Autoimmunity, a main component in nervous system disease, is a misguided immune response to the body's own organs. Neurological autoimmunity can target virtually any structure within the central or peripheral nervous system and often in a highly specific way, targeting a very specific cell population (e.g., Purkinje cells of the cerebellum). Sometimes, when the cell type that is targeted occurs in many different CNS structures (e.g., the astrocyte in neuromyelitis optica), the syndromes that result may be diverse, such as those associated with optic neuritis, myelitis and attacks of brain edema in neuromyelitis optica. Understanding these disorders ultimately requires an analysis of how the target antigen molecules affect immune cellular interactions both to generate the autoimmune reaction and to produce the immune–mediated injury of the nervous system. Cytokines, autoantibodies, and other immune factors culminate the disease process.
Autonomic neuropathy is caused by damage to the peripheral autonomic nerves supplying the internal organs, blood vessels, and the skin.
Symptoms of autonomic neuropathy may include:
- Orthostatic hypotension
- Nausea or vomiting
- Diarrhea or constipation
- Abdominal bloating
- Urinary incontinence
- Erectile dysfunction
Autonomic neuropathies can occur in isolation or with the Guillain–Barre syndrome, paraneoplastic neuropathies, and diabetes, among others.
Neurally Mediated Syncope is a transient loss of consciousness due to a sudden fall in blood pressure that temporarily impairs blood supply to the brain. The most frequent cause of hypotension and syncope (fainting) in apparently normal individuals is neurally mediated syncope (NMS), which may also be referred as vasovagal, vasodepressor, or reflex syncope. NMS is an acute hemodynamic reaction produced by a sudden change in the normal pattern of autonomic nervous system activities that maintain blood pressure in the standing posture. Sympathetic activity suddenly decreases while parasympathetic acutely increases.
Clinical trials are currently being conducted to test the effectiveness of pharmacological agents in the treatment of this disorder.
Vanda Lennon, M.D., Ph.D.'s research program explores the antigenicity of proteins that are targets of paraneoplastic autoimmunity. Synaptic plasma membrane cation channels and neurotransmitter receptors are of particular interest because they readily interact with circulating antibodies. Molecules that are used by tumors for autocrine growth, and possibly metastasis, are in many cases identical to the signaling molecules used by nerve and muscle cells in communicating with each other. The specific antigens we are studying are voltage–gated calcium and potassium channels; nicotinic acetylcholine receptors; and related molecules expressed in carcinomas of lung and ovary, and epithelial thymomas. Tumor proteins of this type initiate the helper T lymphocyte–dependent production of autoantibodies that impair synaptic transmission in the central and peripheral nervous systems. The following projects are in progress:
Nicotinic ACh receptors (AChR) expressed in neoplasms
Dr. Lennon’s group recently discovered that the alpha–3 subunit of the neuronal AChR responsible for synaptic transmission through autonomic ganglia is expressed exclusively in small cell lung cancer (SCLC) cell lines derived from patients with neurological autoimmunity. By immunizing animals with the extracellular domain of that protein, we reproduced the cardinal clinical and electrophysiological signs of autoimmune autonomic neuropathy, thus demonstrating the pertinence of this tumor antigen to a particularly devastating human neurological disorder. In addition to implications for cancer therapy, this animal model allows new treatment strategies to be developed for autoimmune gastrointestinal and cardiovascular disorders.
Myasthenia gravis (MG) is a postsynaptic disorder of neuromuscular transmission that occurs in approximately 35% of patients who have an epithelial thymoma. AChR–binding autoantibodies are pathogenic in this disorder. Their production is thought to reflect immune responses initiated by muscle autoantigens expressed in immunogenic form in thymomas. Researchers are endeavoring to develop neoplastic thymic epithelial cell lines to test this hypothesis. However, the less common association of MG with neoplasms other than thymoma appears not to be fortuitous.
