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.

Brain 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.

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 tumors, 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 Findings

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.

Methodologies

Harnessing innovative methodologies involving:

1. Single-cell RNAseq
2. Super-Resolution microscopy
3. Imaging cytometry
4. 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

We will also 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.