Theoretical and Empirical Examination of the Role of Innate Immune Dysregulation in Sickle Cell Disease Vaso-Occlusive Crisis in Nigerian Adults

Vaso-occlusive crisis in sickle cell disease is the primary driver of hospitalisation and end-organ damage, and its pathophysiology involves complex interactions between sickled erythrocytes, activated neutrophils, vascular endothelium, and innate immune signalling pathways that are incompletely characterised in the African genetic context. This study theoretically and empirically examines the role of innate immune dysregulation in vaso-occlusive crisis in Nigerian adults with sickle cell disease, using a nested case-control design within a prospective longitudinal cohort. Eight hundred adult patients with HbSS genotype are recruited from haematology centres in Lagos, Enugu, Kano, and Maiduguri and followed for 36 months, with crisis events documented and biosampled within 72 hours. Comparisons are made between crisis-phase and steady-state samples within the same patients for neutrophil extracellular trap formation, NLRP3 inflammasome activation, complement pathway markers (C3, C5a), and plasma toll-like receptor 4 signalling intermediates. Single-cell RNA sequencing of neutrophil populations is performed in a biomarker sub-study. The Sterile Inflammation Theory and the Erythrocyte-Immune Cell Crosstalk Model provide the theoretical foundation. Original contributions include the characterisation of sickle cell crisis immunopathology in a large Nigerian cohort, identifying novel therapeutic targets relevant to African HbSS haplotype predominance. Findings will advance the development of adjunct anti-inflammatory crisis prevention strategies. Keywords: sickle cell disease, vaso-occlusive crisis, innate immunity, neutrophil extracellular traps, Nigerian cohort.