We have discovered a role for natural autoantibodies in central nervous system repair, remyelination and axon protection. These natural human antibodies are of the immunoglobulin M (IgM) isotype, and they bind to the surface of neural cells. The epitope of the antibody includes sialic acid because treatment with sialidase disrupts the binding. A fully human recombinant form of one of these IgMs, rHIgM12, has the same properties as the serum-derived IgM. rHIgM12 enhanced polarized axonal outgrowth from primary neurons when presented as a substrate in vitro and improved motor functions in chronically Theiler's virus-infected SJL mice, a model of MS. rHIgM12 bound to neuronal surfaces and induced cholesterol and ganglioside (GM1) clustering, indicating that rHIgM12 functions through a mechanism of axonal membrane stabilization. Our work demonstrates that a natural human neuron-binding IgM can regulate membrane domain dynamics. This antibody has the potential to improve neurologic disease.