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.