Impact of impaired immune function in haemoglobin disorders

Haemoglobin disorders, such as sickle cell disease and β-thalassaemia are the result of mutations in the adult β-globin gene. Patients suffering with the most severe form of the disease require chronic blood transfusion for survival. Ongoing transfusion therapy to counteract anaemia exacerbates iron overload, and necessitates iron chelation therapy. One important clinical feature of these conditions is the increased frequency of infectious complications such as pneumonia and sepsis, which are significantly associated with an increased rate of morbidity and mortality. The increased susceptibility to pathogenic organisms has been attributed to multiple deficiencies affecting both innate and adaptive immune systems. What has become apparent, is that iron overload in chronically anaemic patients contributes to aberrant neutrophil effector functions resulting in increased susceptibility to infection and inflammation-related organ damage. This knowledge, combined with the emergence of novel immunomodulatory function and phenotypes for neutrophils has helped to re-invigorate interest in the field. To further understand the clinical significance of aberrant immune function in β-thalassaemia, we will undertake a comprehensive evaluation of the molecular and cellular mechanisms responsible for aberrant innate immune effector functions in β-thalassaemic mice and β-thalassaemia patients. The work proposed in this project will generate a better understanding of the mechanism underlying aberrant immune functions and provide novel insights into disease progression. Positive outcomes of such studies could pave the way for better treatment strategies for β-thalassaemia and related patients.