November 13, 2018

While much basic autoimmune research has focused on ways to foil the bad behavior of immune cells, Dr. Salmon and her team of investigators at the Hospital for Special Surgery/Weill Cornell Medicine have taken a very different tack. They have been studying whether enhancing the ability of the lining of the blood vessels to act as a barrier and limit escape of molecules that promote inflammation can block inflammatory damage in organs and tissues.

Director of the Lupus and APS Center at Hospital for Special Surgery and senior author of the new study, Dr. Salmon explains that in autoimmune diseases like lupus and RA, “the immune system makes antibodies against the body’s own tissues, and the trigger of injury to organs is often the immune complex—clusters of molecules made up of a self-protein and an antibody that recognizes it. Immune complexes circulate within blood vessels, but they can escape and accumulate in organs. When they do, they activate inflammatory cells that cause tissue damage.”

The cells that line the blood vessels, called endothelial cells, normally stick together tightly and form a strong barrier. Inflammation causes blood vessels to become leaky.  As a result, immune complexes can leave from the blood vessels and deposit in different organs, such as skin, kidneys, and joints, where they cause rash, nephritis and arthritis, respectively.

Leaky blood vessels and inflammation form a feed-forward loop and amplify each other, Dr. Salmon explains. The more inflammation, the leakier the blood vessels become, leading to more inflammation—and so it goes.

Dr. Salmon and her colleagues decided to test the following idea: If you could prevent the immune complexes from escaping from blood vessels, you might have a new way to protect vulnerable tissues and organs from damage.

The researchers decided to target a receptor called S1P₁ (sphingosine-1 phosphate receptor 1) on endothelial cells, known to maintain the cohesiveness of the cells that line blood vessels, in an attempt to limit leakage of immune complex molecules into the surrounding tissues.

In the first step of the study, they deleted the S1P₁ from endothelial cells in mice, and they got the results they expected: without S1P₁ to maintain barrier function, inflammation in the lung and skin caused much greater damage than in mice with intact S1P₁, along with greater leakage from the blood vessels. Then they performed studies using a compound that activated S1P₁ on endothelial cells in mice and found the opposite: Connections between blood vessel cells tightened up, and damage was decreased.

The results of the new study raise the possibility of developing a new treatment that could be added to immunosuppressive therapy — a one-two punch using a defensive strategy to protect vulnerable organs and tissues and an offensive strike against inflammation caused by immune dysfunction.

Dr. Salmon describes this early S1P₁ research as a “proof-of-concept” study, one designed to test an idea. Based on their promising results, the team plans to study S1P₁ further, showing how the pathway influences inflammation and organ damage in mouse models of lupus and RA. If successful, they will study S1P₁ and its family of receptors in humans with the hope of enhancing the S1P₁’s activity to protect patients with autoimmune diseases from tissue injury due to deposits of immune complexes.