CNS Hidden Door (101088881)

  https://cordis.europa.eu/project/id/101088881

  Horizon Europe (2021-2027)

  Uncovering molecular and cellular mechanisms of immune cell trafficking across the blood-CSF barrier in autoimmunity

  ERC CONSOLIDATOR GRANTS (ERC-2022-COG)

  super resolution microscopy  ·  multiple sclerosis  ·  immunology

  2023-05-01 Start Date (YY-MM-DD)

  2028-04-30 End Date (YY-MM-DD)

  € 2,412,448

  Description

Immune cells continuously traverse our body, crossing vascular and epithelial barriers; from lymphatic organs into the blood, and from the blood into various tissues for surveillance or to fight infection. However, the brain has long been considered an immune-privileged organ. Barriers protecting the brain against infection or harmful toxic agents were also thought to block entry of immune cells, leaving immune functions to brain-resident microglia cells. This dogma was recently overturned when it became clear that immune cells cross, mainly for surveillance, especially at the Blood-CSF barrier. Furthermore, while harmful immune cell trafficking is a hallmark of brain autoimmunity, e.g. Multiple Sclerosis and Neuro-Lupus, enhanced trafficking might help to fight brain tumours, and even to resolve neurodegenerative conditions, e.g. Alzheimer’s Disease. Yet the study of immune cell trafficking across the Blood-CSF barrier is severely hampered by a shortage of suitable methodologies. We investigated Blood-CSF barrier dysfunction in Lupus and discovered a brain lymphoid structure with enhanced immune cell trafficking. Dominant transepithelial leukocyte migration (through, rather than in between, cells) will enable us to catch the trafficking events ‘red-handed’ and to identify molecular and cellular trafficking mechanisms. Harnessing innovative methodologies involving single-cell RNAseq, Super-Resolution microscopy, Imaging cytometry, and genetic/pharmacological interventions, we aim to decipher the fundamental question of how leukocytes enter the brain. We will classify specialized immune and epithelial barrier cell types, identify trafficking molecular pathways, and develop approaches to regulate the process. We will also assess this barrier involvement in the pathobiology of human Neuro-Lupus disease. Understanding immune trafficking mechanisms may be the key to a specialized brain portal, leading to therapeutics that can modulate brain-immune interactions.

  Complicit Organisations

1 Israeli organisation participates in CNS Hidden Door.