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Circulating AQP4-specific auto-antibodies alone can induce neuromyelitis optica spectrum disorder in the rat
- Source :
- Acta Neuropathologica
- Publication Year :
- 2018
-
Abstract
- It is well established that the binding of pathogenic aquaporin-4 (AQP4)-specific autoantibodies to astrocytes may initiate a cascade of events culminating in the destruction of these cells and in the formation of large tissue-destructive lesions typical for patients with neuromyelitis optica spectrum disorders (NMOSD). To date, not a single experimental study has shown that the systemic presence of the antibody alone can induce any damage to the central nervous system (CNS), while pathological studies on brains of NMOSD patients suggested that there might be ways for antibody entry and subsequent tissue damage. Here, we systemically applied a highly pathogenic, monoclonal antibody with high affinity to AQP4 over prolonged period of time to rats, and show that AQP4-abs can enter the CNS on their own, via circumventricular organs and meningeal or parenchymal blood vessels, that these antibodies initiate the formation of radically different lesions with AQP4 loss, depending on their mode and site of entry, and that lesion formation is much more efficient in the presence of encephalitogenic T-cell responses. We further demonstrate that the established tissue-destructive lesions trigger the formation of additional lesions by short and far reaching effects on blood vessels and their branches, and that AQP4-abs have profound effects on the AQP4 expression in peripheral tissues which counter-act possible titer loss by antibody absorption outside the CNS. Cumulatively, these data indicate that directly induced pathological changes caused by AQP4-abs inside and outside the CNS are efficient drivers of disease evolution in seropositive organisms. Electronic supplementary material The online version of this article (10.1007/s00401-018-1950-8) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Pathology
medicine.medical_specialty
medicine.drug_class
Central nervous system
T cells
Monoclonal antibody
Kidney
Autoantigens
Aquaporin-4-specific antibodies
Pathology and Forensic Medicine
03 medical and health sciences
Cellular and Molecular Neuroscience
Rats, Nude
0302 clinical medicine
medicine
Animals
Circumventricular organs
Autoantibodies
Aquaporin 4
Original Paper
Neuromyelitis optica
biology
business.industry
Neuromyelitis Optica
Autoantibody
medicine.disease
3. Good health
Rats
030104 developmental biology
medicine.anatomical_structure
Rats, Inbred Lew
biology.protein
Lesions
Neurology (clinical)
sense organs
Antibody
business
Aquaporin-4
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 14320533
- Volume :
- 137
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Acta neuropathologica
- Accession number :
- edsair.doi.dedup.....c245323dd847554aac3c59176e2b74b6