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Autoimmune channelopathies: John Newsom-Davis's work and legacy
Journal of Neuroimmunology 201–202 (2008) 245 – 249 www.elsevier.com/locate/jneuroim
Autoimmune channelopathies: John Newsom-Davis's work and legacy A summary of the Newsom-Davis Memorial Lecture 2008 Angela Vincent ⁎ Department of Clinical Neurology, University of Oxford, Max Plank Institute for Developmental Neurobiology, Tuebingen, Germany Received 15 July 2008; accepted 15 July 2008
Abstract John Newsom-Davis was a key figure in the field of neuroimmunology and combined many outstanding personal qualities with considerable clinical and scientific expertise. His first report of plasma exchange in myasthenia in the late 1970s demonstrated its use both as a treatment and as an experimental tool to establish the pathogenic role of antibodies in neurological disorders. Subsequent investigations into the Lambert Eaton myasthenic syndrome and acquired neuromyotonia showed that these were caused by antibodies to specific ion channels. The field of autoimmune channelopathies is continuing to expand with identification of new antibody-mediated diseases including those affecting the central nervous system. This review will highlight some of his most seminal findings and those that are following on from his work. © 2008 Elsevier B.V. All rights reserved. Keywords: Myasthenia; Lambert Eaton myasthenic syndrome; neuromyotonia; ion channels; receptors; autoantibody; maternal-to-fetal transfer; developmental disorders; aetylcholine receptors; calcium channels; potassium channels; glutamate receptors; aquaporins; encephalopathies
John Newsom-Davis (JND) was a major international figure in the field of neurology and neuroimmunology. He combined clinical expertise with commitment to scientific understanding of disease mechanisms and their implications for treatment. He influenced a generation of neurologists and neuroscientists and his exceptional personal qualities of kindness, intelligence, tolerance, energy and modesty are greatly missed by all. JND brought clinical observations to the laboratory and vice versa. With experience of both muscle spindle electrophysiology and intensive care medicine, in 1973 he started collaborating with Ricardo Miledi and myself at University College London looking at acetylcholine receptor (AChR) numbers and function at the neuromuscular junction in myasthenia gravis (MG). The publication later that year, by Dan Drachman and colleagues, that AChRs were reduced in MG endplates, and by Jon Lindstrom and colleagues, of experimental autoimmune myasthenia in rabbits immunised with purified electric fish ⁎ Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK. Tel.: +44 1865 222321; fax: +44 1865 222402. E-mail address: [email protected]. 0165-5728/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2008.07.007
AChR were seminal in the field. A few years later Jon and others identified antibodies to acetylcholine receptors (AChRs) in serum of the patients, and that, with the demonstration of passive transfer of disease to mice by injection of patients' IgG by Klaus Toyka and Dan Drachman in 1975, clearly indicated the humoral nature of the disease. JND first came into the field by showing the effects of plasma exchange as a treatment. The remarkable efficacy of this therapy – which lasted for several weeks – and the relationship between AChR antibody levels and clinical state following exchange (Newsom-Davis et al., 1978), confirmed that myasthenia was indeed an antibodymediated diseases. The discoveries that followed in JND's and others' laboratories owe much to the implications of this simple clinical experiment. Over the next 20 years, he and our colleagues in London, and later in Oxford, systematically investigated the role of the thymus and involvement of T cell immunity in MG, defined the existence of humoral immunity to voltage-gated calcium channels (VGCC) in the Lambert Eaton myasthenic syndrome (LEMS), and showed similarly that some cases of acquired neuromyotonia were associated with antibodies to voltage-gated potassium channels (VGKC).
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Table 1 Clinical and experimental paradigms that identified neuromuscular junction antibody-mediated diseases Specific in vivo and ex vivo electrophysiology suggesting pre or postsynaptic defects Active immunisation and/or passive transfer of IgG leading to similar changes in mice Specific antibodies identified in patients' sera Antibodies shown to be potentially pathogenic in vitro Patients respond to plasma exchange, steroids and immunosuppressive drugs Note. Whereas for myasthenia gravis, the sequence of events was as shown above, in the Lambert Eaton myasthenic syndrome and in acquired neuromyotonia, it was the response to plasma exchange and passive transfer experiments that were most crucial in demonstrating the role of autoantibodies in the disease, and the identification of the antigenic target followed later.
