Autoantibody-mediated central nervous system channelopathies.

The autoimmune channelopathies represent a rapidly evolving scientific and clinical domain. The description of channels, expressed on neurons and glia, as targets of autoantibodies in neuromyelitis optica, autoimmune encephalitis, and related syndromes have revolutionized many areas of neurologic practice. To date, tens of surface antibody specificities have been described, a number that is likely to continue to increase. A central paradigm for all these disorders is that of pathogenic autoantibodies which target extracellular epitopes accessible for binding in vivo. Hence, in these disorders, the autoantibodies are causative diagnostic tools, and provide valuable reagents to model the diseases. Their production by B-lineage cells provides opportunities to study and modulate their production. Across these syndromes, early recognition and treatment are critical since most respond to immunotherapies. Yet, several unmet medical needs persist within treated patient populations, and widespread clinical under-recognition remains a challenge. In this review, we summarize the neuroscience and immunologic basis of autoantibody-mediated central nervous system channelopathies, the molecular effects of the autoantibodies, clinical phenotypes, and treatment approaches. We describe progress since the inauguration of the field through to open questions and potential future directions.

Novel ORAI1 Mutation Disrupts Channel Trafficking Resulting in Combined Immunodeficiency.

Store-operated Ca2+ entry (SOCE) represents a predominant Ca2+ influx pathway in non-excitable cells. SOCE is required for immune cell activation and is mediated by the plasma membrane (PM) channel ORAI1 and the endoplasmic reticulum (ER) Ca2+ sensor STIM1. Mutations in the Orai1 or STIM1 genes abolish SOCE leading to combined immunodeficiency (CID), muscular hypotonia, and anhidrotic ectodermal dysplasia. Here, we identify a novel autosomal recessive mutation in ORAI1 in a child with CID. The patient is homozygous for p.C126R mutation in the second transmembrane domain (TM2) of ORAI1, a region with no previous loss-of-function mutations. SOCE is suppressed in the patient's lymphocytes, which is associated with impaired T cell proliferation and cytokine production. Functional analyses demonstrate that the p.C126R mutation does not alter protein expression but disrupts ORAI1 trafficking. Orai1-C126R does not insert properly into the bilayer resulting in ER retention. Insertion of an Arg on the opposite face of TM2 (L135R) also results in defective folding and trafficking. We conclude that positive side chains within ORAI1 TM2 are not tolerated and result in misfolding, defective bilayer insertion, and channel trafficking thus abolishing SOCE and resulting in CID.

Ion channelopathies of the immune system.

Ion channels and transporters move ions across membrane barriers and are essential for a host of cell functions in many organs. They conduct K+, Na+ and Cl-, which are essential for regulating the membrane potential, H+ to control intracellular and extracellular pH and divalent cations such as Ca2+, Mg2+ and Zn2+, which function as second messengers and cofactors for many proteins. Inherited channelopathies due to mutations in ion channels or their accessory proteins cause a variety of diseases in the nervous, cardiovascular and other tissues, but channelopathies that affect immune function are not as well studied. Mutations in ORAI1 and STIM1 genes that encode the Ca2+ release-activated Ca2+ (CRAC) channel in immune cells, the Mg2+ transporter MAGT1 and the Cl- channel LRRC8A all cause immunodeficiency with increased susceptibility to infection. Mutations in the Zn2+ transporters SLC39A4 (ZIP4) and SLC30A2 (ZnT2) result in nutritional Zn2+ deficiency and immune dysfunction. These channels, however, only represent a fraction of ion channels that regulate immunity as demonstrated by immune dysregulation in channel knockout mice. The immune system itself can cause acquired channelopathies that are associated with a variety of diseases of nervous, cardiovascular and endocrine systems resulting from autoantibodies binding to ion channels. These autoantibodies highlight the therapeutic potential of functional anti-ion channel antibodies that are being developed for the treatment of autoimmune, inflammatory and other diseases.

