role in another physiological system. This message about the varied roles of the same molecule in contrasting contexts will be repeated throughout this review. And we will see that many molecules of interest to neurobiologists and immunologists alike also play fundamental roles in plant defense mechanisms. Many of the molecules so well known to immunologists, including components of the histocompatibility proteins and elements of the complement cascade which play a major role in autoimmune diseases of the brain, are now known to play

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Review Periphery

Toll-like receptor

NAD

LRR

NACHT Pyd Acvaon of Inflammosome liberang Caspase 3

NF-kβ acvaon

IL-1β Pro IL-1β IL-1R antagonist Brain

IL-1β TNF IL-6

Figure 1. The Innate Immune System and the Brain The innate immune system is driven by Toll receptors on the cell surface and the inflammosome in the cytosol. Toll receptors trigger the activation of NF-kB through a universal adaptor protein MyD88. An intracellular signaling system acting through Nod-like receptors consisting in the case of NALP3 shown here of a pyrin domain (PYR), a NACHT-like domain, and a NAD domain joined to leucine-rich repeats, activates caspase 3. Caspase 3 cleaves pro-IL-1 beta produced from NF-kB activation. The resultant IL-1b triggers certain autoimmune diseases of the nervous system such as CINCA. IL-1 also triggers fever arriving in the brain through fenestrations in the blood brain barrier around the hypothalamus.

When Charles Dinarello first cloned IL-1, he actually had predicted correctly Hypothalamus that it was this cytokine that alerted Fever CINCA hypothalamic neurons of peripheral danger (Dinarello, 1984). IL-1, like other cytokines that play key roles in autoimquite different roles in the development of the nervous system mune diseases, such as TNF and IL-6, can breach the blood (Boulanger, 2009 [this issue of Neuron]; Deverman and Patter- brain barrier in the area surrounding the hypothalamus (Sanson, 2009 [this issue of Neuron], Stevens et al., 2007). Likewise, chez-Alavez et al., 2006; Blatteis, 2007). In addition to anatommolecules that are important in the physiology of the nervous ical fenestrations in the barrier at this point, there are active system or its neurosensory appendages are also key modulators transport mechanisms that allow the entry of these cytokines of immunity. Such molecules, ranging from alpha B crystallin to critical neurons in the hypothalamus. These neurons regulate (cryab), the major component of the lens of the eye and the first temperature, sleep, and appetite. We all have experienced the molecule involved in transduction of visual input, to gamma ami- striking changes that accompany the rise in body temperature nobutyric acid (GABA), the principal inhibitory synaptic trans- seen with fever. There is loss of appetite and a strong drive to mitter of the nervous system have remarkable roles in the sleep in the febrile reaction. While not an autoimmune reaction context of the immune system. Indeed, Cryab and GABA play per se, fever is perhaps the quintessential interaction between large roles in immunity and may account for why the brain and brain and the immune system (Figure 1). IL-1, that same cytothe eye, whose retina is an out pouching of the brain, have often kine driving fever, has now been demonstrated to be at the been regarded as ‘‘immune privileged,’’ and are quite resistant to center of the pathogenesis of a group of rare autoimmune immune attack (Ousman et al., 2007; Bhat et al., 2009). diseases of the brain, driven by this key constituent of innate immunity. IL-1, Inflammosomes: Communication between Brain The Innate and the Adaptive Arms of the Immune System and Immune System Fever, triggered via the cytokine interleukin-1, IL-1, is the quin- The genes encoding antibodies and T cell receptors employ tessential manifestation of the brain’s reaction to an immune elaborate molecular mechanisms for gene rearrangements in danger signal. IL-1 also mediates a group of rare autoimmune their variable portions to generate a tremendous diversity of diseases of the brain. Fever, of course, is the most common molecules to select and bind virtually any antigen. This is the manifestation of a fundamental interaction between the brain fundamental basis of adaptive immunity. To contrast the innate and adaptive arms of immunity, it must and immune system. There is some historical and intellectual sense of justice, that fever is driven by the first cytokine discov- be emphasized that the adaptive immune system is geared ered in the field of immunology. For sure, we all know about fever toward making high-affinity antibodies that bind to antigens from personal experience. Sick days with fever are one of our and T cell receptors that recognize antigens bound to shallow most fundamental neurological memories from childhood. IL-1, clefts, measuring 10 3 10 3 100 A˚, in a variety of histocompatithe first cytokine that was discovered, exemplifies this class of bilty molecules. The process of maturation of a high affinity antimolecules that signals danger and alerts the brain. Cytokines, body takes weeks, and involves the process of somatic hyperthe fundamental messengers that modulate and tune the mutation of immunoglobulin genes, driven via natural selection immune response, have potent effects on neurons and glia. in the regions of the genome encoding the binding sites of these Neurons and glia, like cells of the immune system can produce high-affinity antibodies. The development of a clinically signifimany of these key cytokines as well as respond to them (Stein- cant primary T cell response to an antigen bound to a histocompatibility molecule takes a week to 10 days. man, 2008a; Dinarello and Wolff, 1982).

