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Mark William DiFrancesco, PhD

Assistant Professor

Children’s Hospital Medical Center



Vascular pathophysiology in CNS SLE: The blood-CSF barrier

Systemic lupus erythematosus (SLE) can damage blood vessels throughout the body, including the brain. Special barriers in the brain control how substances transfer between blood vessels and brain tissues. These barriers act as gatekeepers and filters, allowing passage of beneficial nutrients, while controlling entry of molecules that might harm the brain. If these barriers break down, becoming “leaky”, harmful substances can enter the brain, contributing to inflammation that has been shown to cause cognitive deficits.  It is thought that such leakiness may promote the symptoms experienced by patients with neuropsychiatric lupus, which affects 40 percent of all people with SLE. Previously, Dr. DiFrancesco and other scientists have shown that SLE patients have more “leaky” blood vessel walls (the blood-brain barrier) compared to people without lupus.  However, there is another barrier to consider between blood and cerebrospinal fluid (CSF), the fluid that covers brain surfaces, that may also break down in SLE allowing harmful substances to reach brain tissue.

Dr. DiFrancesco will use the Lupus Innovation Award to test whether disruption of the blood-CSF barrier specifically contributes to the progression of neuropsychiatric lupus. The researchers will employ specialized magnetic resonance imaging (MRI) measures of blood flow and other tissue properties to establish evidence of excess leakage between blood vessels and CSF.

What this study means for people with lupus

This research will increase the understanding of how lupus impacts the brain and help identify new treatment targets for neuropsychiatric lupus.

Systemic Lupus Erythematosus (SLE) leads to vascular complications in multiple organ systems, including the brain. Most consequential is damage at the microvascular level, where tissue homeostasis is maintained. Compromise of cerebral microvasculature is widely considered a plausible route by which immune actors in SLE infiltrate the brain parenchyma causing damage. The blood-brain-barrier (BBB), is the most studied regulator of blood-parenchyma exchange comprised of the brain capillary endothelial cell layer with tight junctions. Breakdown of the BBB is a widely accepted mechanism for CNS involvement in SLE. We and others have demonstrated regionally increased permeability of the BBB in SLE compared to healthy controls. Nevertheless, there is little direct evidence of BBB compromise in SLE. A recent murine study of SLE found CSF immune infiltrates in CSF even with the BBB intact, suggesting a currently neglected alternative that infiltration of brain tissue may arise at interfaces between the blood and CSF. Blood-CSF barriers (BCSFB) are comprised of the choroid plexus (CP) within ventricles and at the meningeal barrier surrounding the brain. In the CP, fenestrated capillaries exchange with a stromal layer at the basal side of an epithelium that acts to regulate exchange with ventricular CSF. Once an infiltrate enters the ventricular CSF, it can exchange with parenchyma through the ependymal layer at the ventricular surface. Compromise of the BCSFB at the CP has been hypothesized as a pathogenic mechanism for multiple sclerosis (MS). Recent imaging studies provide evidence for a BCSFB route to MS pathology by observation of periventricular gradients of tissue abnormalities. Investigations of the BCSFB and the CP in humans with SLE using advanced imaging methods are lacking. We propose to investigate alteration of the BCSFB in SLE, specifically at the CP, and demonstrate periventricular gradients in microstructural and microvascular disruption of normal-appearing white matter (NAWM) that is related to cognitive function. We plan to include a cohort of MS patients as positive controls and to explore salient differences between these autoimmune conditions. Our specific aims are:
1. Measure regional blood perfusion properties at the choroid plexus using ASL with multiple label/delay times in groups of pediatric-onset SLE and MS patients, and in healthy controls similar in age range and sex distribution.
2. Measure regional microstructural and microvascular properties of NAWM as a function of distance from the ventricular wall using advanced quantitative imaging.
3. Determine the relationships of disruption of choroid plexus perfusion and NAWM gradient of microstructural and microvascular properties with cognitive scores in SLE and MS patients.
If evidence for a CSF route of brain infiltration is found, it could realign ways to phenotype NPSLE and develop targeted therapies.

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