Autoantibody-mediated diseases of the CNS: Structure, dysfunction and therapy.

The field of neuronal autoantibody associated diseases of the central nervous system has expanded dramatically in the last few years. The range of identified neuronal and glial antibody targets has led to the accurate classification of a number of syndromes which each associate with characteristic clinical features. These diseases are especially important due to their frequent response to immunotherapies. Antibodies against the N-methyl, d-aspartate receptor (NMDAR) and leucine-rich glioma inactivated 1 (LGI1) are the commonest autoantibodies known in patients with autoimmune forms of encephalitis. Patients with NMDAR-antibodies often present with psychiatric symptoms and a movement disorder, whereas patients with LGI1-antibodies have frequent seizures and prominent amnesia. In contrast, aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies are found in patients with inflammation of the spine and optic nerves. The antigenic-specificities appear to determine the associated clinical syndromes, hence the detection of these antibodies informs clinical practice and the biology of these diseases. Indeed, the mechanisms of antibody action are being intensively studied in vitro and in vivo. Overall, these studies confirm the pathogenic potential of the antibodies, and suggest antigen internalisation and complement fixation are the two dominant mechanisms of pathogenicity, and that their relative contributions vary between conditions. In addition to discussing the antigenic targets, the associated clinical features and mechanisms of antibodies, we review the current and future immunotherapy strategies which aim to optimise patient outcomes. This article is part of the Special Issue entitled 'Channelopathies.'

Autoimmune Voltage-Gated Potassium Channelopathy Presenting With Catecholamine Excess.

BACKGROUND: Autoimmune voltage-gated potassium channelopathies have been associated with a range of neurological presenting symptoms, including central, peripheral, and autonomic dysfunction. PATIENT DESCRIPTION: We describe a 12-year-old boy who presented with nine months of pain, anxiety, and 30-pound weight loss. He was admitted for failure to thrive, then noted to be persistently hypertensive and tachycardic. Plasma metanephrines and urine metanephrines and catecholamines were elevated. Extensive investigation for causes of elevated catecholamines, such as hyperthyroidism or catecholamine-secreting tumor, was negative. A paraneoplastic panel was positive for voltage-gated potassium channel antibodies. Treatment with intravenous immunoglobulin and pulse methylprednisolone led to complete resolution of symptoms, weight gain, and normalization of vital signs and plasma metanephrines. CONCLUSION: Voltage-gated potassium channel antibodies should be considered as part of the differential in patients presenting with elevated metanephrine and catecholamine secretion.

Understanding autoimmunity: The ion channel perspective.

Ion channels are integral membrane proteins that orchestrate the passage of ions across the cell membrane and thus regulate various key physiological processes of the living system. The stringently regulated expression and function of these channels hold a pivotal role in the development and execution of various cellular functions. Malfunction of these channels results in debilitating diseases collectively termed channelopathies. In this review, we highlight the role of these proteins in the immune system with special emphasis on the development of autoimmunity. The role of ion channels in various autoimmune diseases is also listed out. This comprehensive review summarizes the ion channels that could be used as molecular targets in the development of new therapeutics against autoimmune disorders.

Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies: a decade later.

