I found an interesting article on channelopathies. It's too long and technical to post here, so I'll post the intro and the part relating to the immune system. I hope other people will find this info useful in the search to understand POIS.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935107/"Channelopathies are a heterogeneous group of disorders resulting from the dysfunction of ion channels located in the membranes of all cells and many cellular organelles. These include diseases of the nervous system (e.g., generalized epilepsy with febrile seizures plus, familial hemiplegic migraine, episodic ataxia, and hyperkalemic and hypokalemic periodic paralysis), the cardiovascular system (e.g., long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), the respiratory system (e.g., cystic fibrosis), the endocrine system (e.g., neonatal diabetes mellitus, familial hyperinsulinemic hypoglycemia, thyrotoxic hypokalemic periodic paralysis, and familial hyperaldosteronism), the urinary system (e.g., Bartter syndrome, nephrogenic diabetes insipidus, autosomal-dominant polycystic kidney disease, and hypomagnesemia with secondary hypocalcemia), and the immune system (e.g., myasthenia gravis, neuromyelitis optica, Isaac syndrome, and anti-NMDA [N-methyl-D-aspartate] receptor encephalitis). The field of channelopathies is expanding rapidly, as is the utility of molecular-genetic and electrophysiological studies. This review provides a brief overview and update of channelopathies, with a focus on recent advances in the pathophysiological mechanisms that may help clinicians better understand, diagnose, and develop treatments for these diseases."
"Channelopathies are diseases that develop because of defects in ion channels caused by either genetic or acquired factors. Mutations in genes encoding ion channels, which impair channel function, are the most common cause of channelopathies. Consistent with the distribution of ion channels throughout the human body, ion channel defects have been implicated in a wide variety of diseases, including epilepsy, migraine, blindness, deafness, diabetes, hypertension, cardiac arrhythmia, asthma, irritable bowel syndrome, and cancer.
There are remarkable causal heterogeneity (especially genetic) and phenotypic variability in channelopathies, which make the diseases challenging to classify. This review will categorize channelopathies based on the organ system with which they are predominantly associated in both clinical and pathophysiological respects. Nomenclature of genetic diseases described in this article can be found at the Online Mendelian Inheritance in Man (OMIM) website:http://www.ncbi.nlm.nih.gov/omim."
"Ion channels are transmembrane proteins that allow the passive flow of ions, both in and out of cells or cellular organelles, following their electrochemical gradients. Because the flux of ions across a membrane results in electrical currents, ion channels play a key role in generating membrane potential and function in diverse cellular activities, such as signal transduction, neurotransmitter release, muscle contraction, hormone secretion, volume regulation, growth, motility, and apoptosis. Ion channels can be classified according to the types of ions passing through them, the factors of their gating, their tissue expression patterns, and their structural characteristics. Ion channels typically exist in one of the three states: open, inactivated closed (refractory period), and resting closed. The gating (opening and closing) of ion channels is controlled by diverse factors, such as membrane potential (voltage), ligands (e.g., hormones and neurotransmitters), second messengers (e.g., calcium and cyclic nucleotides), light, temperature, and mechanical changes. Ion channels are formed from either a single protein (e.g., cystic fibrosis transmembrane conductance regulator, a chloride channel) or, more commonly, from an assembly of several subunits, each a protein encoded by a different gene. More than 400 ion channel genes have been identified. Further diversity comes from a number of mechanisms, which include the use of multiple promoters, alternative splicing, posttranslational modifications, heteromeric assembly of different principal subunits, and interaction with accessory proteins."
"Antibodies against ion channels and associated proteins expressed on the surface of neurons or muscle cells have been implicated in a variety of neurological pathologies ranging from myasthenia gravis (MG) to certain forms of encephalitis. Typical paraneoplastic antibodies generally target intracellular antigens and are not likely pathogenic. However, antibodies responsible for autoimmune channelopathies, often arising under paraneoplastic conditions, directly affect the kinetics and/or membrane density of ion channels or damage cells expressing the channels, which accounts for the favorable response shown by most patients to immunotherapies. Autoimmune channelopathies have been increasingly found in all age group.
MG is the prototype of autoimmune channelopathies. Most MG patients have autoantibodies against muscle nAChRs expressed on the postsynaptic membrane of muscle cells. These antibodies reduce functional nAChRs by direct block of function, complement-mediated damage to the cell membrane, and increased receptor endocytosis and degradation (a process referred to as antigenic modulation). Antibodies against MuSK, which is required for nAChR clustering, have been identified in a subset of MG patients without nAChR antibodies, reminiscent of the pathogenesis of certain cases of congenital myasthenic syndrome that is a clinically similar but distinct disorder (see p. 5).
Autoimmune autonomic ganglionopathy (AAG, also called autoimmune autonomic neuropathy) is an acquired form of autonomic neuropathies in which autoantibodies bind to the ?3 subunit of the neuronal nAChR located in ganglionic synapses of sympathetic, parasympathetic, and enteric nervous systems. Patients present with symptoms of diffuse autonomic failure, such as orthostatic hypotension, hypohidrosis, fixed and dilated pupils, dry eyes and mouth, urinary retention, and constipation or diarrhea. Ganglionic nAChRs mediate fast synaptic transmission in autonomic ganglia. Autoantibodies against ganglionic nAChRs impair cholinergic synaptic transmission, leading to the consequent symptoms of autonomic failure in AAG.