With retirement in 1998, JND stepped aside from the laboratory and, while continuing to see MG patients, and as Editor of Brain, he began to establish a major international trial of thymectomy in MG with Gil Wolfe, Gary Cutter and many others; this was eventually funded by the NIH. His life has already been commemorated in this journal (Willcox, 2008; Raine, 2008) and many of his achievements are celebrated and developed further in this special volume with the main emphasis on the immunology and treatment of MG and LEMS. Here I will review briefly these findings and those that have stemmed directly from his work, and illustrate the considerable scope for further definition and investigation of “autoimmune channelopathies” in the future. 1. Autoimmune channelopathies — the work 1.1. Myasthenia gravis, Lambert Eaton myasthenic syndrome and neuromyotonia It is difficult to overemphasise the importance of the discoveries in myasthenia in the 1970s in showing the way forward for determining the role of antibodies to specific ion channels and receptors in other neurological conditions (Table 1). These findings showed clearly that a very specific physiological defect, neuromuscular transmission failure, could be caused by antibodies to a specific receptor, the AChR; that the antibodies bound to the extracellular domain of the receptor and reduced the number of functional AChRs by a combination of humoral mechanisms; that the disease could be passively transferred to mice; and that patients responded to plasma exchange and other treatments that reduced antibody levels. For detailed reviews see Drachman 1994 and Vincent 2002. The importance of the latter two approaches was demonstrated when JND hypothesised that the Lambert Eaton myasthenic syndrome was also caused by a specific autoantibody. This he based on the known autoimmune disease associations and the presence of small cell lung cancer in around 50% of the patients (defining these cases as “paraneoplastic), and he then showed the response to plasma exchange and the transfer of disease to mice (Lang et al., 1981). In this instance, although the voltage-gated calcium channels were an obvious candidate target from the seminal work of Lambert and Eaton on the physiology of the disease (eg. Lambert and Elmqvist, 1971),
and their presence on small cell lung cancers (Roberts et al., 1985) it was some time before a serum assay for the antibodies was established and their presence formally demonstrated (Motomura et al., 1995; Lennon et al., 1995). Similarly with acquired neuromyotonia, a rare but underrecognised condition that causes painful muscle cramps and excessive sweating, it was the association with autoimmune diseases and thymomas that suggested that this might also be antibody-mediated. The response to plasma exchange and the nature of the defect both in the patients and in mice injected with patients IgG (Sinha et al., 1991; Shillito et al., 1995) suggested that antibodies were involved, and voltage-gated potassium channels on the motor nerve terminal were a likely target, as subsequently shown (Hart et al., 1997, 2002). 1.2. Different types of myasthenia A major interest throughout this time was the patients without the typical AChR antibodies. Their clinical responses to treatment and passive transfer studies indicated that they must have other antibodies (Mossman et al., 1986), and studies over many years tried to clarify the nature of the target. Eventually it seemed that some antibodies were binding to a different muscle protein, and when muscle specific kinase (MuSK) was first described as a neuromuscular junction specific membrane protein, it was an obvious candidate (Hoch et al., 2001). Interestingly, these antibodies appear to differ in frequency at different latitudes, suggesting an environmental influence (Vincent et al in preparation). Moreover, MuSK antibodies have effects on intracellular signalling that warrant further study (Benveniste et al., 2005; Boneva et al., 2006), and are likely related to the very considerable muscle atrophy that some patients experience particularly in facial and tongue muscle (Farrugia et al., 2006). There remained a variable proportion of patients for whom no diagnostic test existed. The presence of thymic changes very similar to those in typical AChR antibody positive MG patients, suggested that they were part of the same spectrum of the disease — and different from the MuSK-MG patients (Lauriola et al., 2005; Leite et al., 2005, 2007). Recently, using molecular techniques to express that AChRs at high density in a cell line, we have demonstrated antibodies in over 60% of these previously “seronegative” patients (Leite et al., 2008). 1.3. Maternal effects on development A few babies born to mothers with established MG have been reported to have a condition called arthrogyrposis multiplex congenital (AMC) which is a syndrome of multiple joint contractures and other deformities caused by lack of fetal movement, that can prove fatal. In these mothers, antibodies to the fetal isoform of the AChR were found to bind in such a manner as to prevent ACh-induced currents through the fetal AChR, without affecting the function of the adult AChR. Thus the antibodies crossed the placenta and paralysed the fetus in utero, leading to the condition. Interestingly, in a few mothers these antibodies were present without maternal disease (Riemersma et al., 1996). These observations raise the
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Table 2 Antibodies to ion channels associated with CNS conditions Antigen
Clinical features
Age range
Evidence for other antibodies causing a similar syndrome
VGKC
Limbic encephalitis, Morvan's syndrome, epilepsies
Mostly N20 years, median 60 years; some tumours but many non-paraneoplastic
NMDA receptors
Encephalopathy with psychiatric, limbic, autonomic, and motor disturbance Rasmussen's encephalitis and other intractable epilepsies Neuromyelitis optica
Mostly young females, some children, usually with teratoma. A few males and older patients Mainly children
Very similar presentations not associated with VGKC antibodies “Neuropil” antibodies may bind a number of targets including VGKC antibodies (Dalmau et al., 2007) Some others reported but no antibodies in routine clinical use High positivity rate in patients with typical neuromyelitis
Glutamate receptor 3 Aquaporin-4 Glycine receptors
Encephalomyelitis with rigidity and myoclonus, presenting with excessive startle
Mainly adults but some children reported (Banwell et al., 2008) One case report published (Hutchinson et al., in press)
There are several other reports of antibodies to these and other CNS ion channels or receptors defined on the basis of western blots or ELISAs, but not yet confirmed to bind to the membrane proteins in their native conformation.