The discovery of AQP4-IgG (a pathogenic antibody that targets the astrocytic water channel aquaporin-4), as the first sensitive and specific biomarker for any inflammatory central nervous system demyelinating disease (IDD), has shifted emphasis from the oligodendrocyte and myelin to the astrocyte as a central immunopathogenic player. Neuromyelitis optica (NMO) spectrum disorders (SDs) represent an evolving spectrum of IDDs extending beyond the optic nerves and spinal cord to include the brain (especially in children) and, rarely, muscle. NMOSD typical brain lesions are located in areas that highly express the target antigen, AQP4, including the circumventricular organs (accounting for intractable nausea and vomiting) and the diencephalon (accounting for sleep disorders, endocrinopathies, and syndrome of inappropriate antidiuresis). Magnetic resonance imaging brain abnormalities fulfill Barkoff criteria for multiple sclerosis in up to 10% of patients. As the spectrum broadens, the importance of highly specific assays that detect pathogenic AQP4-IgG targeting extracellular epitopes of AQP4 cannot be overemphasized. The rapid evolution of our understanding of the immunobiology of AQP4 autoimmunity necessitates continuing revision of NMOSD diagnostic criteria. Here, we describe scientific advances that have occurred since the discovery of NMO-IgG in 2004 and review novel targeted immunotherapies. We also suggest that NMOSDs should now be considered under the umbrella term autoimmune aquaporin-4 channelopathy.

Diseases caused by mutations in ORAI1 and STIM1.

Ca(2+) release-activated Ca(2+) (CRAC) channels mediate a specific form of Ca(2+) influx called store-operated Ca(2+) entry (SOCE) that contributes to the function of many cell types. CRAC channels are composed of ORAI1 proteins located in the plasma membrane, which form its ion-conducting pore. ORAI1 channels are activated by stromal interaction molecule (STIM) 1 and STIM2 located in the endoplasmic reticulum. Loss- and gain-of-function gene mutations in ORAI1 and STIM1 in human patients cause distinct disease syndromes. CRAC channelopathy is caused by loss-of-function mutations in ORAI1 and STIM1 that abolish CRAC channel function and SOCE; it is characterized by severe combined immunodeficiency (SCID)-like disease, autoimmunity, muscular hypotonia, and ectodermal dysplasia, with defects in sweat gland function and dental enamel formation. The latter defect emphasizes an important role of CRAC channels in tooth development. By contrast, autosomal dominant gain-of-function mutations in ORAI1 and STIM1 result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca(2+) levels that are associated with an overlapping spectrum of diseases, including nonsyndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes. The latter two syndromes are defined, besides myopathy, by thrombocytopenia, thrombopathy, and bleeding diathesis. The fact that myopathy results from both loss- and gain-of-function mutations in ORAI1 and STIM1 highlights the importance of CRAC channels for Ca(2+) homeostasis in skeletal muscle function. The cellular dysfunction and clinical disease spectrum observed in mutant patients provide important information about the molecular regulation of ORAI1 and STIM1 proteins and the role of CRAC channels in human physiology.

Autoimmune channelopathies in paraneoplastic neurological syndromes.

Paraneoplastic neurological syndromes and autoimmune encephalitides are immune neurological disorders occurring or not in association with a cancer. They are thought to be due to an autoimmune reaction against neuronal antigens ectopically expressed by the underlying tumour or by cross-reaction with an unknown infectious agent. In some instances, paraneoplastic neurological syndromes and autoimmune encephalitides are related to an antibody-induced dysfunction of ion channels, a situation that can be labelled as autoimmune channelopathies. Such functional alterations of ion channels are caused by the specific fixation of an autoantibody upon its target, implying that autoimmune channelopathies are usually highly responsive to immuno-modulatory treatments. Over the recent years, numerous autoantibodies corresponding to various neurological syndromes have been discovered and their mechanisms of action partially deciphered. Autoantibodies in neurological autoimmune channelopathies may target either directly ion channels or proteins associated to ion channels and induce channel dysfunction by various mechanisms generally leading to the reduction of synaptic expression of the considered channel. The discovery of those mechanisms of action has provided insights on the regulation of the synaptic expression of the altered channels as well as the putative roles of some of their functional subdomains. Interestingly, patients' autoantibodies themselves can be used as specific tools in order to study the functions of ion channels. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

An 11-year retrospective experience of antibodies against the voltage-gated potassium channel (VGKC) complex from a tertiary neurological centre.

