Abstract
INTRODUCTION: Natural autoantibodies are part of the normal human immunoglobulin repertoire. These antibodies react to self-antigens, are usually polyreactive with relatively low affinity, and typically are of the IgM isotype. Natural IgMs in mice that stimulated remyelination in central nervous system (CNS) demyelinating disease all shared the characteristics of binding to the surface of live oligodendrocytes and myelinated tracts in living slices of CNS tissue. METHODS: A screen for human IgMs with similar character resulted in two human natural antibodies, which when injected peripherally into animal models of demyelination induced remyelination. A recombinant human IgM (rHIgM22) that also promoted remyelination in vivo was constructed. RESULTS: Very small doses of this IgM are required for the promotion of remyelination (EC50 is 460 ng per 20-g mouse). It is clear that after peripheral delivery, rHIgM22 enters the CNS and accumulates in CNS lesions. rHIgM22 was tracked in living mice using ferritin-labeled antihuman mu chain antibodies visualized by magnetic resonance imaging and traditional immunocytochemistry. Although the exact antigen recognized by rHIgM22 is not known, all mouse IgMs that promote remyelination bind to myelin membrane lipids, suggesting the antigen for rHIgM22 is similar. CONCLUSIONS: We propose that the IgMs bind to CNS cells and reorganize the membrane, initiating a signal that results in oligodendrocyte proliferation and/or protection with an end result of increased myelin. Recombinant natural human antibodies are potentially important therapeutic molecules that may modulate a wide spectrum of human disease.