possibility that other developmental conditions are caused by antibodies specific for fetal receptors or ion channels. 2. Autoimmune channelopathies — the legacy 2.1. Developmental disorders In order to prove the pathogenicity of the antibodies, we developed a mouse model of “passive maternal-to-fetal” antibody transfer by injecting pregnant mouse dams with the plasma from mothers of AMC babies. We were able to produce newborn mice that showed many of the features of the condition, including muscle paralysis, fixed joints and failure to survive after birth. Appropriately, the mouse dam was unaffected by the antibodies, illustrating their specificity for the fetal AChR (Jacobson et al., 1999). The idea that maternal antibodies might cause neurodevelopmental disorders such as autism is becoming more widely appreciated (eg. Singer et al., 2008). We have reported one pilot study illustrating a role for maternal antibodies in autism (Dalton et al., 2003) although the target of the putative antibodies is not known.
are usually focal but may be or become generalised. In this, relatively acute-onset, condition MRI often shows high intensity signal in one or both medial temporal lobes. Plasma sodium levels may be reduced at presentation. Memory loss can be substantial and incapacitating but recovers considerably after immunosuppressive treatments. These observations stimulated the search for VGKC antibodies in different forms of epilepsy. Raised levels were found in a proportion of patients (McKnight et al., 2005) including a few with long-standing epilepsy (Majoie et al., 2006). There are beginning to be reports of highly raised VGKC antibodies in patients with subacute onset of epileptic disorders in later life, including three recent cases with very frequent brief extratemporal seizures that appeared to respond well to immunotherapies (Irani et al., in press). VGKC antibodies can sometimes be associated with tumours, usually thymoma or rarely small cell lung cancer, particular in neuromyotonia or Morvan's syndrome. VGKC antibodies, often at lower levels, can also be present without the clinical syndromes described above. The widening spectrum of conditions associated with VGKC antibodies has been summarised recently (Tan et al., 2008).
2.2. VGKC antibodies in CNS conditions 2.3. The expanding field of autoimmune encephalopathies It soon became clear that antibodies to VGKCs are found in central nervous system disorders as well as in neuromyotonia (Table 2). Morvan's syndrome includes neuromyotonia with autonomic and additional, often marked, central nervous system (CNS) involvement. The patients present with a range of symptoms including muscle cramps, excessive sweating, cardiac irregularities, constipation, memory loss, sleep disturbance and hallucinations. There may be gross disregulation of Circadian rhythms (Liguori et al., 2001; Spinazzi et al., in press). Most of the few cases described in the literature to date have improved with immunosuppressive treatments, or spontaneously. VGKC antibodies are also being recognised in a (predominatly non-paraneoplastic) form of limbic encephalitis (Buckley et al., 2001; Vincent et al., 2004; Thieben et al., 2004). The patients develop memory loss, confusion, and seizures. These
The field of antibodies in CNS diseases is proving clinically very important, since these conditions are often not paraneoplastic and are usually responsive to immunotherapies (see Vincent et al., 2006). Table 2 summarises some of these “new” antibodies and their clinical associations. Antibodies to glutamate receptors (GluR3) were first reported in a small number of children with Rasmussen's encephalitis (Rogers et al., l994). Further studies suggested that the antibodies could interfere with receptor function by a variety of mechanisms, although these did not explain well an association with seizures (see McNamara et al., 1999). The existence of these antibodies is now somewhat more controversial since, although identified using a peptide ELISA and immunohistochemistry by several groups (eg. Wiendl et al., 2001;
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Bernasconi et al., 2002), they were found in other forms of epilepsy as well, and their presence could not be validated by our laboratory using a variety of approaches (Watson et al., 2004). Indeed, current consensus regarding the aetiology of Rasmussen's encephalitis is more in favour of a T cell mediated immune attack and glutamate receptor antibodies, when present, may be a secondary phenomenon (Bien et al., 2005), although a role for specific antibodies has not been excluded. A particularly exciting development is the report of antibodies to NMDARs in a paraneoplastic form of encephalitis. These patients usually present with psychiatric features, with accompanying amnesia, seizures, movement disorders, autonomic dysfunction, and decreased level of consciousness (Dalmau et al., 2007). Ovarian tumours can be found in the majority, although non-paranoplastic cases are now being recognised in both males and females (Vincent, Bien C, Irani S unpublished observations). The NMDAR antibody-associated encephalopathy is mainly found in young females, including children, and these antibodies may be of particular