Team Makes Major Advance in Showing How Some Immune Cells Cause MS

Therapeutic strategies against multiple sclerosis (MS) should focus on blocking two distinct ways rogue immune cells attack healthy neurons, according to a new study, “Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation,” in Cell Reports.

In MS, immune cells degrade the insulation that protects neurons and allows them to signal to one another; however, little is known about how immune cells penetrate the blood–brain barrier to get to neurons. Researchers led by Sarah Lutz, Ph.D., University of Illinois at Chicago (UIC) College of Medicine while she was a postdoctoral fellow at Columbia University, and Sunil Gandhi, Ph.D., University of California, Irvine, have uncovered two different ways immune cells gain access to neurons and wreak their havoc.

“Lymphocytes cross vascular boundaries via either disrupted tight junctions (TJs) or caveolae to induce tissue inflammation. In the CNS [central nervous system], Th17 lymphocytes cross the blood-brain  barrier (BBB) before Th1 cells; yet this differential crossing is poorly understood. We have used intravital two-photon imaging of the spinal cord in wild-type and caveolae-deficient mice with fluorescently labeled endothelial tight junctions to determine how tight junction remodeling and caveolae regulate CNS entry of lymphocytes during the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis,” write the investigators.

“We find that dynamic tight junction remodeling occurs early in EAE but does not depend upon caveolar transport. Moreover, Th1, but not Th17, lymphocytes are significantly reduced in the inflamed CNS of mice lacking caveolae. Therefore, tight junction remodeling facilitates Th17 migration across the BBB, whereas caveolae promote Th1 entry into the CNS. Moreover, therapies that target both tight junction degradation and caveolar transcytosis may limit lymphocyte infiltration during inflammation.”

“In autoimmune diseases like multiple sclerosis, immune cells that enter the brain and spinal cord cause disease,” said Dr. Lutz, now assistant professor of anatomy and cell biology in the UIC College of Medicine. “A better understanding of how these cells cross the blood–brain barrier will aid our efforts to develop specific therapies to keep them out.”

As they point out, to explore how Th1 and Th17 immune cells gain access to neurons in MS, the team worked with a mouse version of the disease. They genetically labeled blood vessel endothelial cell tight junctions with a fluorescent protein to examine if and how tight junctions are involved in autoimmune encephalomyelitis in vivo in their mice. The researchers observed that the tight junctions were significantly deteriorated in the presence of Th17 cells, and that this took place early in the onset of disease. Approximately three days later in the disease process, Dr. Lutz and colleagues found that Th1 cells were accessing and degrading myelin and neurons,  but these cells did not pass through tight junctions like the Th17 cells did. Instead, the circulating Th1 cells got to neurons by going through the blood vessel endothelial cells using specialized cell membrane structures called caveolae.

Caveolae are small pits or “caves” found on the surface of many cell types and help facilitate the passage of various molecules and cells into and/or through cells. In mice with autoimmune encephalomyelitis bred to lack caveolae, the researchers found almost no Th1 cells in the brain and spinal cord. They determined that caveolae on endothelial cells that make up blood vessels are required to help ferry Th1 cells through the blood–brain barrier.

“This is the first time we have ever seen, in live animals in real-time, the different means by which these two cell types gain access to myelin and nerves,” said Dr. Lutz. “Now that we know how these cells get to neurons, drugs or small molecules can be designed that interfere with or block each of these processes to help treat and possibly prevent MS.”