What Is the Relationship between Haptoglobin, Malaria, and Anaemia?

I n malaria-endemic countries of Africa, anaemia is very common in pregnant women and in children under fi ve. Although anaemia is multifactorial—causative factors include iron defi ciency and other nutritional defi ciencies, helminth infection, and HIV—malaria is clearly an extremely important factor. Over half of malaria-related deaths are attributed to severe malaria anaemia (which is defi ned as malaria parasitaemia and a haemoglobin (Hb) concentration less than 50 g/l) [1]. Several antimalarial interventions have been shown to prevent anaemia, including insecticide-treated nets, residual spraying, malaria chemoprophylaxis, and, more recently, intermittent presumptive treatment of infants (i. e., antimalarials coadministered with childhood immunization). Insecticide-treated nets have been shown to decrease all-cause mortality [2]. The pathogenesis of malaria anaemia remains incompletely understood. Dyserythropoiesis (disordered red cell development, which is, at least in part, due to infl ammatory cytokines acting on erythroid precursors), intravascular haemolysis of infected red cells, and destruction of both parasitized and uninfected erythrocytes by splenic macrophages are all important [3,4]. Interestingly, it has been estimated that ten or more uninfected erythrocytes may be lost for each infected one [5], presumably because malaria infection alters uninfected erythrocytes. The probable causes of red cell loss include oxidation of band 3 (the anion transporter of the erythrocyte membrane) or membrane lipids, and deposition of IgG, complement, or immune complexes on the erythrocyte surface. The glycoprotein haptoglobin (Hp) is the body's main tool for removing circulating, toxic free Hb during intravascular haemolysis. Hp binds rapidly and with high affi nity to free Hb, with the resultant complex being taken up by CD163, which is expressed on monocytes/macrophage lineage cells. Binding of Hp/Hb complexes to CD163 leads to cytokine secretion by macrophages [6]. In the absence of Hp, free Hb can enter and damage renal glomeruli, and is a potent oxidant that can lead to the generation of reactive oxygen species. In humans, unlike other animals, Hp exists in two forms. The Hp 2 gene arose by duplication of a region of the gene encoding the α chain of Hp 1 , leading to three phenotypes—1-1, 2-1, and 2-2. Hp1-1 leads to smaller, more abundant dimers with a higher affi nity for Hb, and to Hp/Hb complexes with a lower affi nity for CD163. Studies have associated the Hp2-2 phenotype with increased morbidity from cardiovascular disease, diabetes, HIV infection, and other conditions—perhaps because concentrations of Hp2-2 are lower, Hp2-2 is less able than Hp1-1 …