Researchers of University of California (UC) San Diego School of Medicine in the US have found that patients suffering from rheumatoid arthritis and taking medications that inhibit interleukin-1beta (IL-1beta) are 300 times more likely to experience invasive Group A Streptococcal infections than those not on the drug.

IL-1beta is a molecule that stimulates the immune system.

Published in Science Immunology, the study also found a critical new role of IL-1beta as the body’s independent early warning system for bacterial infections.

UC San Diego pediatrics and pharmacy professor of Victor Nizet said: “The more we know about each step in the body’s immune response to bacterial infections, the better equipped we are to design more personalised, targeted therapies for autoimmune diseases, therapies that are effective, but minimise risk of infection.”

Stimulating an immune response, IL-1beta calls white blood cells to an infection location so that they can engulf and clear away invading pathogens.

“Inhibiting the body’s bacterial sensor can put a person at risk for invasive infection."

The body initially produces the molecule in a longer, inactive form, which needs to be cleaved to be activated.

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For several years, the scientific community believed that the body on its own could cleave and activate IL-1beta by employing a cellular structure known as the inflammasome.

However, upon using cell cultures and mouse models of infection, the researchers found that SpeB, an enzyme secreted by strep bacteria, also cleaves and activates IL-1beta.

UC San Diego School of Medicine post-doctoral researcher Christopher LaRock said: “This finding may explain why some of the more invasive, flesh-eating strep strains have a genetic mutation that blocks SpeB production, it helps them avoid tripping the alarm and setting off an immune response.”

The researchers hypothesised that for less invasive strains such as those that lead to strep throat, producing SpeB and activating IL-1beta might be advantageous given that the resulting immune response may eliminate competing bacteria and help strep establish a foothold in the body.

To investigate IL-1beta function, Nizet, LaRock and team analysed a US Food and Drug Administration database on adverse events in rheumatoid patients who took anakinra, which is a drug that dampens autoimmunity by inhibiting IL-1beta.

The researchers uncovered that patients taking anakinra were more than 300 times more likely to experience invasive, flesh-eating strep infections than patients not receiving the drug.

LaRock said: “A likely explanation for this increased risk is that with IL-1beta out of the picture, as is the case with patients taking anakinra, strep strains can progress to invasive infection even while producing SpeB, which goes unnoticed by the immune system.”

This finding highlights IL-1beta’s importance as an early warning system that is stiumalated not only by the host, but also directly by bacterial enzymes.

Nizet said: “Inhibiting the body’s bacterial sensor can put a person at risk for invasive infection, but just the fact that we now know that this patient population is at higher risk and why means we can take simple steps, such as close monitoring and prophylactic antibiotics, to prevent it from happening.”

Image: Immune molecule IL-1beta. Photo: courtesy of Regents of the University of California.