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Review Figure 2. Adaptive versus Innate Immunity

Anbody Angen presenng cell Angen

Adapve Immunity T cell

Cytokine receptors

Innate Immunity

TCR

MHC

Chemokine receptors

Toll-like receptors

FcReceptor Mannose receptor

Adaptive immunity features antigen specific recognition via T cell receptors and immunoglobulin. The T cell receptor (TCR) recognizes antigen in the cleft of a molecule from the major histocompatibility complex (MHC). The innate system has multiple ways in which it is driven. Besides tolllike receptors, there are receptors for cytokines, chemokines, sugars—the mannose receptors, as well as for the constant region (FC) fragment of immunolglobulin. Intracellular signaling via cytokines goes via JAK and STAT while other receptors activate NF-kB, culminating in a cascade of inflammatory mediators including cytokines.

JAK

a cytosolic system to sense danger, the Nod-like receptors or NLRs. An intracellular system, the inflammosome is where signals between the TLR system and the NFkB NLR system are integrated. The major currency of the inflammosome is the cytokine, interleukin-1 (Church et al., 2008; Lamkanfi and Dixit, 2009; Martinon Transcripon et al., 2009; Figure 2). Once the toll-like receptor is triggered, cytokines complement and other rapidThe action of antibodies and T cell receptors leads to neutral- acting mediators are produced, primarily in polymorphonuclear ization of the antigen in the case of antibody or destruction of leukocytes, macrophages, and dendritic cells within the immune a cell in the case of a cytotoxic T cell. These cytotoxic T cells system, as well as glial cells within the brain. The NLR system target an antigen bound to a histocompatibility molecule. Both when inappropriately triggered culminates in a group of rare antibody and T cell receptors, as well as histocompatibility mole- but fascinating autoimmune diseases, including some involving cules, are members of the immunoglobulin supergene family, the brain. Thus, the innate immune system is tuned to respond characterized by proteins of about 100 amino acids with a char- immediately to danger signals ranging from small molecules acteristic fold between two antiparallel beta strands. Many like urate deposited in the joints in gout, to peptidoglycans in members of the immunoglobulin supergene family including the cell walls of pathogenic bacteria in septic shock (Martinon neural cell adhesion molecules, and major histocompatibility et al., 2009). molecules play roles in shaping neural systems, including ocular dominance columns in the visual system (Boulanger, 2009; Autoimmune Diseases of Brain Involving Innate Immunity and IL-1 Hunkapiller and Hood, 1989; Williams, 1992). The innate immune system in contrast is a more primitive arm The inflammosome is organized to modulate the secretion of IL-1 of the immune response and does not depend on gene rear- in response to real danger or to ‘‘perceived’’ danger. Autoimrangements–as the adaptive system does—to yield a myriad of mune diseases driven by the inflammosome are likely the result antibodies or T cell receptors of exquisite specificity for each of a mistaken immune response to a perceived danger signal, of billions of potential antigens. Because of this, innate immune probably of a microbial nature. These diseases include some responses can occur much more rapidly than the days to weeks that involve the brain. Autoimmune diseases of the inflammotimescale necessary to launch an adaptive immune response. some include Blau syndrome (with granulomatous arthritis, iritis, For many types of danger, this more immediate immune and skin rash), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), pyogenic sterile arthritis with response is essential. The innate immune system has a number of elements in its pyoderma gangrenosum (PAPA), and chronic infantile neurolrepertoire for making powerful and quick responses to danger. ogical cutanaeous and articular syndrome also known as The innate immune system deals with the most urgent problems neonatal-onset multisystem inflammatory disease, CINCA/ requiring an immediate response and does so in a more stereo- NOMID (Church et al., 2008). The inflammosome has an interesting association with one of typed way, without tailoring a specific receptor to neutralize the danger signal in the form of antigen. Instead, in innate immunity the degenerative neurological diseases, spinal muscular some aspect of the danger signal, often a motif from an infec- atrophy, where the anterior horn cells in the spinal cord controltious microbe, in some cases even a noncoding hexanucleotide ling motor neurons degenerate. In humans, there are 22 NLR sequence from its genome, a so-called CpG motif, can trigger family members including five members of the NOD family a toll-like receptor, the membrane- based sensor of danger (nucleotide-binding oligomerization domain), 14 NALPs, IPAF (Sato et al., 1996). In addition, the innate immune system has (IL-1B-conversting enzyme protease activating factor), NAIP STAT

