Functional Characterization of a Hypomorphic IL-17A Variant Associated with Recurrent Pneumonias

IL-17 cytokines, particularly IL-17A and IL-17F, play a pivotal role in eliciting neutrophils for protection against fungal and bacterial infections. Hypomorphic IL-17F deficiency was reported in 2011 in a child with chronic mucocutaneous candidiasis (CMC), but IL-17A deficiency has not yet been reported. We consulted on a 14-year-old patient, with no history of CMC or autoimmunity, who was hospitalized for a third serious pneumonia. She carried a novel missense variant in IL-17A, resulting in a Y66C mutation. This variant is structurally homologous to a pathogenic S65L variant identified in IL-17F, which is known to impair cytokine function. Functional assays using IL-17–responsive reporter cells demonstrate that the Y66C mutant has significantly impaired signaling compared with wild-type IL-17A. Ongoing studies aim to delineate the molecular and structural consequences of this variant and its impact on host defenses. These findings underscore the importance of IL-17A in lung infections, and the lack of CMC in this patient suggests that IL-17F plays a more important role than IL-17A in the mucosa. We offer here the first report of IL-17A deficiency, expanding our understanding of IL-17–associated immunodeficiencies.