Neuronal antigens recognized by cerebrospinal fluid IgM in multiple sclerosis

Axonal injury is the major cause of disability in patients with multiple sclerosis (MS), but the mechanisms leading to axonal damage are poorly understood. Oligoclonal IgM against lipids predicts an aggressive disease course in MS; however, the antigen that elicits the immune response has not yet been identified. We screened the CSF of 12 patients with MS, 7 patients with neuromyelitis optica (NMO), and 5 controls with non-inflammatory neurological disease (NIND) for the presence of IgM-type antibodies (IgM-Ab) against neuronal surface antigens, and analyzed the relationship between IgM-Ab level and the extent of brain atrophy. The CSF of MS patients displayed significantly higher levels of IgM-Ab compared to NIND or NMO patients. Furthermore, we document for the first time that these IgM-Ab recognize neuronal surface antigens, and that the levels of neuronal-bound IgM-Ab were independent of the IgM concentration and correlate with brain atrophy. Our findings suggest a role for the CSF IgM-Ab in the development of MS pathophysiology.