Immunopathogenesis of Sickle Cell Disease: Mechanisms of Immune Dysregulation and Clinical Consequences, a Narrative Review

Abstract

Sickle cell disease (SCD) is a hereditary haemoglobin abnormality due to a point mutation in the β-globin gene resulting in the production of haemoglobin S. Polymerization of deoxygenated hemoglobin S results in red cell sickling, hemolysis, endothelial injury, ischemia-reperfusion damage, vaso-occlusion, and, in addition to being a hemolytic anaemia and vaso-occlusive condition, SCD is now considered a chronic inflammatory disease with significant immunological abnormalities. This review explores the pathophysiological and immunological basis of SCD, with particular emphasis on how hemolysis, inflammation, innate and adaptive immunity, vulnerability to infection and their implications for current and emerging therapeutics. SCD is characterised by sustained innate and adaptive immune responses, including leukocytosis; neutrophil and monocyte activation; changes in cytokine profiles; complement activation; and T- and B-cell dysfunction. Danger-associated molecular patterns released during hemolysis, including activate inflammasomes, oxidative stress, and endothelial dysfunction through toll-like receptors. Repeat vaso-occlusion maintains sterile inflammation and facilitates coagulation, immune regulation, and vascular damage. Also present are functional asplenia and defective humoral immunity, which predisposes to infection, particularly that caused by encapsulated bacteria. These disruptions help cause vaso-occlusive crises, acute chest syndrome, stroke, pulmonary hypertension, leg ulcers, nephropathy and long-term organ damage. Immunological dysregulation lies at the core of the pathophysiology and complications of SCD. A more detailed understanding of the immune landscape can enhance disease management and inform treatment, including drug administration, transfusion, hematopoietic stem cell transplantation, and gene-based therapies.