Passive immunization with anti-ganglioside antibodies directly inhibits axon regeneration in an animal model.
Recent studies have proposed that neurite outgrowth is influenced by specific nerve cell surface gangliosides, which are sialic acid-containing glycosphingolipids highly enriched in the mammalian nervous system. For example, the endogenous lectin, myelin-associated glycoprotein (MAG), is reported to bind to axonal gangliosides (GD1a and GT1b) to inhibit neurite outgrowth. Clustering of gangliosides in the absence of inhibitors such as MAG is also shown to inhibit neurite outgrowth in culture. In some human autoimmune PNS and CNS disorders, autoantibodies against GD1a or other gangliosides are implicated in pathophysiology. Because of neurobiological and clinical relevance, we asked whether anti-GD1a antibodies inhibit regeneration of injured axons in vivo. Passive transfer of anti-GD1a antibody severely inhibited axon regeneration after PNS injury in mice. In mutant mice with altered ganglioside or complement expression, inhibition by antibodies was mediated directly through GD1a and was independent of complement-induced cytolytic injury. The impaired regenerative responses and ultrastructure of injured peripheral axons mimicked the abortive regeneration typically seen after CNS injury. These data demonstrate that inhibition of axon regeneration is induced directly by engaging cell surface gangliosides in vivo and imply that circulating autoimmune antibodies can inhibit axon regeneration through neuronal gangliosides independent of endogenous regeneration inhibitors such as MAG.
Lehmann
Helmar C
HC
Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
Lopez
Pablo H H
PH
Zhang
Gang
G
Ngyuen
Thien
T
Zhang
Jiangyang
J
Kieseier
Bernd C
BC
Mori
Susumu
S
Sheikh
Kazim A
KA
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000276:immunology; D001369:Axons / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D005732:Gangliosides / Q000276:immunology*; D007116:Immunization, Passive / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000187:drug effects / Q000276:immunology*; D020426:Sciatic Neuropathy / Q000276:immunology* / Q000517:prevention & control*; D016896:Treatment Outcome
D000906:Antibodies; D005732:Gangliosides; C021298:ganglioside, GD1a