relevance to pediatric practice. Antibodies to a peptide representing NMDAR2/3 have been reported in patients with neuropsychiatric lupus but not yet shown to be helpful in defining those patients in clinical practice (DeGiorgio et al., 2001). Another illustration of an autoimmune channelopathy, is neuromyelitis optica or Devic's disease. Neuromyelitis optica is an inflammatory disease that presents with optic neuritis and spinal cord myelitis and can be mistaken for multiple sclerosis at onset. Lennon and colleagues first described immunoreactivity of NMO serum IgG antibodies with microvessels, pia mater and Virchow Robbin spaces and subsequently identified acquaporin4 – a water channel found mainly in the CNS – as the target antigen (Lennon et al., 2005). Detection of antibodies to AQP4 are found in most patients in relapse, and are proving to be very useful in the diagnosis of this condition (Waters et al., 2008). 3. Testing and identifying new autoimmune channelopathies The increasing recognition of immune-mediated CNS diseases means that many clinicians consider such a condition, even when the results of existing tests are negative. Plasma exchange, steroids and immunosuppression are therefore used increasingly in patients with both paraneoplastic and non-paraneoplastic disorders, if non-immune mechanisms have been excluded. Thus there is growing evidence for treatment-responsive CNS diseases and an equal need to define new antibody targets and establish new techniques for their detection. Assays based on binding to cell lines stably or transiently transfected to express a candidate antigen are clearly going to be an important way forward, as evidence by detection of antibodies to AQP4, NMDARs, and glycine receptors by this approach. Indirect immunofluorescence on these cells appears to be highly sensitive and specific (binding to cells expressing an alternative antigen should always be tested in parallel). Incorporation of a fluorescent or enzymatic marker into the antigen allows use of an immunoprecipitation test for large numbers of samples or serial studies (eg. Waters et al., 2008), but may be less sensitive with some antigens. ELISAs based on short peptide sequences, as
reported by several groups for NMDAR and GluR3 antibodies may be positive in some patients but their use in diagnosis or management is tricky and has not yet been established. Finally, how can one identify a completely novel or noncandidate antigen? Immunoprecipitation and proteomic analysis of the immunoprecipitates should be feasible. However, human sera tend to bind non-specifically to many proteins, as do Protein A or Protein G sepharose. The detection of small amounts of a membrane protein against a background of such intracellular proteins can be difficult. But we have recently shown that it is possible to identify membrane antigens with this technique (Littleton, Dreger and Vincent in preparation), and this may be one way forward to define new immunotherapy-responsive antibody-mediated CNS disorders. Conflict of interest I and my laboratory receive royalties and payments for antibody tests. Acknowledgements We are very grateful to all the support we have received over the last three decades from the Myasthenia Gravis Association/Muscular Dystrophy Campaign, the Medical Research Council, Action Research, the Dana Foundation and many others. References Banwell, B., Tenembaum, S., Lennon, V.A., Ursell, E., Kennedy, J., Bar-Or, A., Weinshenker, B.G., Lucchinetti, C.F., Pittock, S.J., 2008. Neuromyelitis opticaIgG in childhood inflammatory demyelinating CNS disorders. Neurology 70, 344–352. Benveniste, O., Jacobson, L., Farrugia, M.E., Clover, L., Vincent, A., 2005. MuSK antibody positive myasthenia gravis plasma modifies MURF-1 expression in C2C12 cultures and mouse muscle in vivo. J. Neuroimmunol. 170, 41–48. Bernasconi, P., Cipelletti, B., Passerini, L., Granata, T., Antozzi, C., Mantegazza, R., Spreafico, R., 2002. Similar binding to glutamate receptors by Rasmussen and partial epilepsy patients' sera. Neurology 59, 1998–2001. Bien, C.G., Granata, T., Antozzi, C., Cross, J.H., Dulac, O., Kurthen, M., Lassmann, H., Mantegazza, R., Villemure, J.G., Spreafico, R., Elger, C.E., 2005. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain 128, 454–471. Boneva, N., Frenkian-Cuvelier, M., Bidault, J., Brenner, T., Berrih-Aknin, S., 2006. Major pathogenic effects of anti-MuSK antibodies in myasthenia gravis. J. Neuroimmunol. 177, 119–131. Buckley, C., Oger, J., Clover, L., Tuzun, E., Carpenter, K., Jackson, M., Vincent, A., 2001. Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann. Neurol. 50, 73–78. Dalmau, J., Tuzun, E., Wu, H.Y., Masjuan, J., Rossi, J.E., Voloschin, A., Baehring, J.M., Shimazaki, H., Koide, R., King, D., Mason, W., Sansing, L.H., Dichter, M.A., Rosenfeld, M.R., Lynch, D.R., 2007. Paraneoplastic anti-Nmethyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann. Neurol. 61, 25–36. Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., Vincent, A., 2003. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533–537. DeGiorgio, L.A., Konstantinov, K.N., Lee, S.C., Hardin, J.A., Volpe, B.T., Diamond, B., 2001. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat. Med. 7, 1189–1193.