A SCLC line established from a patient with MG aberrantly expresses muscle–type AChR. In common with other SCLC tumors, this team’s novel SCLC line has morphologic and cytogenetic markers characteristic of SCLC. It also secretes neuropeptides and has high–voltage–activated calcium channels of neuronal type. Agonist stimulation of this tumor's aberrantly expressed AChR induces an influx of Na+ that is inhibitable by curare and by alpha–bungarotoxin (alpha–BTx), which are both antagonists of muscle AChR. The alpha–BTx receptors solubilized from the tumor cosediment with authentic muscle AChR (i.e., are pentameric) by density gradient centrifugation and they are selectively precipitated by a monoclonal IgG that binds to muscle–type alpha–BTx receptors, but not by a monoclonal IgG that binds to neuronal–type alpha–BTx–receptors. Northern blot reveals mRNA encoding muscle–type AChR subunits. Other SCLC lines are negative. Sequencing of full–length cDNA clones obtained from the MG patient's tumor revealed an mRNA that was derived from the use of a cryptic RNA splice acceptor site. The protein encoded by this mRNA would be truncated, ending with four missense amino acids. This would yield a mutant autoantigen corresponding to the extracellular domain of the alpha–1 subunit of muscle AChR, which is a major target of pathogenic autoantibodes in MG. The non–self epitope at its C–terminus is potentially stimulatory for helper T–lymphocytes.
This data supports our hypothesis that paraneoplastic MG can be initiated by a tumor that expresses muscle–type AChR in a highly immunogenic form. Immune responses driven by distinct AChR subtypes expressed in cancer cells may account for the spectrum of autoimmune disorders affecting cholinergic systems that can complicate SCLC, including autoimmune autonomic neuropathies, seizures, dementia, movement disorders, and sensory and motor neuronopathies.
A corollary of the hypothesis is that the immune responses responsible for impairing neurological function may also impair tumor growth and metastasis. To address these neurologic and oncologic hypotheses, researchers are using affinity purified channel proteins, recombinant subunit fragments and synthetic peptide antigens to produce neuronal antibodies of defined specificities. These antibodies are to be tested for effects on: a) viability and regulated ion–flux responses in cultured human neuronal cell lines; b) transmission at neuromuscular and autonomic synapses in rodents; and c) growth of cancer cells in vitro and in immunodeficient mice. We are using DNA vaccines to activate cytotoxic effector T cells.
Drs. Lennon and Sean Pittock, M.D. studied rapidly progressive dementia, which has a variety of causes, including Creutzfeldt–Jakob disease (CJD) and neuronal voltage–gated potassium channel (VGKC) autoantibody–associated encephalopathy. They sought to describe patients thought initially to have CJD, but found subsequently to have immunotherapy–responsive VGKC autoimmunity. By analyzing clinical features, magnetic resonance imaging abnormalities, electroencephalographic patterns, cerebrospinal fluid analyses, and responses to immunomodulatory therapy, they found all these 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. They concluded that 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. This study was published in the Archives of Neurology. 2008 Oct;65(10):1341–6.
Dr. Pittock studied the neuromyelitis optica IgG autoantibody (NMO–IgG), a validated biomarker for NMO and an emerging spectrum of inflammatory central nervous system–demyelinating disorders. Its antigen is the astrocytic water channel aquaporin–4; NMO–IgG has not been described in a cancer context. This observational study reported: (1) neurologic and oncologic correlates for patients incidentally identified as NMO–IgG seropositive in a blinded evaluation for paraneoplastic autoantibodies; and (2) the frequency of cancer in NMO–IgG–seropositive patients. He found that aquaporin–4–specific IgG in some cases of NMO may reflect a paraneoplastic immune response. The clinical utility of this autoantibody as a cancer marker warrants prospective investigation. This study was published in the Archives of Neurology. 2008 May;65(5):629–32.
Dr. Pittock and his colleague Dr. Lucchinetti reviewed the literature on the pathological hallmarks of the multiple sclerosis (MS) lesion, which consists of focal demyelination, inflammation, scar formation, and variable axonal destruction. Despite years of classical histopathological study and more recent intensive use of magnetic resonance technology, the MS lesion is incompletely understood. How it is initiated; changes over time; correlates with clinical symptoms and other markers of disease activity; and is impacted by therapeutic intervention all are largely unknown. As the site of disease pathology, the MS lesion remains the target of attack for therapy. Therefore, it is essential we better understand MS lesion evolution and its clinical, as well as paraclinical, correlates. Researchers found that the introduction of new technologies has contributed to a better appreciation regarding the complexity of the MS lesion. The discovery of heterogeneity in demyelinating lesions has suggested that different mechanisms may be involved in MS pathogenesis. This observation may be important for future studies on the etiology and therapy of the disease. However, the potential to apply these findings to the clinic will rely on the development of technologies that allow the stratification of MS subtypes without being dependent on brain biopsies. This study is in The Neurologist. 2007 Mar;13(2):45–56.