Autoimmunity to Axonal and Neuronal Antigens in Chronic Neurological Disease

Sandra Amor, Ph.D.

University of Amsterdam VU Medical Center

Funded in December, 2006: $100000 for 2 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Characterizing an Animal Model of Nerve Cell Damage in Autoimmune Multiple Sclerosis

Researchers will characterize a new animal model they are developing of the autoimmune disease multiple sclerosis (MS), to determine whether immune system attacks on a specific protein in nerve cell bodies and their communication cables (axons) are a primary feature of MS.

MS is a degenerative central nervous system (CNS) disease in which the brain and spinal cord nerves are attacked by the body’s own immune cells, producing inflammation, which in turn generates additional immune responses.  This process is called “autoimmunity.”  The disease course is usually “relapsing and remitting,” with patients experiencing episodic periods of symptoms followed by stabilization.  Symptoms can include muscle weakness, pain, loss or disordered sensory perception, and sometimes problems with memory and cognitive functions. Most of the research in past years has concentrated on immune attacks on the myelin sheath, a fatty covering that insulates axons and helps them to convey electrical signals from one cell to another in the brain and spinal cord.  Yet periods of symptom relapse are not correlated with immune attacks on myelin.  Instead, periods of relapse appear to correlate with damage to the nerve axons themselves. Research now indicates that early MS entails inflammatory damage to myelin, which is partly reversible, while later-stage damage to nerve axons is irreversible.

Damage to axons, the researchers have found, may result from immune antibody attacks against a specific protein called “neurofilament light” (NF-L) protein, which is found in nerve cell axons.  Antibodies against NF-L proteins have been found in the blood and cerebrospinal fluid of MS patients.  Moreover, the researchers have discovered “immunoglobulins,” or antibodies, in nerve cells.  The investigators have found that mice that are immunized with NF-L protein develop a clinical neurological disease involving muscle spasticity and weakness that is strikingly similar to that seen in MS patients.  This model, involving spasticity, is far more analogous to human MS than the current animal model, called EAE (experimental allergic encephalitis), which produces flaccid paralysis rather than spasticity.  Pivotally, preliminary research suggests that symptoms correlate with inflammatory axonal damage in the NF-L animal model.  They now will fully characterize this new animal model, describing the disease processes and determining where damage occurs.

Significance:  This potential new animal model of autoimmune MS may advance research on the disease processes involved in immune system damage to nerve axons, and provide a means to test new therapies designed to block this process.

ABSTRACT

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Autoimmunity to Axonal and Neuronal Antigens in Chronic Neurological Disease

It has gradually become clear that in initial stages of multiple sclerosis (MS), partly reversible inflammatory damage to the myelin sheath is a predominant feature, whereas the defining event at later stages of disease is irreversible damage to axons. Interestingly, accumulation of clinical deficits in MS patients correlate more strongly with axonal damage than with inflammatory demyelination, as has been clarified by multiple MRI studies. While autoimmune-mediated attacks of myelin-associated components have been under study for many years, much less is known of mechanisms mediating axonal damage. Yet defining these mechanisms is probably key to the development of effective long-term therapy.

Similar to the immune-mediated destruction of myelin, axonal damage could be due to autoimmune responses to neuronal and/or axonal antigens. Antibodies directed to axonal proteins are pathogenic in vivo, damage neurites in vitro, prevent neurite outgrowth, and cause reactive changes in the neuronal cell bodies. Indeed, antibodies to neurofilament light (NF-L) protein, an important component of the axonal cytoskeleton, have been found in the serum and CSF of MS patients. While these antibodies have so far only been considered as surrogate markers of axonal damage, our recent findings indicate that autoimmune responses to axons and neuronal proteins in fact play an important role in mediating axonal damage. Thus, they may be highly relevant also to the chronic neurological disability as observed in MS.

Following immunization with NF-L protein mice develop a clinical neurological disease characterized by spasticity and limb weakness similar to MS patients. The disease triggered by NF-L immunization is distinct from traditional EAE induced by MOG, which involves flaccid paralysis. Importantly, the clinical neurological disease observed in our new spastic model in mice correlates with inflammatory axonal damage, also in the grey matter and spinal cord. A striking feature in affected tissue is that immunoglobulins against NF-L are present inside neuronal cell bodies, which could be highly relevant for their ability to cause neuronal defects and degeneration.

Our studies thus indicate that, rather than act as merely a surrogate marker of disease as described in MS, autoimmune responses to NF-L (and probably other axonal antigens) directly contribute to axonal damage and clinical neurological disease. In the proposed research we will:  1) fully characterize the model with regard to the pathology and localization of the lesions; 2) determine the specific immune mechanisms that contribute to axonal damage by adoptive transfer studies of T cells and antibodies in vivo and 3) in neuronal cultures to study the impact on neuronal function.

By clarifying mechanisms of axonal damage, we aim to identify novel therapeutic targets with unique relevance to the stage of irreversible axonal damage that is the predominant cause of permanent disability in MS patients.

INVESTIGATOR BIOGRAPHIES

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Sandra Amor, Ph.D.

Dr. Sandra Amor is a Senior Scientist in the Dept. of Pathology at the Vrije University Medical Centre.  She graduated with honors from London University (UK) and received her Ph.D. in Pathology in 1988.  Her thesis on tropical virus infections of the central nervous system in the Rayne Institute at St. Thomas’s Hospital with Professor Hugh Webb led her into autoimmunity and multiple sclerosis. Dr. Amor gained continual support for her research and her group from the Multiple Sclerosis Society of Great Britain and Northern Ireland.  Her main research lines were the study of the mechanisms underlying demyelinating and neurodegenerative disorders to aid the development of therapeutic strategies, particularly for MS.

Dr. Amor’s research extends across virology, immunology, and neurosciences, and she has made major contributions to the field of myelin biology, virology, and neuroinflammation. She has also been instrumental in establishing novel research tools to develop novel therapeutic approaches, for which she received two internationally recognized awards. Her interests in mechanism of myelin damage has led to the use of her novel MOG-model of chronic neurological disease and more recently autoimmune-induced neuronal damage.

In 1999, Dr. Amor was the first foreign scientist to be awarded a prestigious Senior Fellowship award by the Dutch MS Society. After developing her group at the BPRC Institute in Rijswijk, where she aimed to carry out translational research, she moved to the Pathology Department at VU University Amsterdam to gain more experience and develop her research in MS using human tissues, as well as developing mouse models to reflect the neurodegenerative aspects of MS.

Dr. Amor is a well-recognized international scientist and has published more than 90 papers, as well as numerous book chapters and reviews.  She is a member of several scientific review boards and journal and grant review committees. Her commitment and dedication to research extends to understanding the needs of people with MS by organizing forums for the interactions between patients and scientists and by facilitating public awareness of MS.