Patients with progressive multiple sclerosis have elevated antibodies to neurofilament subunit

Objective: The cause of axonal loss, an important contributor to disability in MS, is poorly understood. This study investigated whether progression in MS is associated with CSF antibodies to the 68-kd light neurofilament subunit (NF-L), an axonal cytoskeletal protein, and compared this with antibodies against tubulin and the heavy neurofilament subunit (NF-H). Methods: IgG to NF-L, tubulin, and NF-H was measured by immunoassay in matched CSF and serum samples from patients with relapsing-remitting MS (RRMS; n = 39), primary progressive MS (PPMS; n = 10), and secondary progressive MS (SPMS; n = 18); patients with other inflammatory (n = 21) and noninflammatory (n = 40) neurologic diseases; and healthy controls (n = 12). Immunocytochemistry was performed to assess antibody binding to human brain sections, and isoelectric focusing with immunoblotting was performed to assess oligoclonal anti-NF-L production. Results: Intrathecal production of anti-NF-L antibodies was significantly elevated in PPMS and SPMS. In contrast, there were no significant differences in CSF levels of antibodies to tubulin or NF-H between the groups. Anti-NF-L, antitubulin, and anti-NF-H levels correlated with the duration of disease before lumbar puncture and Expanded Disability Status Scale levels. Immunocytochemistry demonstrated binding of CSF or serum antibodies to axonal or neuronal components in six of seven RRMS patients, seven of seven PPMS patients, and eight of 10 SPMS patients tested. Isoelectric focusing demonstrated independent CSF oligoclonal bands reactive with NF-L in six of 13 Specimens tested. Conclusions: Anti-NF-L antibodies seem to be raised in progressive MS and may serve as a marker for axonal loss and disease progression. They may contribute to axonal loss and the accumulation of disability.