Interleukin-23 autoantibodies linked to severe opportunistic infections

1. In this cohort study, neutralizing autoantibodies against interleukin-23 (anti-IL-23) were associated with severe, persistent opportunistic infections in patients with invasive bacterial, mycobacterial, and fungal infections.

2. Among a cohort of patients with thymoma, anti-IL-23 was associated with higher infection status.

Evidence Rating Level: 2 (Good)

Study Rundown: Anti-cytokine antibodies are increasingly recognized in immunodeficiency and severe infectious conditions. IL-23 and interleukin-12 (IL-12), whose structures share a common protein subunit (p40), are two cytokines that both engage the IL-12Rβ1 receptor and are essential for the production of interferon-γ. However, unlike IL-12, IL-23 is essential in controlling inflammation in various skin, lungs, gastrointestinal tract, and brain tissues. It is secreted by dendritic cells and macrophages in response to mycobacteria and fungi. Interestingly, patients with thymoma, in whom anti-IL-12 is commonly found, have exhibited a low incidence of opportunistic infections. Moreover, anti-IL-23 has been described as a cross-reactive phenomenon in thymoma patients who exhibit anti-IL-12. This prompted a series of cohort studies that investigated the presence of anti-IL-23 in patients who had the presence of anti-IL-12 (discovery cohort), thymoma (validation cohort), and infections similar to those seen in thymoma (expansion cohort). Overall, neutralizing anti-IL-23 was associated with more severe, persistent opportunistic infections among patients with invasive, mycobacterial, and fungal infections. In addition, in the validation cohort of patients with thymoma, anti-IL-23 was associated with higher infection status. The generalizability of the study findings is limited, given that patients were recruited based on underlying conditions or infections.

Click to read the study in NEJM

In-Depth [retrospective cohort]: This series of retrospective cohort studies aimed to investigate the role of anti-IL-23 with respect to opportunistic infection. From 2007 to 2021, multiple groups of patients (discovery, validation, and expansion cohorts) were evaluated for the presence anti-IL-23 using blood samples from the National Institutes of Health. In the discovery cohort, 30 patients with anti-IL-12 and 30 healthy controls were tested for anti-IL-23. Among the patients with anti-IL-12, 23 patients (77%) had binding activity to anti-IL-23, and 15 patients (50%) had neutralizing activity against IL-23-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation, responsible for the maturation of various immune system cells. The degree of neutralization by anti-IL-23 was correlated to the severity of infection. In the validation cohort, 91 patients with thymoma, in whom anti-IL-12 is often detected, were evaluated for the presence of anti-IL-23. Of these patients, 24 (26%) had IL-23 binding activity, and 17 (19%) had neutralizing activity against IL-23-induced STAT3 phosphorylation. In total, 10 of the 17 patients with neutralizing anti-IL-23 had opportunistic infections. Moreover, 64 patients without neutralizing anti-IL-23 activity did not have infections. In the expansion cohort, 128 patients with other severe intracellular infections (without anti-IL-12 or thymoma) were evaluated for anti-IL-23 to determine its role in uncommon infection presentations. In addition, anti-IL-23 binding activity was detected in 6 of 32 patients (19%) with severe intracellular infections, 2 of 16 patients (12%) with unusual intracranial infections, and 3 of 30 patients (10%) with invasive mold infections. These cohort studies demonstrate that neutralizing anti-IL-23 is associated with severe opportunistic infections.

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