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Autoimmune channelopathies: John Newsom-Davis's work and legacy A summary of the Newsom-Davis Memorial Lecture 2008 Angela Vincent ⁎ Department of Clinical Neurology, University of Oxford, Max Plank Institute for Developmental Neurobiology, Tuebingen, Germany Received 15 July 2008; accepted 15 July 2008
Abstract John Newsom-Davis was a key figure in the field of neuroimmunology and combined many outstanding personal qualities with considerable clinical and scientific expertise. His first report of plasma exchange in myasthenia in the late 1970s demonstrated its use both as a treatment and as an experimental tool to establish the pathogenic role of antibodies in neurological disorders. Subsequent investigations into the Lambert Eaton myasthenic syndrome and acquired neuromyotonia showed that these were caused by antibodies to specific ion channels. The field of autoimmune channelopathies is continuing to expand with identification of new antibody-mediated diseases including those affecting the central nervous system. This review will highlight some of his most seminal findings and those that are following on from his work. © 2008 Elsevier B.V. All rights reserved. Keywords: Myasthenia; Lambert Eaton myasthenic syndrome; neuromyotonia; ion channels; receptors; autoantibody; maternal-to-fetal transfer; developmental disorders; aetylcholine receptors; calcium channels; potassium channels; glutamate receptors; aquaporins; encephalopathies
John Newsom-Davis (JND) was a major international figure in the field of neurology and neuroimmunology. He combined clinical expertise with commitment to scientific understanding of disease mechanisms and their implications for treatment. He influenced a generation of neurologists and neuroscientists and his exceptional personal qualities of kindness, intelligence, tolerance, energy and modesty are greatly missed by all. JND brought clinical observations to the laboratory and vice versa. With experience of both muscle spindle electrophysiology and intensive care medicine, in 1973 he started collaborating with Ricardo Miledi and myself at University College London looking at acetylcholine receptor (AChR) numbers and function at the neuromuscular junction in myasthenia gravis (MG). The publication later that year, by Dan Drachman and colleagues, that AChRs were reduced in MG endplates, and by Jon Lindstrom and colleagues, of experimental autoimmune myasthenia in rabbits immunised with purified electric fish ⁎ Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK. Tel.: +44 1865 222321; fax: +44 1865 222402. E-mail address: [email protected]. 0165-5728/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2008.07.007
AChR were seminal in the field. A few years later Jon and others identified antibodies to acetylcholine receptors (AChRs) in serum of the patients, and that, with the demonstration of passive transfer of disease to mice by injection of patients' IgG by Klaus Toyka and Dan Drachman in 1975, clearly indicated the humoral nature of the disease. JND first came into the field by showing the effects of plasma exchange as a treatment. The remarkable efficacy of this therapy – which lasted for several weeks – and the relationship between AChR antibody levels and clinical state following exchange (Newsom-Davis et al., 1978), confirmed that myasthenia was indeed an antibodymediated diseases. The discoveries that followed in JND's and others' laboratories owe much to the implications of this simple clinical experiment. Over the next 20 years, he and our colleagues in London, and later in Oxford, systematically investigated the role of the thymus and involvement of T cell immunity in MG, defined the existence of humoral immunity to voltage-gated calcium channels (VGCC) in the Lambert Eaton myasthenic syndrome (LEMS), and showed similarly that some cases of acquired neuromyotonia were associated with antibodies to voltage-gated potassium channels (VGKC).
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Table 1 Clinical and experimental paradigms that identified neuromuscular junction antibody-mediated diseases Specific in vivo and ex vivo electrophysiology suggesting pre or postsynaptic defects Active immunisation and/or passive transfer of IgG leading to similar changes in mice Specific antibodies identified in patients' sera Antibodies shown to be potentially pathogenic in vitro Patients respond to plasma exchange, steroids and immunosuppressive drugs Note. Whereas for myasthenia gravis, the sequence of events was as shown above, in the Lambert Eaton myasthenic syndrome and in acquired neuromyotonia, it was the response to plasma exchange and passive transfer experiments that were most crucial in demonstrating the role of autoantibodies in the disease, and the identification of the antigenic target followed later.
