Background: It is unclear why AQP4-IgG primarily causes central nervous system lesions by activating complement, but generally spares peripheral AQP4-expressing organs. Objectives: To determine whether peripheral AQP4-expressing cells are protected from complement-mediated damage by expressing complement regulators. Methods: Human tissue and cultured human cells were immunostained for aquaporin-4 (AQP4), CD46, CD55 and CD59. We also determined the vulnerability to AQP4-IgG and complement-mediated damage of astrocytes cultured alone or co-cultured with endothelial cells. Results: In normal brain, astrocyte end-feet express AQP4, but are devoid of CD46, CD55 and CD59. Immunoreactivity for CD46, CD55 and CD59 is not increased in or around neuromyelitis optica lesions. In kidney AQP4 is co-expressed with CD46 and CD55, in stomach AQP4 is co-expressed with CD46 and in skeletal muscle AQP4 is co-expressed with CD46. Astrocytes cultured alone co-express AQP4 and CD59 but, in astrocyte-endothelial co-cultures, AQP4 is found in cell processes devoid of CD59. Astrocytes co-cultured with endothelial cells are more vulnerable to AQP4-IgG and complement-mediated lysis than astrocytes cultured alone. Conclusions: Complement regulators protect peripheral organs, but not the central nervous system, from AQP4-IgG and complement-mediated damage. Our findings may explain why neuromyelitis optica primarily damages the central nervous system, but spares peripheral organs.
Persistent microscopic active inflammatory lesions in the central nervous system of a patient with neuromyelitis optica treated with oral prednisolone for more than 40 years