Acquired diseases classically associated with VGKC-complex antibodies include peripheral nerve hyperexcitability (PNH), Morvan's syndrome, limbic encephalitis (LE), and epilepsy. However, not all such patients have VGKC-complex antibodies and antibodies have been reported in patients without a defined immune-mediated syndrome. To analyse the clinical relevance of positive VGKC-complex antibodies requested on the basis of initial clinical suspicion. We retrospectively analysed patients with positive VGKC-complex antibodies (>100 pM) referred to our institution between 2001 and 2011. 1,614 VGKC-complex assays were performed in 1,298 patients. Titres >100 pM were detected in 57/1,298 (4 %) patients. A classic VGKC-complex channelopathy (60 %) was associated with VGKC-complex antibody titres >400 pM (p = 0.0004). LGI1 or CASPR2 antibodies were only detected in classic VGKC-complex channelopathies (LE; n = 3/4 and PNH; n = 1/5). VGKC-complex antibody titres <400 pM were seen with PNH (n = 15/22; 68 %) but also a heterogeneous range of central and/or peripheral nervous system disorders. Electromyography was supportive of PNH in 65 % of cases and symptomatic treatment was beneficial in 46 % of patients. Irrespective of titre, the rate of malignancy in patients with VGKC-complex antibodies was higher than the age-matched national incidence of malignancy (OR 19.9, 95 % CI 8.97-44.0 p<0.0001). Clinical phenotyping and antibody titres >400 pM can help determine VGKC-complex antibody relevance. Antibody titres <400 pM are associated with PNH but also a more heterogeneous clinical spectrum. The antibody association in the latter is of doubtful clinical relevance. The rate of malignancy was significantly higher than the national incidence irrespective of titre.

Developments in autoimmune channelopathies.

Autoimmune forms of encephalopathy have become a hot topic in neurology. These conditions are now known to be associated with antibodies to neuronal or glial cell surface proteins, such as ion channels, receptors or associated proteins. The most common conditions are a form of limbic encephalitis associated with antibodies to voltage-gated potassium channel complex proteins, and a more complex encephalopathy with antibodies to the NR1 subunit of the N-methyl-D aspartate receptor, a class of glutamate receptor. In addition, a very inflammatory disease of the nervous system, neuromyelitis optica, associated with blindness as well as spinal cord damage, can be distinguished by the presence of antibodies to aquaporin-4, a water channel. Many other antibodies are now being identified, but their frequencies are less clear. Most importantly, these new antibody-mediated diseases are being identified in patients of all ages, and in the majority of cases, the patients improve substantially with immunotherapies.

[Autoimmune channelopathies]. / Canalopathies auto-immunes.

Autoimmune channelopathies are rare neuromuscular diseases that have been characterized clinically for several decades but for which the evidence of associated antibodies has only been recently demonstrated. Ion channels have an important role of activation, inhibition and regulation in neuromuscular transmission. Myasthenia gravis, generally associated with the presence of anti-acetylcholine receptor antibody, is the best-known channelopathy. Other anti-channel antibodies, including voltage-dependent, are associated with several neurological diseases, as illustrated by anti-voltage-gated calcium channels found in Lambert-Eaton myasthenic syndrome and paraneoplastic cerebellar ataxia, and anti-voltage-gated potassium channels found in neuromyotonia, Morvan's syndrome and limbic encephalitis. The treatment of autoimmune channelopathies is logically based on corticosteroids, immunosuppressant drugs, intravenous immunoglobulins and plasmapheresis.

Autoimmune channelopathies: well-established and emerging immunotherapy-responsive diseases of the peripheral and central nervous systems.