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Review (neuronal apoptosis inhibitor factor), and CIITA (major histocompatibility complex class II transactivator) (Church et al., 2008). NAIP is partially deleted in children with spinal muscular atrophy, a neurodegenerative disease affecting the anterior horn cell, with many features of amyotrophic lateral sclerosis, the quintessential motor neuron disease (Liston et al., 1996). NAIP gene deletion is correlated with a more severe phenotype in SMA (Gendron and MacKenzie, 1999). CIITA, another key component of the inflammosome, is a master regulator of class II major histocompatibility expression. Certain mutations of CIITA are associated with profound immune deficiency (Dziembowska et al., 2002). The core of the inflammosome contains a pyrin domain, a caspase recruitment domain (CARD), and an intermediary nucleotide-binding domain (NBD; NACHT or NAD); and a C-terminal LRR (leucine-rich repeat) (Church et al., 2008). Mutations in the NACHT domain of NALP3 are linked to CINCA/NOMID, FCAS, and MWS [Church et al., 2008]. Manifestations of CINCA/NOMID begin in the neonatal period. Clinically, manifestations of CINCA/ NOMID include urticaria, skin rashes with ‘‘hive’’-like features, fevers, and recurrent meningitis. Elevated intracranial pressure, hearing loss, seizures, and delayed and impaired neurological development ensue. Visual loss occurs from increased intracranial pressure. The increased pressure and chronic inflammation lead to brain atrophy. Sixty percent of patients have a mutation in the cold-induced autoinflammatory syndrome (CIAS1) gene (Church et al., 2008; Neven et al., 2004). Because of this mutation in the inflammosome involving a cryopyrin, caspase 1 activity is not regulated. Therefore, IL-1 activity in brain increases. The IL-1 receptor antagonist, Anakinra, has produced dramatic improvement in patients with CINCA/NOMID with amelioration of seizures and meningitis. Clinical improvement is dramatic after administration of Anakinra, with cessation of seizures and marked improvement in neurological deficits (Hedrich et al., 2008). While CINCA/NOMID is a rare condition, the inflammosome may play a vital role in the major degenerative disease of the central nervous system, Alzheimer’s. As reviewed in detail recently (Lucin and Wyss-Coray, 2009 [this issue of Neuron]; Steinman, 2008a), Alzheimer’s disease has all the hallmarks of involvement of the innate aspect of the immune system. There is, however, no infiltration of B cells producing antibodies or T cells in the Alzheimer’s brain. Instead, there is evidence of activation of other components of the immune system including complement, interleukin 1 alpha and beta, and other cytokines including tumor necrosis factor TNF and transforming growth factor beta (Griffin et al., 1989; Wyss-Coray, 2006). Complement of course has recently been shown to play a key role in synaptic elimination (Stevens et al., 2007). Whether its more traditional role as an opsonin is at play in the brain of Alzheimer’s disease remains an open question. Other elements of innate immunity including the cytokine TGF play a role in AD. Activation of TGF beta in microglial cells was associated with increased clearance of beta amyloid, which is the center of great attention in research on AD (Wyss-Coray, 2006; Steinman, 2008a). Still, the greatest amount of attention in Alzheimer’s is focused on beta amyloid. Mutations in amyloid precursor protein and in presenilin genes encoding proteins involved in processing amyloid are associated with early onset and familial AD

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(Wyss-Coray, 2006). Beta amyloid itself is a danger signal capable of triggering the innate immune system (Salminen et al., 2009). In summary, from its role in rare diseases like CINCA/NOMID to its potential role in the most prevalent neurological disease in adults, Alzheimer’s, the innate immune system without accompaniment from the adaptive immune has prominence in a swathe of neurological diseases. Autoimmunity in Brain Characterized by an Adaptive Immune Response Multiple sclerosis affects about 1.5 million people worldwide. The disease is characterized in the majority of cases by a period of relapses and remissions. The relapses affect various aspects of the nervous system depending on the anatomical location of the attack. Visual, motor, sensory, and autonomic deficits all occur. The period of attack is often followed by a remarkable amount of recovery and a long period of quiescence of disease termed remission. Some of the key molecules involved in relapse and remission, including alpha-4 integrin, osteopontin, and alpha B crystallin, have been recently described in a review (Steinman, 2009a). About a third of patients progress within a decade or two from disease onset to a form of MS called secondary progressive disease, where relapses and remissions are not prominent. In secondary progressive MS, the disease with its accompanying neurological disability progresses insidiously. In multiple sclerosis, there is a strong imprimatur of an adaptive immune response. Within the central nervous system CD4, CD8, and NKT cells are found along with B cells (Goverman, 2009). Perivascular cuffs of lymphocytes are found particularly in the white matter in acute lesions. Among the most prevalent proteins found in the affected lesions are immunoglobulins. In fact, within the central nervous system of MS patients, there is a net synthesis of immunoglobulin, above and beyond what is made outside the nervous system. This measurement of immunoglobulin synthesis within the brain compartment was at one time a key confirmatory measurement to confirm the diagnosis of multiple sclerosis. Such measurements are still valid, but one usually relies on magnetic resonance imaging for confirmation of clinical diagnosis (McFarland and Martin, 2007). Antibodies are found in the cerebrospinal fluid with specificities for all the major myelin proteins and many of the myelin lipids. On electrophoresis there is evidence of restricted clonality of the immunoglobulin response. Sequencing of immunoglobulin gene rearrangements in the central nervous system (CNS) demonstrates that there are clonally derived responses. Disrupted myelin is often associated with deposits of immunoglobulin and activated complement (Scolding et al., 1989). The specificity of these oligoclonal immunoglobulin responses remains enigmatic. Similarly, at the T cell level there are CD4, CD8, and NK T cells with specificity for the major myelin proteins, and some of the myelin lipids. Similar to the restricted clonality of certain immunoglobulin sequences in MS brain (Obermeier et al., 2008; Lambracht-Washington et al., 2007), one can also demonstrate restricted clonality of certain T cell responses. Some of these clonally restricted T cells have specificity for myelin proteins (Oksenberg et al., 1993; Babbe et al., 2000). The two major elements of adaptive immunity produce toxic mediators and in turn interact with other inflammatory mediators.

