Abstract
Neurofascin was recently reported as a target for axopathic autoantibodies in patients with multiple sclerosis (MS), a response that will exacerbate axonal pathology and disease severity in an animal model of multiple sclerosis. As transplacental transfer of maternal autoantibodies can permanently damage the developing nervous system we investigated whether intrauterine exposure to this neurofascin-specific response had any detrimental effect on white matter tract development. To address this question we intravenously injected pregnant rats with either a pathogenic anti-neurofascin monoclonal antibody or an appropriate isotype control on days 15 and 18 of pregnancy, respectively, to mimic the physiological concentration of maternal antibodies in the circulation of the fetus towards the end of pregnancy. Pups were monitored daily with respect to litter size, birth weight, growth and motor development. Histological studies were performed on E20 embryos and pups sacrificed on days 2, 10, 21, 32 and 45 days post partum. Results: Immunohistochemistry for light and confocal microscopy confirmed passively transferred anti-neurofascin antibody had crossed the placenta to bind to distinct structures in the developing cortex and cerebellum. However, this did not result in any significant differences in litter size, birth weight, or general physical development between litters from control mothers or those treated with the neurofascin-specific antibody. Histological analysis also failed to identify any neuronal or white matter tract abnormalities induced by the neurofascin-specific antibody. Conclusions: We show that transplacental transfer of circulating anti-neurofascin antibodies can occur and targets specific structures in the CNS of the developing fetus. However, this did not result in any pre- or post-natal abnormalities in the offspring of the treated mothers. These results assure that even if anti-neurofascin responses are detected in pregnant women with multiple sclerosis these are unlikely to have a negative effect on their children.
Highlights
Neurofascin (Nfasc) is a cell adhesion molecule belonging to the immunoglobulin superfamily (IgSF)
In order to see whether intravenously applied antibody reached the central nervous system (CNS) of the developing fetus, immunohistochemistry for mouse IgG was performed on pups sacrificed at E20 of pregnancy
During the second trimester the antibodies can access the fetal brain resulting in a 50–70 fold increase in IgG in fetal compared with maternal brains [28]
Summary
Neurofascin (Nfasc) is a cell adhesion molecule belonging to the immunoglobulin superfamily (IgSF). Neuronal neurofascin (Nfasc186) is localized at the nodes of Ranvier and axonal initial segments (AIS) of myelinated fibers where it interacts with voltage gated sodium channels and other proteins such as ankyrin G and ß IV-Spectrin [7,8]. Nfasc155 interacts with the axonal Caspr-Contactin complex at these sites [10] to form electron dense assemblies characteristic of this paranodal junction complex. These complexes play a critical role in maintaining saltatory conduction by physically separating NaV1.6 channels at the node from Kv1.1 and 1.2 potassium channels located within the juxtaparanodal domain of the axolemma [11,12]
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