Cellular mechanisms of central nervous system repair by natural autoreactive monoclonal antibodies

Abstract

Natural autoreactive monoclonal IgM antibodies have demonstrated potential as therapeutic agents for central nervous system (CNS) disease. These antibodies bind surface antigens on specific CNS cells, activating intracellular repair-promoting signals. IgM antibodies that bind to surface antigens on oligodendrocytes enhanced remyelination in animal models of multiple sclerosis. IgM antibodies that bind to neurons stimulate neurite outgrowth and prevent neuron apoptosis. The neuron-binding IgM antibodies may have utility in CNS axon- or neuron-damaging diseases, such as amyotrophic lateral sclerosis, stroke, spinal cord injury, or secondary progressive multiple sclerosis. Recombinant remyelination-promoting IgM antibodies have been generated for formal toxicology studies and, after Food and Drug Administration approval, a phase 1 clinical trial. Natural autoreactive monoclonal antibodies directed against CNS cells represent novel therapeutic molecules to induce repair of the nervous system.

Figure 1. rHIgM22-binding interactions are dependent upon a CST substrate

Images (100x) of O4 (sulfatide; A,G), rHIgM22 (B,H) or MOG (C, I) reactivity shown using live cerebellar sections (200µm) subsequently fixed, FITC immunostained and DAPI counterstained (D–F, J–L). Wild-type showed reactivity to all in contrast cst ^(−/−) showed MOG but lacked O4 and rHIgM22 reactivity.

Figure 2. Neuron-Binding Antibodies Demonstrate Temperature-Dependent, Surface Membrane Rearrangement

sHIgM42 reactivity shown using live cerebellar granule neurons subsequently fixed, FITC immunostained and DAPI counterstained. sHIgM42 demonstrated binding interactions at 0°C (A) and membrane rearrangements at 15°C (B). Note formation of small punctuate domains along neurites at 15°C but not at 0°C.

Figure 3. Mechanism of NA Monoclonal Antibody-mediated CNS Repair

Pentameric interactions of antibody binding to plasma membrane glycolipids (A) and proteins (B) on live cells induce membrane rearrangements. Signaling molecule (C) activation of pathways including calcium flux, MAP kinase activation and blocking caspase-3 activation that converge on transcriptional regulation of genes promoting CNS protection and repair.