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Review Innate Autoimmunity CINCA

Figure 3. Comparison of Innate and Adaptive Autoimmunity in Brain

Meningis Seizures

IL-1

Fever

NAD

Visual loss

NACHT Pyd Hearing loss Adapve Autoimmunity

Intracranial pressure Delayed development Clonal expansion of T cells with TCR Clonal expansion of B cells Immunoglobulin

MS, NMO, Paraneoplasc syndromes Oligoclonal Ig in spinal fluid (MS)

Perivascular T cells, B cells, macrophages

In CINCA, IL-1 is activated leading to fever, meningitis, seizures, visual and hearing loss, increased intracranial pressure, delayed neurological development, and brain atrophy. All this is reversed by administration of IL-1 receptor antagonist, the drug anakinra. In contrast, in multiple sclerosis there are perivascular infiltrations of T cells, B cells, and macrophages. Microglia are activated as well. Oligoclonal nests of T cells with restricted diversity in their T cell receptors (TCRs) found in brain, and oligoclonal immunoglobulins (Ig) are found in the cerebrospinal fluid. In MS, some of these restricted responses are directed to known components of the myelin sheath. In the paraneoplastic syndromes, the adaptive immune response targets cancer antigens that are shared by various structures in the central nervous system. In neuromyelitis optica, the aquaporin 4 (Aqp4) water channel is targeted by the adaptive immune response.

Immunoglobin to Aqp4 in spinal fluid (NMO)

Immunoglobulins interact with complement via their Fc receptors. One can find a set of complement proteins, membrane attack complexes, in the spinal fluid. These complexes are prima facie evidence of immune damage to critical oligodendrocyte membranes (Scolding et al., 1989). T cells and their accompanying presenting cells produce a long list of proinflammatory cytokines, chemokines, and other cytokine-like molecules (Figure 3). There is hot debate about whether so-called TH1 or TH17 cytokines mediate brain inflammation (Bettelli et al., 2007; Tzartos et al., 2008; Kebir et al., 2007; Steinman, 2008b). What is certain is that the hallmark cytokine of TH1, gamma interferon, when given to MS patients induced disease (Panitch et al., 1987). Another molecule, osteopontin, modulates both TH1 and TH17 and is found to be elevated during relapse. Osteopontin is a member of a family of small integrin binding proteins, the SIBLING family. Osteopontin binds a4b1 integrin (reviewed in Steinman, 2009a). This integrin is critical in migration of lymphocytes to the brain in MS. Blockade of a4b1 integrin with a monoclonal antibody approved for treatment of relapsing remitting MS, called Natalizumab, reduces relapses by two-thirds (Polman et al., 2006). This reduction in the relapse rate comes with a price, for blockade of homing to the brain carries with it the risk of fatal infection with dormant viruses in the brain with a disease called progressive multifocal leukoencpephalopathy (reviewed in Steinman, 2009a). At present, there is great controversy about what triggers MS. Some argue that a microbe somehow induces MS. Others argue that some degenerative, biochemical disturbance is a possibility. After all, in X-linked adrenoleukodystrophy (ALD), there is a primary biochemical disturbance in brain caused by a mutation in an ABC transporter. This biochemical abnormality subsequently elicits an inflammatory lymphocytic infiltrate in brain, a pathology reminiscent of MS, but a picture quite different than what is seen in AD for example (Mosser et al., 1993). So