BACKGROUND: The role of antibodies in neuromuscular junction disorders is well established with antibodies to acetylcholine receptor, muscle-specific kinase, and voltage-gated calcium channels. The diseases associated with these antibodies, myasthenia gravis and the Lambert-Eaton myasthenic syndrome, respond well to symptomatic treatments (e.g., cholinesterase inhibitors) and to immunotherapies such as plasma exchange, intravenous immunoglobulin, oral steroids, and steroid-sparing drugs. The role of the antibodies has been established by a variety of in vitro and in vivo approaches. More recently, antibodies to voltage-gated potassium channels have been identified in patients with autoimmune forms of acquired neuromyotonia. Over the last decade, antibodies to CNS membrane receptors or ion channels have begun to be identified and these antibodies define antibody-mediated CNS diseases that also respond to immunotherapies. SUMMARY: The paradigms gained from the study of the peripheral conditions has led to a better appreciation of the role of antibodies in neurological disorders and a growing recognition of their role in central nervous system (CNS) diseases.

Voltage-gated potassium channel autoimmunity mimicking creutzfeldt-jakob disease.

BACKGROUND: Rapidly progressive dementia has a variety of causes, including Creutzfeldt-Jakob disease (CJD) and neuronal voltage-gated potassium channel (VGKC) autoantibody-associated encephalopathy. OBJECTIVE: To describe patients thought initially to have CJD but found subsequently to have immunotherapy-responsive VGKC autoimmunity. DESIGN: Observational, prospective case series. SETTING: Department of Neurology, Mayo Clinic, and the Memory and Aging Center, University of California, San Francisco. Patients A clinical serologic cohort of 15 patients referred for paraneoplastic autoantibody evaluation. Seven patients were evaluated clinically by at least one of us. Clinical information for the remaining patients was obtained by physician interview or medical record review. MAIN OUTCOME MEASURES: Clinical features, magnetic resonance imaging abnormalities, electroencephalographic patterns, cerebrospinal fluid analyses, and responses to immunomodulatory therapy. RESULTS: All the patients presented subacutely with neurologic manifestations, including rapidly progressive dementia, myoclonus, extrapyramidal dysfunction, visual hallucinations, psychiatric disturbance, and seizures; most (60%) satisfied World Health Organization diagnostic criteria for CJD. Magnetic resonance imaging abnormalities included cerebral cortical diffusion-weighted imaging hyperintensities. Electroencephalographic abnormalities included diffuse slowing, frontal intermittent rhythmic delta activity, and focal epileptogenic activity but not periodic sharp wave complexes. Cerebrospinal fluid 14-3-3 protein or neuron-specific enolase levels were elevated in 5 of 8 patients. Hyponatremia was common (60%). Neoplasia was confirmed histologically in 5 patients (33%) and was suspected in another 5. Most patients' conditions (92%) improved after immunomodulatory therapy. CONCLUSIONS: Clinical, radiologic, electrophysiologic, and laboratory findings in VGKC autoantibody-associated encephalopathy may be confused with those of CJD. Serologic evaluation for markers of neurologic autoimmunity, including VGKC autoantibodies, may be warranted in suspected CJD cases.

Autoimmune channelopathies.

Autoimmune disorders of the neuromuscular junction remain a paradigm for our understanding of autoimmunity. Since the role of autoantibodies to acetylcholine receptors in the pathogenesis of myasthenia gravis was first recognized in the 1970s, a range of antibody-mediated disorders of the neuromuscular junction have been described, each associated with an autoantibody to a specific ligand-gated receptor, voltage-gated ion channel or related protein. In addition, antibodies to a ganglionic form of acetylcholine receptor have been detected in autoimmune forms of autonomic neuropathy. In the past few years, a role for antibodies in disorders of the CNS has begun to emerge, challenging our previous concepts regarding the blood-brain barrier and the role of the humoral immune system in CNS pathology. Although it has not yet been definitively shown that these CNS conditions are antibody-mediated, the detection of the specific antibody supports a trial of immunosuppressive therapy to which many patients appear to respond. In this article, we review the roles of antibodies to receptors and ion channels in the peripheral and central nervous systems, concentrating on the recently defined autonomic and CNS conditions and on the role of antibody measurement in diagnosis and management.