Neuron-binding human monoclonal antibodies support central nervous system neurite extension.
Two human IgMs (sHIgM12 and sHIgM42) were identified that supported in vitro central nervous system (CNS) neurite extension equal to the potent neurite stimulatory molecule laminin. Both IgMs bound to multiple cell types in unfixed CNS tissue and to the surface of neurons in culture. Both monoclonal antibodies (mAbs) overrode the inhibitory effect of CNS mouse myelin on granule cell neurite extension. Neither mAb bound to the surface of mature oligodendrocytes or strictly colocalized with myelin proteins. Sialidase treatment eliminated the neuronal surface binding of both mAbs, whereas blocking sphingolipid synthesis with Fumonisin B1 or removing GPI-linked proteins with PIPLC did not. When used as substrates for mixed neuron/glia aggregates, sHIgM12 and sHIgM42 supported robust neurite extension while astrocytes remained in the aggregates. In contrast, laminin supported astrocyte migration and spreading. Human mAbs that support neurite extension are novel factors that may be of use in encouraging axon repair following injury while minimizing glial cell infiltration. Both human mAbs were isolated from individuals with monoclonal gammopathy. Each individual has carried high mAb titers in circulation for years without detriment. sHIgM12 and sHIgM42 are therefore unlikely to be systemically pathogenic.
Warrington
Arthur E
AE
Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. warrington.arthur@mayo.edu
Bieber
Allan J
AJ
Van Keulen
Virginia
V
Ciric
Bogoljub
B
Pease
Larry R
LR
Rodriguez
Moses
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000254:growth & development* / Q000276:immunology*; D005911:Gliosis / Q000276:immunology / Q000517:prevention & control; D020439:Growth Cones / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D007797:Laminin / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009185:Myelin Proteins / Q000378:metabolism; D009414:Nerve Growth Factors / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D009416:Nerve Regeneration / Q000187:drug effects / Q000276:immunology*; D009439:Neuraminidase / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000276:immunology* / Q000648:ultrastructure; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013107:Sphingolipids / Q000037:antagonists & inhibitors / Q000378:metabolism
D000911:Antibodies, Monoclonal; D007075:Immunoglobulin M; D007797:Laminin; D009185:Myelin Proteins; D009414:Nerve Growth Factors; D013107:Sphingolipids; D009439:Neuraminidase