Lambert-Eaton myasthenic syndrome (LEMS) is a presynaptic disorder that is characterized by proximal muscle weakness, autonomic dysfunction, and areflexia. LEMS results from an autoimmune process in which autoantibodies react against presynaptic P/Q type voltage-gated calcium channels (VGCCs). Presynaptic VGCCs are involved in the depolarization-induced calcium influx that causes neurotransmitter release from nerve terminals. Autoantibodies against VGCCs are known to deplete the channels, reduce calcium influx, and cause a reduction of acetylcholine release. Approximately 50% of patients with LEMS have an underlying malignancy, such as small cell lung cancer (SCLC) in which SCLC cells express VGCCs on their surface, suggesting a cross reactivity of antibodies with presynaptic VGCCs. Accumulating evidence indicates that VGCCs also play a pathogenic role in certain patients with paraneoplastic cerebellar degeneration associated with SCLC.
Neuromyotonia (NMT) is a form of peripheral nerve hyperexcitability that is characterized by muscle fasciculations, cramps, pseudomyotonia (slow relaxation following muscle contraction), hyperhidrosis, and variable paraesthesias. NMT can be inherited or acquired. Evidence of a channelopathy can be found in one type of acquired NMT, called Isaac syndrome, in which autoantibodies are directed against ?-dendrotoxin (?-DTX)-sensitive voltage-gated potassium channel (VGKC) complexes expressed in motor and sensory nerves. The ?-DTX-sensitive VGKC complex consists of a VGKC (a Kv1 tetramer with auxiliary ? subunits) and associated proteins, such as leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein 2 (CASPR2), and contactin-2. VGKCs help repolarize depolarized cells and prevent repetitive discharges. Autoantibodies against components of VGKC complexes result in loss of functional VGKCs, reduced outward potassium currents, and spontaneous repetitive firing of action potentials, which leads to peripheral nerve hyperexcitability and enhanced muscle contraction. A combination of NMT and CNS manifestations (e.g., insomnia, confusion, hallucination, delirium, and amnesia) can be detected in Morvan syndrome, in which most patients have VGKC complex antibodies, predominantly against CASPR2. Cramp-fasciculation syndrome is another phenotype of peripheral nerve hyperexcitability that can be caused by VGKC complex antibodies, and this disease is characterized by the occurrence of severe muscle ache, cramps, and twitching in otherwise healthy individuals.
Limbic encephalitis (LE) is the most common CNS syndrome associated with increased levels of VGKC complex antibodies. LE is characterized by acute or subacute amnesia, confusion, seizures, and personality change or psychosis, with a high signal in the medial temporal lobes on MRI (indicating swelling and/or inflammation). Autoantibodies against ion channels other than VGKC have also been reported in LE patients, including antibodies against ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), GABAB receptor, and N-methyl-D-aspartate receptor (NMDAR). LE can arise as a paraneoplastic syndrome. Most LE patients have antibodies against the LGI1 component of VGKC complexes and do not usually have a tumor, whereas a small proportion of LE patients have CASPR2 antibodies and display an increased incidence of thymomas.
Anti-NMDAR encephalitis is characterized by sequential clinical manifestations that proceed from psychosis, amnesia, confusion, dysphasia, and seizures into dyskinesias, and autonomic and breathing instability, typically requiring management in the intensive care unit. Anti-NMDAR encephalitis is recognized as the most prevalent antibody-associated encephalitis and the second most common immune-mediated encephalitis after acute disseminated encephalomyelitis. A substantial proportion of patients with this disease are children and young adults with or without an associated tumor. The frequency of underlying tumors (usually ovarian teratoma) depends on age and sex and is lower in younger patients. Patients have antibodies against the NMDAR in blood and cerebrospinal fluid and exhibit high intrathecal synthesis of the antibodies. The NMDAR, a non-selective cation channel, is a glutamate receptor that modulates excitatory neurotransmission and synaptic plasticity in the CNS and plays a critical role in memory, learning, mood, and behavior. Anti-NMDAR antibodies have been demonstrated to lower the membrane density of postsynaptic NMDARs by enhancing receptor internalization and degradation, which can lead to reduced excitability of GABAergic neurons expressing NMDARs at high levels and to the deregulation of excitatory pathways. In more than 50% of patients with systemic lupus erythematosus (SLE), autoantibodies that react with NMDARs also cause neurological and psychological manifestations, which are often described as neuropsychiatric SLE.
Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disorder that primarily affects the optic nerves and spinal cord. Patients develop symptoms of optic neuritis and transverse myelitis, including blindness, paralysis, sensory defects, and bladder dysfunction, with frequent relapse and increasing disability. Most patients have autoantibodies against aquaporin-4 (AQP4), the main water channel in the CNS that is predominantly expressed on astrocytes. Astrocytes perform many important functions in the CNS, including the regulation of neurotransmission, immune responses, blood flow, and energy metabolism, and the maintenance of the blood-brain barrier (BBB). Autoantibodies against AQP4 have been suggested to induce complement-mediated astrocyte damage, local inflammatory reactions, and BBB disruption. These initial reactions are predicted to lead to oligodendrocyte injury, demyelination, neuronal damage, and the subsequent clinical manifestations of NMO. Alternative underlying mechanisms for the disorder have also been proposed, including antibody-mediated internalization of AQP4s and glutamate transporters, and antibody-induced activation of effector cells, such as natural-killer cells, which cause cytotoxicity in astrocytes."