With retirement in 1998, JND stepped aside from the laboratory and, while continuing to see MG patients, and as Editor of Brain, he began to establish a major international trial of thymectomy in MG with Gil Wolfe, Gary Cutter and many others; this was eventually funded by the NIH. His life has already been commemorated in this journal (Willcox, 2008; Raine, 2008) and many of his achievements are celebrated and developed further in this special volume with the main emphasis on the immunology and treatment of MG and LEMS. Here I will review briefly these findings and those that have stemmed directly from his work, and illustrate the considerable scope for further definition and investigation of “autoimmune channelopathies” in the future. 1. Autoimmune channelopathies — the work 1.1. Myasthenia gravis, Lambert Eaton myasthenic syndrome and neuromyotonia It is difficult to overemphasise the importance of the discoveries in myasthenia in the 1970s in showing the way forward for determining the role of antibodies to specific ion channels and receptors in other neurological conditions (Table 1). These findings showed clearly that a very specific physiological defect, neuromuscular transmission failure, could be caused by antibodies to a specific receptor, the AChR; that the antibodies bound to the extracellular domain of the receptor and reduced the number of functional AChRs by a combination of humoral mechanisms; that the disease could be passively transferred to mice; and that patients responded to plasma exchange and other treatments that reduced antibody levels. For detailed reviews see Drachman 1994 and Vincent 2002. The importance of the latter two approaches was demonstrated when JND hypothesised that the Lambert Eaton myasthenic syndrome was also caused by a specific autoantibody. This he based on the known autoimmune disease associations and the presence of small cell lung cancer in around 50% of the patients (defining these cases as “paraneoplastic), and he then showed the response to plasma exchange and the transfer of disease to mice (Lang et al., 1981). In this instance, although the voltage-gated calcium channels were an obvious candidate target from the seminal work of Lambert and Eaton on the physiology of the disease (eg. Lambert and Elmqvist, 1971),
and their presence on small cell lung cancers (Roberts et al., 1985) it was some time before a serum assay for the antibodies was established and their presence formally demonstrated (Motomura et al., 1995; Lennon et al., 1995). Similarly with acquired neuromyotonia, a rare but underrecognised condition that causes painful muscle cramps and excessive sweating, it was the association with autoimmune diseases and thymomas that suggested that this might also be antibody-mediated. The response to plasma exchange and the nature of the defect both in the patients and in mice injected with patients IgG (Sinha et al., 1991; Shillito et al., 1995) suggested that antibodies were involved, and voltage-gated potassium channels on the motor nerve terminal were a likely target, as subsequently shown (Hart et al., 1997, 2002). 1.2. Different types of myasthenia A major interest throughout this time was the patients without the typical AChR antibodies. Their clinical responses to treatment and passive transfer studies indicated that they must have other antibodies (Mossman et al., 1986), and studies over many years tried to clarify the nature of the target. Eventually it seemed that some antibodies were binding to a different muscle protein, and when muscle specific kinase (MuSK) was first described as a neuromuscular junction specific membrane protein, it was an obvious candidate (Hoch et al., 2001). Interestingly, these antibodies appear to differ in frequency at different latitudes, suggesting an environmental influence (Vincent et al in preparation). Moreover, MuSK antibodies have effects on intracellular signalling that warrant further study (Benveniste et al., 2005; Boneva et al., 2006), and are likely related to the very considerable muscle atrophy that some patients experience particularly in facial and tongue muscle (Farrugia et al., 2006). There remained a variable proportion of patients for whom no diagnostic test existed. The presence of thymic changes very similar to those in typical AChR antibody positive MG patients, suggested that they were part of the same spectrum of the disease — and different from the MuSK-MG patients (Lauriola et al., 2005; Leite et al., 2005, 2007). Recently, using molecular techniques to express that AChRs at high density in a cell line, we have demonstrated antibodies in over 60% of these previously “seronegative” patients (Leite et al., 2008). 1.3. Maternal effects on development A few babies born to mothers with established MG have been reported to have a condition called arthrogyrposis multiplex congenital (AMC) which is a syndrome of multiple joint contractures and other deformities caused by lack of fetal movement, that can prove fatal. In these mothers, antibodies to the fetal isoform of the AChR were found to bind in such a manner as to prevent ACh-induced currents through the fetal AChR, without affecting the function of the adult AChR. Thus the antibodies crossed the placenta and paralysed the fetus in utero, leading to the condition. Interestingly, in a few mothers these antibodies were present without maternal disease (Riemersma et al., 1996). These observations raise the
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Table 2 Antibodies to ion channels associated with CNS conditions Antigen
Clinical features
Age range
Evidence for other antibodies causing a similar syndrome
VGKC
Limbic encephalitis, Morvan's syndrome, epilepsies
Mostly N20 years, median 60 years; some tumours but many non-paraneoplastic
NMDA receptors
Encephalopathy with psychiatric, limbic, autonomic, and motor disturbance Rasmussen's encephalitis and other intractable epilepsies Neuromyelitis optica
Mostly young females, some children, usually with teratoma. A few males and older patients Mainly children
Very similar presentations not associated with VGKC antibodies “Neuropil” antibodies may bind a number of targets including VGKC antibodies (Dalmau et al., 2007) Some others reported but no antibodies in routine clinical use High positivity rate in patients with typical neuromyelitis
Glutamate receptor 3 Aquaporin-4 Glycine receptors
Encephalomyelitis with rigidity and myoclonus, presenting with excessive startle
Mainly adults but some children reported (Banwell et al., 2008) One case report published (Hutchinson et al., in press)
There are several other reports of antibodies to these and other CNS ion channels or receptors defined on the basis of western blots or ELISAs, but not yet confirmed to bind to the membrane proteins in their native conformation.
