Project Details
Projekt
Cellular and molecular mechanisms of blood-brain barrier disruption in anti-AQP4-antibody mediated neuromyelitis optica
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
from 2017 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 391468659
Neuromyelitis optica spectrum disorders (NMOSD) are chronic disabling CNS autoimmune diseases. Previously regarded a variant of multiple sclerosis characterized by severe and recurrent affection of the optic nerves and spinal cord, aquaporin-4 (AQP4) has recently been identified as the target antigen of the humoral immune response in around 70% of the patients with NMOSD. AQP4 is a water channel highly expressed on astrocytic end-feet and thus localized immediately adjacent to brain capillaries. Early NMO lesions in these patients are characterized by immune-mediated destruction of astrocytes and diminished AQP4 expression.By magnetic resonance imaging (MRI), CNS lesions of patients with NMOSD show a prolonged and intensified enhancement with gadolinium-DTPA, indicating a major disruption of the blood-brain barrier (BBB). In the present project, we strive to determine the time course and cellular and molecular mediators of BBB disruption in NMOSD related to anti-AQP4 autoimmunity. We will take advantage of a well-characterized experimental model based on focal intracerebral injection of recombinant human anti-AQP4 antibodies into rodents, reproducing key features of the human disease. Preliminary results obtained in this model indicate that granulocytes might play a major role in disrupting the BBB and facilitating NMOSD lesion induction. By applying pharmacologic and genetic manipulations accompanied by functional and molecular assessment of the BBB, we will gain insights into the mechanisms of BBB disruption and lesion formation in NMOSD and the contribution of granulocytes to these processes. Experimental results will be validated on biopsy and autopsy tissue from well characterized anti-AQP4-seropositive NMOSD patients.
DFG Programme
Research Grants
