番茄社区

People mounting an immune attack on interleukin-23 (IL-23) were prone to severe opportunistic infections rarely seen in the clinic, a study found.

After investigations showed that anti-IL-23 antibodies could lead to persistent infections, researchers led by Steven Holland, MD, of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, then found that six of 32 patients with mysterious severe infections were positive for IL-23 autoantibodies.

These autoantibodies were also identified in two of 16 people with "unusual" intracranial infections, and another three of 30 with invasive fungal infections. As well, seven out of 754 patients with COVID-19 also carried the autoantibodies, suggesting that anti-IL-23 activity could contribute to almost any type of infection, the group reported in the .

Overall, the authors concluded, "the identification of uncommon but pathogenic autoantibodies against cytokines, such as anti-interleukin-23, represents the first step toward the development of actionable strategies for improving patient outcomes."

The study is the latest to find that cytokines can be autoimmune targets, with serious consequences. Earlier work had determined that patients with thymomas -- tumors originating in thymic cells -- commonly developed autoantibodies against IL-12. But only a minority of such patients experience serious infections suggestive of immune deficiency.

Mihai Netea, MD, PhD, and Frank van de Veerdonk, MD, PhD, both of Radboud University Medical Center in Nijmegen, the Netherlands, commented that the present study "provides support that anti-interleukin-23 autoantibodies contribute to adult-onset immunodeficiency, but questions remain."

In an , they suggested further work assessing "the capacity of anti-interleukin-23 autoantibodies to modulate the function of other lymphocyte populations" as well as "the design of new diagnostic tests and therapeutic approaches based on anti-interleukin-23 autoantibodies in patients with rare and severe infections of unknown cause."

Interest in IL-23 as an autoimmune target began more than 10 years ago, when a in a Cambodian woman with persistent Burkholderia gladioli infection. Further investigation showed that she also had IL-23 autoantibodies. That in turn led Holland and colleagues to see how widespread IL-23 autoimmunity might be.

That both IL-12 and IL-23 could be targeted simultaneously was not itself a major surprise because the two species share a protein sequence known as p40, and autoantibodies against both had been found in some thymoma patients.

What distinguishes the new study is that it now appears that the anti-IL-23 activity is what primarily drives immune deficiency.

Following their discoveries with the Cambodian woman, Holland and colleagues first examined a cohort of 30 thymoma patients known to carry IL-12 autoantibodies and who had histories of severe opportunistic infections. Half of this group were found to have IL-23-neutralizing antibodies as well. Moreover, the group wrote, "[t]he potency of such neutralization was correlated with the severity of these infections [and] the neutralizing activity of anti-interleukin-12 alone was not associated with infection."

The researchers then sought to validate these findings in a different group of 91 thymoma patients. Of these, 74 did not have anti-IL-23 antibodies, and only 10 of those experienced invasive infections. For the other 17 that did have IL-23 autoantibodies, invasive infections occurred in 10. As well, four patients lacking IL-23 neutralizing antibodies but with autoantibodies targeting immune components downstream from IL-23 (e.g., IL-17A) also had serious infections.

Holland's group then assembled a third cohort of 128 patients with severe infections and unknown autoantibody status. This was the cohort in which significant numbers turned out to be positive for anti-IL-23 antibodies. This group also included two people negative for IL-12 autoantibodies but positive for anti-IL-23, both of whom had intracranial infections (one involving Cladophialophora bantiana, the other Mycobacterium avium complex).

The researchers also revisited the case of the initial Cambodian patient. They treated the woman with the B-cell depleting agent rituximab (Rituxan). A first course led to remission, but when the drug was stopped the B. gladioli infection returned, as did anti-IL-23 titers.

"At the time of this report, the patient was receiving 6 monthly doses of rituximab and had not had a relapse because the B cells remained depleted and the neutralizing activity of anti-interleukin-23 remained low," Holland and colleagues wrote.

Rheumatologists may find these results especially interesting because IL-12, IL-17A, and IL-23 also happen to be targets for drugs frequently prescribed for autoimmune inflammatory conditions including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. For example, ustekinumab (Stelara) blocks both IL-12 and IL-23; guselkumab (Tremfya) and risankizumab (Skyrizi) are selective for IL-23; and IL-17A is the target for secukinumab (Cosentyx) and ixekizumab (Taltz).

All these agents come with warnings about increased risks for infections, highlighting the role that various interleukins play in protecting against invasive pathogens. And, Holland and colleagues noted, the new findings "may help to explain the divergent effects of interleukin-23 and interleukin-17 blockade in inflammatory colitis" -- a reference to studies that showed ustekinumab was effective whereas secukinumab was not.

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