possibility that other developmental conditions are caused by antibodies specific for fetal receptors or ion channels. 2. Autoimmune channelopathies — the legacy 2.1. Developmental disorders In order to prove the pathogenicity of the antibodies, we developed a mouse model of “passive maternal-to-fetal” antibody transfer by injecting pregnant mouse dams with the plasma from mothers of AMC babies. We were able to produce newborn mice that showed many of the features of the condition, including muscle paralysis, fixed joints and failure to survive after birth. Appropriately, the mouse dam was unaffected by the antibodies, illustrating their specificity for the fetal AChR (Jacobson et al., 1999). The idea that maternal antibodies might cause neurodevelopmental disorders such as autism is becoming more widely appreciated (eg. Singer et al., 2008). We have reported one pilot study illustrating a role for maternal antibodies in autism (Dalton et al., 2003) although the target of the putative antibodies is not known.
are usually focal but may be or become generalised. In this, relatively acute-onset, condition MRI often shows high intensity signal in one or both medial temporal lobes. Plasma sodium levels may be reduced at presentation. Memory loss can be substantial and incapacitating but recovers considerably after immunosuppressive treatments. These observations stimulated the search for VGKC antibodies in different forms of epilepsy. Raised levels were found in a proportion of patients (McKnight et al., 2005) including a few with long-standing epilepsy (Majoie et al., 2006). There are beginning to be reports of highly raised VGKC antibodies in patients with subacute onset of epileptic disorders in later life, including three recent cases with very frequent brief extratemporal seizures that appeared to respond well to immunotherapies (Irani et al., in press). VGKC antibodies can sometimes be associated with tumours, usually thymoma or rarely small cell lung cancer, particular in neuromyotonia or Morvan's syndrome. VGKC antibodies, often at lower levels, can also be present without the clinical syndromes described above. The widening spectrum of conditions associated with VGKC antibodies has been summarised recently (Tan et al., 2008).
2.2. VGKC antibodies in CNS conditions 2.3. The expanding field of autoimmune encephalopathies It soon became clear that antibodies to VGKCs are found in central nervous system disorders as well as in neuromyotonia (Table 2). Morvan's syndrome includes neuromyotonia with autonomic and additional, often marked, central nervous system (CNS) involvement. The patients present with a range of symptoms including muscle cramps, excessive sweating, cardiac irregularities, constipation, memory loss, sleep disturbance and hallucinations. There may be gross disregulation of Circadian rhythms (Liguori et al., 2001; Spinazzi et al., in press). Most of the few cases described in the literature to date have improved with immunosuppressive treatments, or spontaneously. VGKC antibodies are also being recognised in a (predominatly non-paraneoplastic) form of limbic encephalitis (Buckley et al., 2001; Vincent et al., 2004; Thieben et al., 2004). The patients develop memory loss, confusion, and seizures. These
The field of antibodies in CNS diseases is proving clinically very important, since these conditions are often not paraneoplastic and are usually responsive to immunotherapies (see Vincent et al., 2006). Table 2 summarises some of these “new” antibodies and their clinical associations. Antibodies to glutamate receptors (GluR3) were first reported in a small number of children with Rasmussen's encephalitis (Rogers et al., l994). Further studies suggested that the antibodies could interfere with receptor function by a variety of mechanisms, although these did not explain well an association with seizures (see McNamara et al., 1999). The existence of these antibodies is now somewhat more controversial since, although identified using a peptide ELISA and immunohistochemistry by several groups (eg. Wiendl et al., 2001;
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Bernasconi et al., 2002), they were found in other forms of epilepsy as well, and their presence could not be validated by our laboratory using a variety of approaches (Watson et al., 2004). Indeed, current consensus regarding the aetiology of Rasmussen's encephalitis is more in favour of a T cell mediated immune attack and glutamate receptor antibodies, when present, may be a secondary phenomenon (Bien et al., 2005), although a role for specific antibodies has not been excluded. A particularly exciting development is the report of antibodies to NMDARs in a paraneoplastic form of encephalitis. These patients usually present with psychiatric features, with accompanying amnesia, seizures, movement disorders, autonomic dysfunction, and decreased level of consciousness (Dalmau et al., 2007). Ovarian tumours can be found in the majority, although non-paranoplastic cases are now being recognised in both males and females (Vincent, Bien C, Irani S unpublished observations). The NMDAR antibody-associated encephalopathy is mainly found in young females, including children, and these antibodies may be of particular relevance to pediatric