Role of CSF flow and meningeal barriers in the development of inflammatory lesions at the CNS–PNS transition zone of cranial nerves in autoimmune demyelinating diseases

Patients with autoimmune inflammatory demyelinating diseases have been shown to present with trigeminal and cochlear nerve lesions restricted at the root transition zone, which contrasts with the relatively extensive distribution of lesions in optic neuritis. To better understand the mechanism underlying the different distribution pattern for cranial nerve lesions in these autoimmune neuroinflammatory diseases, we focused on the CNS-PNS transition zone (TZ) of the trigeminal and cochlear nerves in a MOG-driven active EAE model. These nerves were found to exhibit unique arrangements of anatomical barrier layers including the arachnoid and glia limitans, which affected cerebrospinal fluid (CSF) tracer distribution as well as CCR2⁺ immune cell infiltration. Our data demonstrated that CCR2⁺ immune cells accumulate at the TZ on both CNS side and PNS side of the trigeminal nerve and cochlear nerve, which mirror the locations of cranial nerve pathology observed clinically in patients with inflammatory demyelinating disease. On the other hand, the optic and olfactory nerves, which both lack a TZ, did not exhibit restrictions in immune cell localization. Overall, our results reconcile with the hypothesis that the segment of the cranial nerve that is exposed to CSF flow is more susceptible to CCR2⁺ immune cell infiltration.