SUMMARY
Vanda A. Lennon, M.D., Ph.D., is a leader in neuroimmunology research, with interests that encompass autoimmunity and tumor immunology.
Dr. Lennon works to improve care for patients with paraneoplastic disorders. These conditions exhibit a remarkable overlap of autoimmunity and cancer, where the cancer itself usually does not show up when the patient first seeks medical attention.
Patients with these conditions have undiagnosed thymic epithelial tumors or carcinomas of the lung, ovary or breast. Their first manifestations of cancer are unusually autoimmune neurological symptoms and signs. These include disabling symptoms that affect the brain, nerves and muscles, but reflect tumor immune responses that limit the growth and spread of cancer. In some patients, an attack on autonomic neurons causes profound gastrointestinal dysmotility and dysregulation of the cardiovascular system. These varying symptoms result from immune responses that the body initiates against tumor proteins with counterparts in healthy neurons and muscle.
The central theme of Dr. Lennon's research program is the antigenicity of proteins that are targets of paraneoplastic autoimmunity. She is particularly focused on synaptic plasma membrane cation channels and neurotransmitter receptors, which readily interact with circulating antibodies. In many cases, molecules tumors use to grow — and possibly metastasize — are identical to the signaling molecules that nerve and muscle cells use to communicate with each other. Specifically, Dr. Lennon studies:
- Voltage-gated calcium and potassium channels.
- Nicotinic acetylcholine receptors.
- Related molecules expressed in lung and ovary carcinomas, and epithelial thymomas.
These types of tumor proteins initiate the helper T lymphocyte-dependent production of autoantibodies that impair synaptic transmission in the central and peripheral nervous systems.
Dr. Lennon also studies IgG autoantibodies of neuronal or muscle specificity, which serve as surrogate markers of T lymphocyte activation. Healthy people do not have these autoantibodies, but more than 50% of all patients with small-cell lung cancer or thymic epithelial neoplasia do have them. By establishing permanent lines of tumor cells from patients who have paraneoplastic autoimmunity, Dr. Lennon's group has begun to define the molecular basis for the immunogenicity of these tumors and the mechanisms responsible for bypassing self-tolerance.
The multidisciplinary nature of Dr. Lennon's basic and clinical research interests has fostered strong long-term collaborative links with investigators in other areas at Mayo Clinic:
Focus areas
- Nicotinic ACh receptors (AChR) in neoplasms. Dr. Lennon and her colleagues recently discovered that the alpha-3 subunit of the neuronal AChR is expressed exclusively in small-cell lung cancer cell lines derived from patients with neurological autoimmunity. By immunizing animals with the extracellular domain of that protein, her team reproduced the cardinal clinical and electrophysiological signs of autoimmune autonomic neuropathy. The team thereby demonstrated the role of this tumor antigen to neoplasms, a particularly harmful human neurological disorder. In addition to implications for cancer therapy, this research opens the door for new treatment strategies for autoimmune gastrointestinal and cardiovascular disorders.
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Myasthenia gravis. Myasthenia gravis 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 disease. Dr. Lennon's research team hypothesizes that production of these autoantibodies reflects immune responses initiated by muscle autoantigens. The team is developing neoplastic thymic epithelial cell lines to test this hypothesis.
Dr. Lennon's team has established a small-cell lung cancer cell line from a patient with myasthenia gravis. This cell line aberrantly expresses muscle-type AChR. In common with other small-cell lung cancer tumors, Dr. Lennon's cell line has morphologic and cytogenetic markers characteristic of this type of cancer. 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 by density gradient centrifugation along with authentic muscle AChR, which are pentameric. 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 small-cell lung cancer lines are negative.
Sequencing of full-length cDNA clones obtained from the tumor of a patient with myasthenia gravis 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 autoantibodies in MG. The nonself epitope at its C-terminus is potentially stimulatory for helper T-lymphocytes.
These data support Dr. Lennon's hypothesis that paraneoplastic myasthenia gravis 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 small-cell lung cancer, including autoimmune autonomic neuropathies, seizures, dementia, movement disorders, and sensory and motor neuronopathies.
- Immune responses of neuronal antibodies. A corollary of Dr. Lennon's hypothesis is that the immune responses impairing neurological function also may diminish tumor growth and metastasis. To address these neurologic and oncologic hypotheses, her team uses affinity purified channel proteins, recombinant subunit fragments and synthetic peptide antigens to produce neuronal antibodies of defined specificities. The team is testing the effects of these antibodies on:
- Viability and regulated ion-flux responses in cultured human neuronal cell lines.
- Transmission at neuromuscular and autonomic synapses in rodents.
- Growth of cancer cells in vitro and in immunodeficient mice.
- DNA vaccines. Dr. Lennon also uses DNA vaccines to activate cytotoxic effector T cells.
Significance to patient care
Dr. Lennon's research shows that immune responses can harm neurological function and account for a variety of autoimmune disorders. But at the same time, these responses may be preventing the growth or spread of the cancer. Dr. Lennon's studies are aimed at finding and treating tumors earlier.
Professional highlights
- Dorothy A. Adair Professorship in Gastrointestinal Research, Mayo Clinic, 2012.