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Beyond genetic mutation, dysregulation of immune\u2010related genes such as those regulating NF\u2010\u03baB signalling, inflammasome activation and type I interferon responses exacerbates the inflammatory milieu and drives many of the complications observed in SCD. Chronic inflammation, linked to disease severity, highlights the crucial role of the immune system in SCD pathophysiology. Immune dysregulation in SCD leads to chronic inflammation, heightened infection risk and possible autoimmune reactions. Immune dysregulation is driven by splenic damage and pro\u2010inflammatory cytokines from sickled red blood cells. While progress has been made studying innate immune cell roles, the adaptive immune system's contributions remain poorly understood. T\u2010cell abnormalities in SCD highlight the complexity of adaptive immune responses. Alterations in T\u2010cell counts, shifts in Th1\/Th2 responses and changes in regulatory T\u2010cell behaviour reflect immune dysregulation, further contributing to chronic inflammation and disease progression. While studies have focused on polyclonal T\u2010cell phenotyping, antigen\u2010specific T\u2010cells, crucial for immune activation, remain underexplored. Focusing on antigen\u2010specific T\u2010cell responses will deepen our understanding of adaptive immune dysfunction in SCD and aid in developing targeted therapies to manage the disease. Furthermore, there is significant impairment in the B cell compartment in SCD, including reduced B cell proliferation, fewer memory B cells and abnormalities in class\u2010switching memory B cells. These defects weaken antigen\u2010specific immune responses, mainly by lowering IgM\u2010secreting memory B cells, essential for early defence against infections. The loss of these cells also diminishes vaccine effectiveness, leaving patients more vulnerable to infections. Additionally, impaired memory B cell differentiation and class switching contribute to an increased risk of infections and autoimmune complications, highlighting the need for targeted immune therapies in the management of SCD. This review highlights the need to explore dysregulation in innate and adaptive immune mechanisms in SCD. Investigating T and B cell dysfunctions, especially antigen\u2010specific immune activation, is crucial for developing immune\u2010targeted therapies and improving vaccine responses, ultimately advancing treatments and enhancing the quality of life and survival for SCD patients.<\/jats:p>","DOI":"10.1111\/imm.70080","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T01:42:33Z","timestamp":1765590153000},"page":"445-456","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Unravelling the Immunological Enigma of Sickle Cell Disease: Current Understanding and Future Directions"],"prefix":"10.1111","volume":"177","author":[{"given":"Sumit","family":"Jamwal","sequence":"first","affiliation":[{"name":"Department of Pediatrics Yale University School of Medicine  New Haven Connecticut 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