Regulatory Role of FoxP3 and Immune Dysregulation in β-Thalassemia Major in South Asia: A Systematic Review
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Abstract
Beta-thalassemia major (BTM) continues to be one of the most common inherited hemoglobinopathies in "thalassemia belt" of hemoglobinopathies. In Pakistan, the burden of BTM is comparatively high due to consanguineous marriages and high carrier frequency. Frequent blood transfusion therapy has greatly increased the survival rate of patients but iron overload and long-term transfusion therapy cause persistent immunological dysregulation. According to new research, immunological homeostasis and immune tolerance are primarily regulated by the FoxP3 (Forkhead Box P3) transcriptional factor, and failure of T-regulatory cells (Tregs) may have a significant impact on hemoglobinopathies. This review emphasizes on FoxP3-associated genetic polymorphisms such as rs3761548 and rs2232367, which further highlights the current understanding of the molecular and immunological pathways responsible for immune dysfunction in BTM patients. The article provides recent research supporting the validity of the "Multi-Hit Theory" of thalassemic immune failure. Treg inflammatory progression and instability are caused by a combination of chronic antigenic stimulation from frequent transfusions, iron-mediated oxidative damage and inherited genetic susceptibility. Additionally, the present review study emphasizes how clinically relevant outcomes such alloimmunization, leukocyte apoptosis, cytokine imbalance, vascular damage and increased cardiovascular failure are linked to FoxP3 dysregulation. Exonic and promoter domain of FoxP3 polymorphisms are highlighted as biological markers that can detect genetically susceptible patients who show acute immune stress. This review also covers the clinical significance of Tetra-Primer Amplification Refractory Mutation System PCR (T-ARMS PCR) as a cost-effective and successful genotyping method ideal for healthcare systems with limited resources. All of the evidence points to the increasing necessity for precision medicine methods based on genetics in the treatment of thalassemia patients. Early detection of immune-related genotypes may enhance chelation therapy, reduce long-term immunological and other pathological problems in susceptible groups and improve transfusion techniques
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