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Rheumatoid arthritis may be triggered by a missing molecular “anchor,” but new research suggests a fix

Stanford scientists have dug up a defect at the heart of rheumatoid arthritis: a faulty "anchor" that should be tethering a key molecule to the spot inside immune cells where it has to be in order to do its job.  It seems this defect can be reversed with a not yet commercially available small-molecule drug.

In a study published in Nature Immunology, Stanford rheumatologist Connie Weyand, MD, PhD, and her colleagues have dug up a defect thought to lead to rheumatoid arthritisIt seems this defect can be reversed with a not-yet-commercially available small-molecule drug.

If rheumatoid arthritis isn’t the most common autoimmune disorder, it’s close, affecting about 1 percent of the population. It involves the destruction of synovia — soft tissue that lubricates joints to prevent bones from scraping together, by cells of the body’s immune system. The inflammatory character of rheumatoid arthritis also causes systemic problems. For example, it doubles the risk of heart disease, Weyand told me when I interviewed her for a news release about the study.

Existing medications — a few of them costly enough to rank in the ten top-selling drugs globally by sales — relieve symptoms but don’t actually eradicate the disease by rectifying the behavior of the immune cells causing it. Why those cells go on the attack to begin with has been mysterious.

As I've written before, many immune cell have an odd job description, which calls for them to mostly sit around and loaf their lives away but, as soon as they recognize — or get a bit trigger-happy and think they recognize — a foreign intruder such as a viral or bacterial pathogen, to spring into action, multiply and spout war whoops, and attack the invader, then to simmer down once the pest's wiped out.

Weyand's team focused on a particular type of immune cell called a T cell that, in mistakenly overreacting to a normal protein in or on the cells of healthy synovial tissue, can spur rheumatoid arthritis.

Weyand and her associates have unearthed one of this painful disease’s critical secrets by experimentally peering inside a T cell. There, in cells affected by rheumatoid arthritis, an “anchor” ordinarily attached to a key "braking" molecule tasked with keeping immune cells from overreacting is missing. With no anchor, that braking molecule becomes unmoored (instead of firmly fastened to a subcellular compartment called a lysosome as it should be in order to do its job) and drifts in the sea of immune cells' cytoplasm, leaving the immune cells without a critical check on their misbehavior.

Having this braking molecule unanchored jams the cells into angry hyperdrive. They start feverishly fashioning various substances — proteins, nucleic acids, membranes and the like — for building new copies of themselves, generating a mob.

"This cellular army ... makes its way to synovial tissues, takes up residence there and instigates the inflammatory damage that’s the hallmark of rheumatoid arthritis," Weyand told me.

But, in addition to identifying the source of the problem in rheumatoid arthritis (the missing anchor), the researchers have also identified a potential solution. They've identified an exploratory compound that causes the braking protein to work right, even when it’s just floating around in the cell instead of anchored to a lysosome. In tests in mice, the compound alleviated rheumatoid-arthritis T cells’ propensity to infiltrate and damage human synovial tissue.

"Now we’ve shown we can reverse this behavior and make these cells behave as they should," Weyand told me. She expects to test the compound or a derivative among rheumatoid arthritis patients in a clinical trial, hopefully soon.

Photo by Karen Arnold

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