Autoimmunity to neuronal proteins in neurological disorders

Autoreactive T-cell responses directed to myelin proteins in the central nervous system (CNS) are widely believed to be fundamental in the pathology of multiple sclerosis (MS). This view has dominated the research field in MS for many years and led to the reliance on experimental models of neurological disease following immunisation with myelin antigens. Such experimental diseases have developed as the central paradigm to investigate underlying mechanisms operating in MS as well as the preclinical development of therapeutic strategies.This long-standing concept has recently shifted and evidence is rapidly accumulating indicting a significance role of axonal damage and neurodegeneration in disease. Indeed axonal damage is now considered to be the major cause of irreversible neurological disability in MS patients. One correlate of axonal damage in MS is the presence of antibodies against neurofilament light protein, a major component of the axonal cytoskeleton. Contrary to extensive literature on pathogenic myelin autoimmunity the possible pathogenic role of autoimmunity to axonal antigens in MS has so far been ignored. Our recent experimental data indicate that autoimmunity to axonal antigens, as described in MS, is pathogenic rather than acting merely as a surrogate marker for axonal degeneration.As validation of the concept that autoimmunity directed to neuronal antigens plays a role in disease we define four criteria. First that autoreactivity to neuronal antigens are consistently present in neurological disease in humans and experimental neurological disease in animals. Secondly that transfer of such neuronal reactive T cells and/or antibodies are pathogenic either in vivo or in vitro model systems. Thirdly, that immunization with neuronal antigens induces pathogenic autoimmune responses and leads to neurological disease in experimental animals and finally that inhibition of such responses ameliorates neurological disease.Using these criteria we review the evidence for autoimmunity to neuronal antigens in several neurodegenerative disorders such as paraneoplastic disorders, and discuss how similar mechanisms may also operate in MS. Using the experimental models we describe our recent data to indicate that while clinical disease in MS models is due to autoimmune attack on myelin, neurons and axons can be also target for pathogenic autoimmunity. Understanding the factors leading to neuronal injury and neurodegenerative disorders is key to the development of effective therapies to prevent progression of disease and irreversible damage.