They are found in healthy individuals and are usually IgMs. and ganglioside (GM1) clustering, indicating that rHIgM12 functions through a mechanism of HIF-C2 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. Keywords: CNS repair, IgM, Membrane raft, Multiple sclerosis, Motility Introduction Restoring damaged central nervous system (CNS) networks is an integral goal of treating neurologic disease. There is evidence that neuronal and axonal injury ultimately result in permanent neurologic deficits [1]. Development of therapies to protect spared CNS axons and to prevent injured axons from degeneration is critical to limit and prevent permanent disability. Many studies indicate that reparative-signaling cascades are initiated at the cell membrane [2]. Cell membranes are composed of a mixture of cholesterol, sphingolipids, and proteins that are embedded and/or anchored in a bilayer of glycerolphospholipids. Different classes of lipids behave very differently within the membrane. Glycerolphospholipids have a tendency toward mobile fluidity, whereas sphingolipids and cholesterol are more tightly packed. In the physiological membrane, lipid assemblies are segregated into domains of different sizes and functions. The so-called lipid raft concept was proposed more than ten years ago; these structures are confirmed biophysical entities now commonly referred to as membrane rafts [3, 4]. Membrane rafts are more accurately defined as dynamic, nanoscale, sterol-sphingolipidCenriched, ordered assemblies of protein-lipid organizations. VAV1 They can be stimulated to coalesce into larger, more stable domains. Membrane rafts are involved in almost every aspect of cell life, including intracellular-molecule/vesicle trafficking, cell division, cell migration/differentiation to synaptic plasticity in the CNS, virus-infection/replication, and T- and B-cell activation and signaling. Therefore, membrane raft signaling molecules are attractive therapeutic targets. The understanding that membrane rafts may be involved in CNS repair arises from early observations that natural and semi-synthetic glycosphingolipids are neuro-protective. When added to primary cultured neurons, glycosphingolipids protect neurons against excitatory amino acid-induced toxicity [5, 6]. When administered to animals with spinal cord injury, trauma, or HIF-C2 brain ischemia, monosialotetrahexosylganglioside (GM1) improved functional recovery [7, 8]. Although gangliosides are essential to the maintenance of membrane raft integrity, [9], gangliosides such as GM1 and its derivatives are antigenic [10]. In autoimmune peripheral neuropathy, especially Guillain-Barre syndrome (GBS), autoantibodies against gangliosides are often present in patient sera [11]. Anti-ganglioside antibodies may be generated following bacterial infections in which the microbial glycans induce immunogenicity by mimicking endogenous gangliosides [10, 12]. Anti-ganglioside antibodies can exacerbate inflammatory destruction of glial and neuronal structures. Reagents that mimic the action of exogenous gangliosides or that maintain membrane raft stability without the side effects of immunogenicity are attractive candidates as reparative drugs. For example, targeting caveolin-1, a raft molecule, promotes neuronal arborization [13]. The study of ganglioside-deficient mice emphasizes the necessity and protective role of gangliosides in the neuronal membrane; in these mice, neurons HIF-C2 degenerate with age [9]. Natural human antibodies are commonly encoded by germline sequences and belong to the normal immunoglobulin repertoire [14, 15]. In contrast to conventional antibodies that are produced to exogenous antigen stimulation, natural antibodies are generated without obvious antigen activation. Many natural antibodies belong to IgM class, have relatively low affinity but high avidity due to their pentameric structure. Avrameas et al. has proposed that natural autoantibodies have natural physiological role and are important for homeostasis [16]. It has been shown that the repertoire of natural antibodies differ between individuals, but within one individual the levels seem to be stable with aging HIF-C2 [17]. Here we HIF-C2 report an important role for a human natural monoclonal IgM that regulates membrane raft motility, promotes polarized axon outgrowth, and improves functional recovery in a mouse model of multiple sclerosis (MS). We propose that these effects are driven by IgM-mediated membrane raft reorganization. Materials and Methods Antibodies.