in principle, mutations in biochemical pathways in the nervous system may underlie an inflammatory demyelinating condition like MS, just as it does in ALD. So far, however, there is not a great deal of evidence to support this contention. One piece of evidence that does exist came from studies on MS brain lesions. Abnormalities in fumarate metabolism have been noted in MS lesions, with increased transcription of fumarylacetoacetate hydrolase in both acute and chronic lesions of MS (Lock et al., 2002). Fumarate esters have shown promise in early stage clinical trials of MS (Kappos et al., 2008). Other possibilities have also been hinted at from various research studies. An intriguing report showed that in the earliest pathological lesions there is no evidence of lymphocytic infiltration, instead extensive apoptosis in oligodendroglial cells and activation of microglia were observed. The apoptotic oligodendrocytes might be the trigger of the adaptive immune response (Barnett and Prineas, 2004). Another possibility is a microbial infection of brain, with subsequent bystander damage to neighboring brain structures (Steinman and Oldstone, 1997), though searches for microbes triggering MS have been altogether unsuccessful. Spurts of enthusiasm for one or another potential culprit continue to appear, and currently EBV is the microbe eliciting the most enthusiasm based on some tantalizing data (Serafini et al., 2007). There is also the potential possibility that the underlying trigger for MS stems from the astonishing mimicry between components of a variety of common microbes and constituents of the myelin sheath and even neurons, suggesting that MS may be an inappropriate ‘‘auto’’-antibody response. In one of the most intensively studied examples, attention has been focused on the motif of four amino acids HFFK. These four amino acids include the main anchors to both a hydrophobic pocket in the class II HLA molecule HLA DR2, and the primary contact with both the T cell receptors and immunoglobulins that recognize a particular dominant immunogenic region of MBP, between residues 82 and 98 (Wucherpfennig et al.,

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Review 1997). There are well-known examples of molecular mimicry between other viruses like Hepatitis B and myelin oligodendroglial glycoprotein, and Hepatitis A viral polymerase and myelin basic protein (Fujinami and Oldstone, 1985). Despite the attraction of these molecular similarities between microbes and components of the myelin sheath, no single microbe has been impugned in the pathogenesis of MS. In contrast, in the inflammatory polyneuropathy known as Guillain Barre syndrome, Campylobacter jejuni has been implicated as the trigger for acute axonal motor neuropathy, a type of inflammatory neuropathy resembling Guillain Barre. Campylobacter jejuni contains glycolipids that are also found in motor axons (Hao et al., 1998). Immune attack against these glycolipids triggers acute motor axon neuropathy. While it may be debated what actually causes MS, the presence of the adaptive immune response is widespread in MS. Adaptive immunity is evident both in acute lesions of MS and even in more active chronic lesions of MS. This has been shown indisputably with a number of histological, immunological, molecular, and proteomic technologies. While current approved treatments for MS either target innate immunity via beta interferon or glatiramer acetate or block homing of lymphocytes to the inflamed brain via a4 integrin blockade (Polman et al., 2006; Steinman, 2009a), alternative approaches aimed at adaptive immunity are promising. Tolerizing the adaptive immune system to myelin antigens is one such promising approach. It has been demonstrated in a phase II clinical trial that tolerizing the immune system to myelin basic protein reduces antibodies to this myelin component that are detectable in the spinal fluid. Tolerization to myelin basic protein was accompanied by a reduction in magnetic resonance lesions indicative of brain inflammation in patients with relapsing remitting MS (Garren et al., 2008). Furthermore, recently it has been shown that not only is white matter targeted in MS, but gray matter is affected, resulting in cognitive disturbances and ultimately brain atrophy (Geurts et al., 2009; Han et al., 2008). Some of the targets of adaptive immunity involving gray matter have recently been described. Among the targets is contactin-2, which is located at the node of Ranvier, a critical location in the myelinated axon, where conduction of the electrical impulse, known as the action potential, actually cycles inward to depolarize the neuronal membrane. The nodes are located between stretches of myelinated, insulated axon (Derfuss et al., 2009; Steinman, 2009b). Tolerizing the adaptive immune system so that it does not produce antibodies and pathological T cell responses to these gray matter targets, especially those at the Node of Ranvier, warrants exploration. Multiple Sclerosis Exemplifies Dual Roles of Key Molecules in Brain Autoimmunity and in Neurobiology The mechanism of control of relapse and induction of remission bring together one of the more interesting intersections in our understanding of the brain and the immune system. It has long been contended that certain anatomical locations in the body have immune privilege. These are regions where it is extremely difficult to induce inflammation. They include the brain, the testis, the gravid uterus, and the lens of the eye. In these sites, transplants are unlikely to be rejected. Interestingly, in these fetal tissues, small heat shock proteins (sHSPs) of the crystallin family

