Puentes F, van der Star BJ, Boomkamp SD, Kipp M, Boon L, Bosca I, Raffel J, Gnanapavan S, van der Valk P, Stephenson J, Barnett SC, Baker D, Amor S. Neurofilament Light as an Immune Target for Pathogenic Antibodies. Immunology. 2017. doi: 10.1111/imm.12797. [Epub ahead of print]
Antibodies to neuronal antigens are associated with many neurological diseases including paraneoplastic neurological disorders, epilepsy, amyotrophic lateral sclerosis and multiple sclerosis. Immunisation with neuronal antigens such as neurofilament light NF-L, a neuronal intermediate filament in axons, has been shown to induce neurological disease and spasticity in mice. Also, while antibodies to NF-L are widely used as surrogate biomarkers of axonal injury in amyotrophic lateral sclerosis and multiple sclerosis, it remains to be elucidated if antibodies to NF-L contribute to neurodegeneration and neurological disease. To address this, we examined the pathogenic role of antibodies directed to NF-L in vitro using spinal cord co-cultures and in vivo in experimental autoimmune encephalomyelitis (EAE) and optic neuritis animal models of multiple sclerosis. Here we show that peripheral injections of antibodies to NF-L augmented clinical signs of neurological disease in acute EAE, increased retinal ganglion cell loss in experimental optic neuritis and induced neurological signs following intracerebral injection into control mice. The pathogenicity of antibodies to NF-L was also observed in spinal cord co-cultures where axonal loss was induced. Taken together, our results reveal that as well as acting as reliable biomarkers of neuronal damage, antibodies to NF-L exacerbate neurological disease, suggesting that antibodies to NF-L generated during disease may also be pathogenic and play a role in the progression of neurodegeneration.
When nerves are damaged they breakdown and release their contents and these products are measured as a marker of disease activity. However, it is clear that neurofilament directed antibodies are generated to clear up these breakdown products.
We have shown that if you cause the antibodies to be produced in mice that they can cause neurological problems.
This study shows that these antibodies, however can be potentially damaging and so clearly shows there is autoimmunity occurring in MS. In this study neurofilament specific antibodies were injected into animals and it made EAE worst, once T cells had opened the blood brain barrier to allow the antibody to enter the brain. This was not surprising as this has been shown with a number of antibodies. More surprisingly when injected directly into the brain these antibodies caused signs of disease. It was surprising because neurofilament is inside a nerve and so would not be easily assessable. The signs occurring were very different to the signs occurring when antibodies targeting basal ganglia from a person with a tic disease was injected into the brain.
These neurofilment directed antibodies can kill nerves and so could contribute to damage in MS.
CoI. This is work bt TeamG