practice. Antibodies to a peptide representing NMDAR2/3 have been reported in patients with neuropsychiatric lupus but not yet shown to be helpful in defining those patients in clinical practice (DeGiorgio et al., 2001). Another illustration of an autoimmune channelopathy, is neuromyelitis optica or Devic's disease. Neuromyelitis optica is an inflammatory disease that presents with optic neuritis and spinal cord myelitis and can be mistaken for multiple sclerosis at onset. Lennon and colleagues first described immunoreactivity of NMO serum IgG antibodies with microvessels, pia mater and Virchow Robbin spaces and subsequently identified acquaporin4 – a water channel found mainly in the CNS – as the target antigen (Lennon et al., 2005). Detection of antibodies to AQP4 are found in most patients in relapse, and are proving to be very useful in the diagnosis of this condition (Waters et al., 2008). 3. Testing and identifying new autoimmune channelopathies The increasing recognition of immune-mediated CNS diseases means that many clinicians consider such a condition, even when the results of existing tests are negative. Plasma exchange, steroids and immunosuppression are therefore used increasingly in patients with both paraneoplastic and non-paraneoplastic disorders, if non-immune mechanisms have been excluded. Thus there is growing evidence for treatment-responsive CNS diseases and an equal need to define new antibody targets and establish new techniques for their detection. Assays based on binding to cell lines stably or transiently transfected to express a candidate antigen are clearly going to be an important way forward, as evidence by detection of antibodies to AQP4, NMDARs, and glycine receptors by this approach. Indirect immunofluorescence on these cells appears to be highly sensitive and specific (binding to cells expressing an alternative antigen should always be tested in parallel). Incorporation of a fluorescent or enzymatic marker into the antigen allows use of an immunoprecipitation test for large numbers of samples or serial studies (eg. Waters et al., 2008), but may be less sensitive with some antigens. ELISAs based on short peptide sequences, as
reported by several groups for NMDAR and GluR3 antibodies may be positive in some patients but their use in diagnosis or management is tricky and has not yet been established. Finally, how can one identify a completely novel or noncandidate antigen? Immunoprecipitation and proteomic analysis of the immunoprecipitates should be feasible. However, human sera tend to bind non-specifically to many proteins, as do Protein A or Protein G sepharose. The detection of small amounts of a membrane protein against a background of such intracellular proteins can be difficult. But we have recently shown that it is possible to identify membrane antigens with this technique (Littleton, Dreger and Vincent in preparation), and this may be one way forward to define new immunotherapy-responsive antibody-mediated CNS disorders. Conflict of interest I and my laboratory receive royalties and payments for antibody tests. Acknowledgements We are very grateful to all the support we have received over the last three decades from the Myasthenia Gravis Association/Muscular Dystrophy Campaign, the Medical Research Council, Action Research, the Dana Foundation and many others. References Banwell, B., Tenembaum, S., Lennon, V.A., Ursell, E., Kennedy, J., Bar-Or, A., Weinshenker, B.G., Lucchinetti, C.F., Pittock, S.J., 2008. Neuromyelitis opticaIgG in childhood inflammatory demyelinating CNS disorders. Neurology 70, 344–352. Benveniste, O., Jacobson, L., Farrugia, M.E., Clover, L., Vincent, A., 2005. MuSK antibody positive myasthenia gravis plasma modifies MURF-1 expression in C2C12 cultures and mouse muscle in vivo. J. Neuroimmunol. 170, 41–48. Bernasconi, P., Cipelletti, B., Passerini, L., Granata, T., Antozzi, C., Mantegazza, R., Spreafico, R., 2002. Similar binding to glutamate receptors by Rasmussen and partial epilepsy patients' sera. Neurology 59, 1998–2001. Bien, C.G., Granata, T., Antozzi, C., Cross, J.H., Dulac, O., Kurthen, M., Lassmann, H., Mantegazza, R., Villemure, J.G., Spreafico, R., Elger, C.E., 2005. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain 128, 454–471. Boneva, N., Frenkian-Cuvelier, M., Bidault, J., Brenner, T., Berrih-Aknin, S., 2006. Major pathogenic effects of anti-MuSK antibodies in myasthenia gravis. J. Neuroimmunol. 177, 119–131. Buckley, C., Oger, J., Clover, L., Tuzun, E., Carpenter, K., Jackson, M., Vincent, A., 2001. Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann. Neurol. 50, 73–78. Dalmau, J., Tuzun, E., Wu, H.Y., Masjuan, J., Rossi, J.E., Voloschin, A., Baehring, J.M., Shimazaki, H., Koide, R., King, D., Mason, W., Sansing, L.H., Dichter, M.A., Rosenfeld, M.R., Lynch, D.R., 2007. Paraneoplastic anti-Nmethyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann. Neurol. 61, 25–36. Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., Vincent, A., 2003. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533–537. DeGiorgio, L.A., Konstantinov, K.N., Lee, S.C., Hardin, J.A., Volpe, B.T., Diamond, B., 2001. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat. Med. 7, 1189–1193.
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