While improvements in the treatment of multiple sclerosis (MS) have focused on reducing the frequency of flare-ups, preventing MS-related disability has remained a struggle. Multiple sclerosis and other immune-inflammatory diseases can flare up when white blood cells go rogue—exerting their inflammatory effects where they shouldn’t. Scientists have recently identified methods to corral these rogue cells, lessening their ability to inflict damage, by blinding them to the signposts that lead them astray. The latest research now aims to refine this method, to lessen potentially dangerous side effects.
Unwanted, uncontrolled inflammation can wreak havoc in the body. It’s at the root of multiple sclerosis and countless other disorders, including Crohn’s disease and ulcerative colitis. Research has shown that the damage can be partly blamed on an invasion of white blood cells called lymphocytes. As a result, several strategies have been devised to interfere with their migration to inflammation sites.
In one such strategy, lymphocytes are made “blind” to the signals that lead them out of hiding and send them off in search of inflammation. When they aren’t off finding enemies to fight, lymphocytes can often be found hanging out in lymph nodes, where they are relatively harmless. But they can be lured out of nodes by a signaling molecule called sphingosine 1‐phosphate (S1P). Nodes have little S1P, while the blood vessels they sit near have much more S1P, and the white blood cells follow the trail of S1P to escape their hiding spots.
Once in the bloodstream, lymphocytes are free to wander to places where they might do damage—like an inflamed intestine, in the case of Crohn’s disease, or a vulnerable neuron, in the case of multiple sclerosis. But their escape from lymph nodes can be blocked by modulating the receptors that sense S1P, known as the sphingosine 1‐phosphate receptor (S1PR) family.
Therapies that interfere with S1PR aim to trap lymphocytes in lymph nodes, reducing their numbers in the bloodstream and tissues. And at least one such therapy has been successful in treating certain forms of multiple sclerosis.
Interfering with the S1PR family can have its drawbacks, though. For instance, since one S1PR member is involved in cardiac function, patients have to be monitored for several hours after their first dose, to ensure their heart continues to work properly. As a result, researchers are looking for therapies that more specifically target only the S1PR members that let lymphocytes out of nodes. The aim is to improve the reduction in inflammation while also reducing the chances of potentially dangerous side effects.
Members of the S1PR family belong to a class of membrane receptors known as G-protein-coupled receptors (GPCR). These proteins are like signal transducers—taking messages from the environment in the form of sugars, fats, protein and even light and translating them into changes inside cells.
Humans have almost 1,000 different GPCRs, and each recognizes and responds to a particular signal. They have so many different functions that it’s thought between a third and a half of all marketed drugs act by binding to GPCRs.
GPCRs have a very distinctive shape and structure: a protein chain that wraps back and forth seven times from the outside of the cell to the inside and back. The loops facing out of the cell form a landing site for signaling molecules. Inside the cell, GPCRs interact with the partners that give the receptors their name: G proteins.
G proteins are like on-off switches that can be flipped depending on the state of its GPCR. G proteins have three parts: α, β and γ. When the three are bound together with their GPCR, α binds a compound called guanosine diphosphate (GDP), which keeps it in an “off” state.
When the right signal outside the cell—a sugar, for example—binds to the GPCR, the receptor changes shape, kicking α and its GDP out of the group. The change also causes GDP to be replaced with guanosine triphosphate (GTP), which creates an “on” state. It’s this active α subunit that travels through the cell turning on specific cellular activities.
Back at the cell membrane, the now lonely β and γ portions of the G protein also relay messages into the cell. For instance, they can activate (or inhibit) enzymes or open up (or close) ion channels. The resulting metabolic changes allow the cell to respond to an ever-evolving environment.