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including aB crystallin are also increased in expression. These sHSPs have played important roles all through evolution. They play key roles in the defense of plants against a variety of pathogenic and metabolic stresses (Maimbo et al., 2007). aB crystallin is also known to inhibit inflammation and apoptosis via inhibition of p38 map kinase and cleavage of caspase 3, respectively. In acute multiple sclerosis lesions, expression of aB crystallin is dramatically increased and, in animal models of MS, administration of aB crystallin dramatically induces remission and reverses ongoing paralytic disease. It is remarkable that the major structural protein of the lens of the eye, so well known in its role for refracting light, is also a remarkable guardian molecule protecting the brain and other vital tissues from undesired inflammatory responses (Ousman et al., 2007; Ransohoff, 2007). Members of this sHSP family also play a potential role in a variety of brain diseases beyond MS, including Alzheimer’s disease, stroke, Alexander’s disease, caused by a mutation in glial fibrillary acidic protein, and Parkinson’s disease (Steinman, 2009a). The nervous system responds to inflammatory stress by also inducing a spectrum of beta interferon-induced mediators (Han et al., 2008). Beta interferon itself is highly anti-inflammatory and is the most widely used form of therapy for relapsing remitting MS. Though other forms of therapy like blockade of a4b1 integrin are more efficacious then beta interferon, they carry the large risk of immune suppression within the brain. To date, 13 cases of progressive multifocal leukoencephalopathy have been reported in the first 50,000 patients under therapy. The majority of these cases occur after blockade of the a4b1 integrin for a year or more (Steinman, 2009a). Examination of databases of proteomic and transcriptomic analyses of well-defined lesions in MS brains indicates that the brain’s GABAergic inhibitory system is modulated in active and chronic lesions in MS (Han et al., 2008; Lock et al., 2002; Tajouri et al., 2003; Dutta and Trapp, 2007). GAD (glutamic acid decarboxylase, the enzyme that synthesizes GABA), GABA receptor subunits and associated proteins, and a GAT (GABA reuptake transporter) are altered in MS, both at the level of gene transcripts and protein expression (Lock et al., 2002; Han et al., 2008). Examination of gene transcripts in lesions from MS brains indicates that GAD is decreased in both acute and chronic lesions, and various GABA-receptor subunits are either increased or decreased in the lesions (Lock et al., 2002; Tajouri et al., 2003). Transcripts for GABA-A receptor subunit g2, for example, increase in acute plaque but decrease in chronic active plaque. GABA-A receptors are chloride channels formed by heteropentameric assemblies of these subunits with subunit composition determining receptor specificity and other aspects of receptor function. The g2 subunit is involved with GABA-A receptor trafficking and synaptic clustering. Thus, these subunit alterations in MS may lead to functional changes in the receptors and signal transfer. In chronic MS lesions in motor cortex, GAD, various GABA receptor subunits, and GABA receptor associated protein (GABRAP) are all decreased (Dutta and Trapp, 2007). At the level of protein expression, GAD and GAT1 are increased in acute plaque and GABRAP is increased in chronic plaque (Han et al., 2008). The reasons underlying these differences in transcriptomic versus proteomic data represent aspects of active regulatory processes. Furthermore, the implications of these findings

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Review have been tested in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS in use for over 75 years. A comparison of levels of GAD, GABA transaminase (GABAT, the enzyme that degrades GABA), and various GABA receptor subunits showed significant decreases in the spinal cord of these gene transcripts in the first acute phase of EAE (Bhat et al., 2007). When these data are considered together, such findings indicate that the GABA system is pathologically regulated in MS brains. The dysregulation of molecules in the GABA pathway in human MS and in EAE could be a cause, consequence, or just a correlation with the disease process. To begin to address this, the GABA system has been manipulated by specifically increasing GABAergic activity in EAE. When topiramate, a GABA receptor type A agonist, is administered, there is an increase in GABA-mediated signaling. When vigabatrin, an irreversible blocker of GABAT, GABA transaminase, the main enzyme that degrades GABA, there is a decrease in GABA degradation. This causes an effective increase in systemic GABA concentrations. Both these agents greatly reduce the incidence and severity of paralysis in EAE in mice immunized with a myelin peptide when started at the time of immunization. This demonstrates that these agents inhibit the development of acute EAE including the paralysis of the arms and legs that accompanies the experimental disease. These pharmaceuticals also reverse paralysis significantly when given after establishment of disease. These effects were in part due to direct significant inhibition of immune cells through GABA-A receptors (Bhat et al., 2007, 2009) Since levels of GABA are decreased in serum of MS patients (Demakova et al., 2003), this GABA effect on peripheral immune cells may also be important in human MS. GABA in the CNS is synthesized and utilized by neurons and glia through GABA receptors and reuptake transporters, and GABA is present in both gray and white matter (Jensen et al., 2005; Choi et al., 2006). There is recent evidence of significant GABA release in white matter with subsequent high-affinity uptake and catabolism (Henjum and Hassel, 2007). In injured white matter, there may be an upregulation of GABA receptors and accordingly, it was postulated that GABA receptor expression in white matter may be protective during hypoxia in the adult and in the developing brain (Henjum and Hassel, 2007). GABA is also produced and secreted by immune cells (Bhat et al., 2009). White matter lesions in MS are typically characterized by significant immune cell infiltration. Thus, within white matter lesions of MS as well, this neurotransmitter may be performing dual roles in both inhibition of inflammation and prevention of nerve injury and crosstalk between the cells of the nervous and immune systems. The biochemical pathways associated with GABA, like those associated with the small heat-shock proteins, are part of an ancient physiological system. The GABA pathways are present in plants where they serve to protect against various types of stress including heat (Taiz and Zeiger, 2006). The GABA pathways restrict levels of reactive oxygen intermediates in plants (Bouche et al., 2003). The known function of GABA as an inhibitory transmitter in the nervous system is paralleled by a role in the immune system where it guards against dangerous inflammation in sensitive tissues like the brain. The role of MHC in susceptibility to MS is another area where there is an interesting intersection between neurobiology and

