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

Introduction

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.

Immune Privilege and Barriers

Barriers protecting the brain against infection or harmful toxic agents were also thought to block the 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.

Implications of Immune Cell Trafficking

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.

Research Focus

We investigated Blood-CSF barrier dysfunction in Lupus and discovered a brain lymphoid structure with enhanced immune cell trafficking.

Methodology

1. 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.
2. Harnessing innovative methodologies involving:
   • Single-cell RNAseq
   • Super-Resolution microscopy
   • Imaging cytometry
   • Genetic/pharmacological interventions

We aim to decipher the fundamental question of how leukocytes enter the brain.

Goals

We will:

• Classify specialized immune and epithelial barrier cell types.
• Identify trafficking molecular pathways.
• Develop approaches to regulate the process.
• Assess this barrier's involvement in the pathobiology of human Neuro-Lupus disease.

Conclusion

Understanding immune trafficking mechanisms may be the key to a specialized brain portal, leading to therapeutics that can modulate brain-immune interactions.