A human IgM signals axon outgrowth: coupling lipid raft to microtubules

Abstract

Mouse and human IgMs support neurite extension from primary cerebellar granule neurons. In this study using primary hippocampal and cortical neurons we demonstrate that a recombinant human IgM, rHIgM12, promotes axon outgrowth by coupling membrane domains (lipid rafts) to microtubules. rHIgM12 binds to the surface of neuron and induces clustering of cholesterol and ganglioside, GM1. After cell binding and membrane fractionation, rHIgM12 segregated into two pools, one associated with lipid raft fractions and the other with the detergent-insoluble cytoskeleton-containing pellet. Membrane-bound rHIgM12 co-localized with microtubules and co-immuno precipitated with β3-tubulin. rHIgM12-membrane interaction also enhanced the tyrosination of α-tubulin indicating a stabilization of new neurites. When presented as a substrate rHIgM12 induced axon outgrowth from primary neurons. We now demonstrate that a recombinant human mAb can induce signals in neurons that regulate membrane lipids and microtubule dynamics required for axon extension. We propose that the pentameric structure of the IgM is critical to crosslink membrane lipids and proteins resulting in signaling cascades.

Human-derived natural antibodies: biomarkers and potential therapeutics

“…Serum-derived human IgM 22 (sHIgM22) that binds to mature oligodendrocytes promotes remyelination in the Theiler’s Murine Encephalomyelitis Virus (TMEV) model of multiple sclerosis (MS) [4]; sHIgM12 binding to neurons supports neurite extension in vitro [57], and protects neurons when administrated in vivo either in the TMEV model of MS [4] or in models of amyotrophic lateral schlerosis induced by expressing the genetic mutants of human superoxide dismutase 1 (SOD1) (Rodriguez laboratory unpublished observation). Recombinant forms of sHIgM22 and sHIgM12 (rHIgM22 and rHIgM12) manufactured in GMP quality have confirmed efficacy in promoting remyelination in animal models of MS [58] (rHIgM22); supporting axonal outgrowth in neuronal cultures [59] (rHIgM12); and improving neurological functions in mouse models of MS [58] (rHIgM22 or rHIgM12) and amyotrophic lateral schlerosis (rHIgM12). A Phase I clinical trial of rHIgM22 in patients with MS is ongoing [60].…”

“…A Phase I clinical trial of rHIgM22 in patients with MS is ongoing [60]. NAbs binding to neural cells apparently function through a lipid-raft mechanism [59]. Indeed, accumulating evidence has demonstrated that the IgM type of NAbs recognize lipid components of neural membranes.…”

“…New evidence indicates that HIgM12 binds to antigens of both glycoprotein and glycolipid that are decorated with sialic acids. The glycolipid components are actually a group of glycosphingolipids, called complex gangliosides (Figure 3) [59]. Therefore, it is likely that the sialic acids participate to form the epitope(s) for HIgM12 binding.…”

Antibody Binding Specificity for Kappa (Vκ) Light Chain-containing Human (IgM) Antibodies: Polysialic Acid (PSA) Attached to NCAM as a Case Study

“…Antibody HIgM12 was identified from patients with Waldenstrom's macroglobulinemia, stimulates neurite outgrowth in vitro [12][13][14] and targets polysialic acid (PSA) attached to the neural cell adhesion molecule (PSA-NCAM) 15,16 . The three major NCAM isoforms termed NCAM180, NCAM140, and NCAM120, are alternative splice variants of a primary transcript that vary only in their cytoplasmic domain.…”

Mechanisms of autoimmunity in the central nervous system: Disturbance of natural autoimmunity, infectious agents, cell contribution and antibody signatures

“…17 Recent studies also show that aggregation of monoclonal antibodies can induce the clustering of cholesterol and gangliosides, regulating the membrane raft dynamics and enhancing the cytoskeleton-membrane interaction inducing axon outgrowth. 18 All previous findings illustrate the possibility of the existence of a physiological autoantibody network in the CNS, which is likely involved in developmental processes and neurorepair.…”