immunology. For the past 35 years, it has been well known that the major gene conferring a risk of susceptibility to MS resides in the major histocompatibility complex. Recent studies have pinpointed the HLA DRB1*1501 gene as the main susceptibility allele (Fugger et al., 2009). Other susceptibility loci within the HLA class I and II region may modify the effect of HLA DRB1*1501 by acting in trans. The pioneering studies of Shatz and colleagues have indicated that the role of MHC genes is not always in simply providing the appropriate protein molecule for presenting antigen to T cell receptors. Shatz and colleagues have shown that the development of the visual system is altered in mice with deficient MHC class I expression (Huh et al., 2000; Boulanger and Shatz, 2004). There is failure of segregation of ipsilateral and contralateral connections in the lateral geniculate projections of retinal ganglion cells in mice with deficient expression of MHC class I. In these MHC class I deficient mice there was enhancement of long term potentiation in the hippocampus, while long term depression was absent. Clearly, the MHC has dramatic effects on the anatomy and physiology of neurological synapses. MHC class I leads to weakening and structural retraction of synaptic connections. Remarkably the GABA system has an opposite effect on synaptic plasticity. Mice with glutatmic acid decarboxylase 65 knocked out, deficient in GABA, show absence in the plasticity of ocular dominance columns, with inability to shift dominance to the more active eye. The GAD65 knockout mice have diminished GABA release, and this translates into alteration of NMDA excitatory transmission. These effects in the GABA knockout are restored by adding a critical amount of excitatory transmission through NR2A-containing NMDA receptors (Kanold et al., 2009). Thus, there are fine tuned and intertwined regulatory mechanisms for synaptic plasticity involving MHC class I molecules, their receptors like the Paired-immunoglobulin-like receptor B (PirB), the GABA system and NMDA transmission (Atwal et al., 2008). Clearly the roles of MHC and GABA extend from the nervous system to the immune system. The underlying mechanisms however may be quite different and fascinating. Other Adaptive Immune Disorders An adaptive immune response to aquaporin 4 underlies an unusual chronic demyelinating condition, termed neuromyelitis optica. As the name of the condition anticipates, the optic nerve and spinal cord are involved in the typical form of NMO. Antibodies play a key role in its pathogenesis as shown with the following evidence: (1) gammaglobulin and complement deposition are present in spinal cord lesions, (2) attacks, which occur much more frequently than relapses in MS, respond to treatment with plasmapharesis, whereas MS does not improve with plasmapheresis, and (3) an auto-antibody (NMO-IgG) directed against aquaporin 4 (AQP4) distinguishes NMO from multiple sclerosis, where such antibodies are not detected. Finally, (4) AQP4 is lost in acute lesions in the spinal cord in acute NMO (Lennon et al., 2005; Hinson et al., 2008). These findings emphasize a pathological role for NMO-IgG in this demyelinating disorder of the central nervous system. One of the more fascinating examples of adaptive immunity driving an autoimmune disease occurs at the interface of cancer and the immune response in what we call ‘‘tumor surveillance.’’

