Autosomal-recessive IL-1RacP deficiency – a novel Inborn Error of Immunity supporting a non-redundant role of IL-1 signalling in Invasive Pneumococcal Disease

Background: Despite widespread pneumococcal conjugate vaccination, invasive pneumococcal disease (IPD) still constitutes a relevant disease burden in children. Progression from frequent asymptomatic carriage to disease typically reflects host susceptibility due to malnutrition, co-infections or genetic factors. Monogenic defects in genes involved in Toll-like/Interleukin-1 receptor (TIR) signaling (e.g., MYD88, IRAK4 ) predispose to IPD. However, the specific role of IL-1 signaling in humans is unknown. The interleukin-1 receptor accessory protein (IL-1RacP) is an indispensable component of the heterotrimeric IL-1β/IL-1R1/IL-1RacP complex that recruits MyD88 to activate NF-κB/MAPK and initiate robust acute phase response. Human IL-1RacP deficiency has not been reported before. Case presentation: A term male infant of consanguineous parents presented at six weeks with fever, tachypnoea, and increased work of breathing. His condition deteriorated rapidly with respiratory exhaustion and he required mechanical ventilation and repeated pleural drainages for several weeks. CT thorax showed necrotizing pneumonia with seropneumothorax. Streptococcus pneumoniae was detected in tracheal secretions. Peripheral blood immune phenotyping revealed absent cytokine production upon IL-1β stimulation, yet preserved production upon TLR ligands, indicating a selective IL-1 pathway defect. Genetic sequencing identified a homozygous IL1RACP canonical donor splice-site variant, absent from population and clinical databases. SpliceAI predicted complete donor loss with exon-skipping and/or intron-retention causing premature termination. Segregation analysis confirmed autosomal-recessive inheritance. Interval MRI showed near-complete resolution of pleural thickening with regressing bilateral nodular consolidations, no effusion, and smaller post-inflammatory cystic lesions. Long-term management, by analogy to TIR-pathway IEI, includes antibiotic prophylaxis and monitoring of IgG and vaccine titers. Conclusion: This first human IL-1RacP deficiency supports a non-redundant role of IL-1-dependent signaling in early-life defense against pneumococci , independent of TLR signaling. This novel IEI expands the genetic basis of IPD and has implications for diagnostic work-up, counselling, and preventive care. Publication History Article published online: 26 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany