Multiple Sclerosis

How are structural components of the BBB affected in diseases of the brain and spinal cord, where barrier function is impaired?

Blood vessels in the EAE spinal cord

Blood vessels in the EAE spinal cord

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). Pathological studies of CNS tissue have shown that inflammation of endothelial cells (ECs), associated with focal breakdown of the blood-brain barrier (BBB) and pathogenic neo-angiogenesis, is prevalent in demyelinating plaques for both human MS and the animal model experimental autoimmune encephalitis (EAE). Neo-angiogenesis and BBB damage contribute to leakage of serum components and infiltration of immune cells into the CNS, which promote neuroinflammation, axonal demyelination, neuronal dysfunction and disease progression.

Our research seeks to understand how the BBB breaks down in multiple sclerosis. In particular, the roles of BBB structural components such as tight junctions (TJs) and transcytosis vesicles (caveolae), that regulate the transport of small or large molecules, respectively, to cross the BBB, are poorly defined for the pathogenesis of brain disorders associated with leaky BBB.

Using a novel transgenic strain where tight junctions are labeled with GFP (Tie2p::eGFP::Claudin-5), we imaged TJs in brain capillaries using two-photon microscopy in vivo, combined with quantitative analysis of fluorescent tracer leakage across the BBB. We observed that immune cells were able to exploit loose junctions to cross the BBB and enter the brain. One type of immune cell, Th17, slips through the loosened cell junctions, while another immune cell, Th1, is transported across the endothelial cell via caveolae and released into the CNS. In mice lacking these specialized vesicles, few Th1 cells are found in the central nervous system of mice with MS, reducing their symptoms.

Ongoing research in the lab is employing single cell RNA sequencing, fluorescent in situ hybridization (FISH) and immunofluorescence staining to determine at a molecular level both the sites and the driving mechanisms of neo-angiogenesis in EAE. Most therapies currently used to treat MS are disease-modifying agents to reduce both inflammation and infiltration of immune cells into the CNS. Abnormal angiogenesis may contribute to sustained CNS leaky blood vessel pathology during the chronic neuroinflammatory state in MS. Understanding the signaling pathways and the molecular mechanisms that induce CNS vascular pathologies in MS/EAE, may allow us to develop novel treatments, focused on the vascular component, that aim to reduce pathogenic neo-angiogenesis and repair BBB function.

Related publications

Current projects

Investigating the mechanisms of blood brain barrier breakdown and repair in Experimental Autoimmune Encephalomyelitis.

The CNS is sequestered from systemic circulation by a series of barriers that tightly regulate the CNS microenvironment to allow proper functioning of the neural tissue, and provide protection from toxins, pathogens and other potentially harmful agents. One of these barriers, the BBB is formed by specialized endothelial cells (ECs) that have impermeable tight junctions (TJs) and reduced transcellular transcytosis and pinocytosis to restrict the entry of leukocytes, antibodies and other serum proteins into the CNS parenchyma.

In the healthy BBB, TJ proteins are degraded and recycled at a low rate via Rab5/Rab7-mediated endolysosomal trafficking and degradation. BBB function is impaired in neuroinflammation which allows paracellular or transcellular migration of leukocytes via either disrupted TJs or increased transcytosis, respectively. However, the mechanisms by which TJ disruption occurs at the BBB in the context of MS/EAE remain poorly understood. Changes in the normal rate of endolysomal trafficking and degradation of TJ proteins may underlie BBB breakdown in EAE/MS. Wnt/B-catenin signaling has been shown to be required for both the development and maintenance of the BBB.

Our laboratory has previously shown that spinal cord ECs upregulate the Wnt/B-catenin signaling pathway during EAE, and inhibition of this pathway exacerbates the clinical course of the disease. However, the role of the Wnt/B-catenin signaling pathway in barrier repair during EAE remains unresolved. We are investigating whether inhibition of endolysomal degradation and upregulation of Wnt/B-catenin signaling in the neurovasculature prevents BBB breakdown, reduces immune cell infiltration and ameliorates disease outcomes during EAE.


Findings from Lutz et al. (2017) were featured by the CUIMC Newsroom