Neuron 64, October 15, 2009 ª2009 Elsevier Inc. 129

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Review There are a constellation of syndromes associated with an antibody and T cell response directed to a shared antigen expressed on a solid tumor and on a component of the central nervous system. Thus, in the course of ‘‘tumor surveillance’’ an autoimmune disease in the nervous system is instigated. The most common example of a paraneoplastic syndrome is the cerebellar syndrome, where clinical findings include ataxia and tremor so severe that even handwriting is often impaired, in some individuals with ovarian cancer. The antigen expressed on the ovarian cancer is also expressed on Purkinje cells in the cerebellum. Often the neurological disorder becomes apparent before there is any diagnosis of malignancy (Darnell and Posner, 2006). The immune system mounts an adaptive response to a protein called cdr2, and the antibodies are often termed anti-Yo antibodies. Other forms of paraneoplastic cerebellar disease have anti-Hu antibodies (Shams’ili et al., 2003). There are several other examples of paraneoplastic syndromes involving the central nervous system including stiff person syndrome, where the immune response is directed to glutamic acid decarboxylase and to amphiphysin, resulting in some circumstances in both Type 1 diabetes mellitus and extreme stiffness of skeletal musclature (Darnell and Posner, 2006). The paraneoplastic syndromes exemplify the remarkable relationships between antigens found on cancer and shared with structures in specific anatomic locations of the nervous system. In addition to cerebellar syndromes and stiff person syndromes, there are examples of myelopathies, motor neuron disease, encephalomyelitis, and limbic encephalitis, all representing different paraneoplastic syndromes. To date, there are no animal models where a cancer is induced that leads to a neurological syndrome. In fact, good autoimmune models of paraneoplastic phenotypes in the CNS are nonexistent (Darnell and Posner, 2003). There are some mouse models where phenotypes are shared with human paraneoplastic syndromes, including a ‘‘rolling mouse’’ with a with a R1262G mutation in the alpha-1 subunit of the P/Q-type (Ca(v)2.1) calcium channel that has manifestations including leg weakness characteristic of Lambert Eaton syndrome (Molenaar, 2008). However, this model of Lambert Eaton is not induced with autoimmunity. Another mouse model induced via immunization with this channel was described in a small group of rats, who developed weakness, but over the years there has been a lack of follow on publications (Komai et al., 1999). Such models of paraneoplastic syndromes, with both cancer and autoimmunity, would allow one to test whether the autoimmune response to the cancer, with its unwanted consequences in the nervous system, is actually a consequence of effective tumor surveillance. But to date, there are no good models of the paraneoplastic syndromes, akin to the models of MS with EAE, or transgenic models of AD, induced with overexpressed beta amyloid. There is some anecdotal evidence suggesting that treatment of the autoimmune disease with immune suppression leads to worsening of the tumor. Such studies, however, are not definitive. For paraneoplastic disease and the underlying cancer, neuro-oncologists recommend immune suppression to relieve the symptoms of the autoimmune disease in the nervous system, while also treating the cancer. Cancer therapy would include an optimal regimen with surgical intervention, if warranted, chemo-

130 Neuron 64, October 15, 2009 ª2009 Elsevier Inc.

Table 1. Comparative Roles of Molecules in the Nervous System and the Immune System Neurobiology

Immunology

Complement

Eliminate synapses

Opsonize bacteria, destroy brain structures

MHC

Modulate plasticity

Present antigen to T cells

GABA

Inhibitory neurotransmitter

Inhibit inflammation

Alpha B Crystallin

Lens protein, refract light, provide immune privilege

Inhibit inflammation

therapy, if possible, and radiation therapy, when amenable (Darnell and Posner, 2003). The field is clearly fascinating. We are learning that such syndromes are not oddities and may some day be amenable to interventions that alleviate both the burden of the tumor and the consequences of autoimmunity targeting the nervous system. A Discipline ‘‘Comes of Age’’: Neuroimmunology Research in neurobiology and immunology has achieved a certain confluence. Many of the key molecules in one system have been shown to play starring roles in the other system. Though the molecules are identical, in different contexts they take on new and unexpected roles. In this review, the matter of molecules having different roles in the nervous system and in the immune system has been exemplified with discussions of the Toll receptors, the inflammosome, the histocompatibility complex, the complement cascade, aB crystallin, and GABA. We realize that ancient defense systems in plants used these same molecules. Plants defend themselves with molecules with homology to Toll, to alpha B crystallin, and to IL-1beta. Plants employ all the components of the GABA biochemical pathway in their response to various stresses including heat stress. All this illuminates the interrelations between biological systems. The immune system and the nervous system are remarkable ensembles that are at once sensors of impending danger and responders to those dangers. These systems muster a remarkable array of solutions and in many cases employ the very same molecules to solve widely divergent problems. Both systems have memory and remarkable specificity. A key lesson in all these examples is that one should not become overly worried when encountering a molecule in a system, where its presence is largely unknown. Just because a molecule is well known to one system does not mean it does not have an amazing though different role in another system (Table 1). One of the modern problems with ‘‘informatics’’ is that it informs us of what we know and excludes what we do not. Lists of ‘‘immune molecules’’ or ‘‘neurobiological molecules’’ and ‘‘pathway analyses’’ are recipes for stereotypic thinking. ‘‘Immuno’’-centricity and ‘‘neuro’’-centricity should be shunned. We must look at the boundaries of the fields of neurobiology and immunology with a healthy dose of skepticism. In many cases, plants already employed the molecules we now study in the brain and in the immune system. The synthesis of neurobiology and immunology in neuroimmunology is coming of age, aided by input from the whole world of biology.

Neuron

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