Biotrack

Synaptic and neuronal cell surface autoimmunity

REF: PD 23
Principle investigator:
Josep Dalmau
Contact details:

Josep.dalmau(ELIMINAR)@uphs.upenn.edu, jdalmau(ELIMINAR)@clinic.ub.es

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Research framework

My research is at the intersection of cancer, autoimmunity, and the nervous system with the principal theme of the comprehensive characterization, from clinical to cellular and molecular levels, of autoimmune disorders targeting brain proteins. This includes the description of novel syndromes and associated immune-mechanisms, isolation of the target antigens, and development of diagnostic tests and treatment strategies. This research led to the isolation of 18 autoantigens and the development of five diagnostic tests currently used worldwide.

Over the last 6 years we have discovered 6 immune-mediated disorders of memory, behavior, cognition, and psychosis affecting children and adults with or without cancer. Each disorder occurs in association with immune responses to synaptic proteins, including among others, the NMDA receptor, the AMPA receptor, and the GABA(B) receptor.

Moreover, work done during the last year has lead to the discovery that a substantial number of patients with seronegative myasthenia gravis have in fact antibodies against presynaptic molecular targets of the neuromuscular synapse. Once the antigens are identified our studies focus on elucidating the cellular and molecular mechanisms underlying the associated immune disorder and syndrome. For example, comprehensive studies done in collaboration with colleagues at the Department of Neuroscience at the University of Pennsylvania (where Dr. Dalmau is adjunct professor in the Department of Neurology) have demonstrated that using cultures of dissociated rodent hippocampal neurons the antibodies from patients with anti-NMDAR or AMPAR encephalitis cause a dramatic decrease of the density of cell surface receptors, synaptic localization, and specific NMDAR- or AMPAR-mediated currents.

In contrast, patients’ antibodies did not affect dendritic branching, spine density, or neuronal survival. We identified that the mechanisms by which antibodies cause a decrease of the corresponding receptor is by capping and cross-linking resulting in receptor internalization. Infusion of antibodies into rodent hippocampus results in a titer-dependent decrease of the corresponding receptors, and animal models of these disorders are currently being pursued. A variety of techniques are used, including tissue processing, small animal surgery, confocal microscopy, molecular biology, and electrophysiology.

Our findings have impacted multiple clinical disciplines and neuroscience, providing a link between immunologic processes and neuronal events involved in memory, cognition, seizures, and neuronal degeneration. Dr. Dalmau’s laboratory located at IDIBAPS-Hospital Clinic includes a team of researchers trained in Barcelona and the University of Pennsylvania with multiple collaborative projects between both centers.

Keywords

Autoimmunity, encephalitis, synaptic receptors, cell surface antigens

Main Challenges

At the clinical level, the main challenges include the identification of the etiology of a number of neurological disorders for which there is strong evidence of autoimmune mechanisms, but the target autoantigens remain unknown. Disorders in this category include several forms of acute epilepsy syndromes in children, several forms of encephalopathies with autistic features, opsoclonus-myoclonus (a disorder of control of eye movements in children and adults), several forms of rapidly progressive dementia, and disorders that associate with rapid presentation of amnesia.

At a more basic level, the challenges are to determine the immune mediated mechanisms that cause neuronal dysfunction. After identifying the target cell surface or synaptic antigens, the challenge is to determine in vitro and in vivo how antibodies cause structural or functional changes in the target antigens (e.g., blocking function, internalizing the antigen, or acting as activators of the antigen or receptors) and the mechanism of neuronal recovery. In parallel experiments we determine the behavioral effects of patients’ antibodies in animal models, and relate the findings with the human disease.

Applicants should be familiar with basic molecular biology techniques, working with rodents, general immunology techniques, immunohistochemistry, tissue sectioning, primary cultures of neurons, and confocal microscopy. Several projects include techniques with single particle tracking imaging and high resolution confocal microscopy.

Team strategic objective in IDIBAPS

The overall team strategic objective is to clinically characterize new immune mediated neurological disorders and the mechanisms involved. This will lead to the development of unambiguous diagnostic tests (e.g., cell-based assays). In addition we will determine the cellular and synaptic mechanisms of the indicated disorders, develop animal models, and better treatment strategies

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