Beyond anemia: unraveling neutrophil defects and infection susceptibility in β-Thalassemia

β-Thalassemia is characterized by defective β-globin synthesis and chronic transfusion dependence. Beyond anemia and iron overload, patients with β-thalassemia display heightened susceptibility to infections. Neutrophil granulocytes (NGs) are crucial innate immune cells that protect against bacteria through phagocytosis, degranulation, generation of reactive oxygen species (ROS), and neutrophil extracellular trap (NET) formation. Neutrophils in patients with thalassemia exhibit impaired functions, including defective chemotaxis, reduced phagocytic killing, attenuated respiratory burst, and abnormal NET formation. Chronic immune activation and iron overload, with consequent oxidative stress, are key contributors to these defects. Iron accumulation leads to excess free iron and heme, catalyzing ROS production that damages neutrophil membranes and enzymes and induces heme oxygenase-1 (HO-1), which suppresses immune responses. Neutrophils from patients with thalassemia often show an immature phenotype and increased apoptosis, further compromising innate immunity. A growing body of evidence confirms that systemic iron overload is inversely correlated with neutrophil bactericidal activity. These neutrophil defects contribute to the high risk of infection in thalassemia. Therapeutic strategies such as intensive iron chelation, antioxidants, and modulation of the HO-1 pathway hold promise for restoring neutrophil function. A deeper understanding of these mechanisms may guide the development of new interventions to reduce infectious complications and improve patient outcomes.