Albertine Donker

Iron Function and Iron Handling from Fetus to Adult 65 2 give information on brain iron are lacking until now, hampering the assessment of brain dysfunction due to both cerebral ID -before the occurrence of IDA- and of cerebral iron excess. 77 Moreover, how iron enters the central nervous system, still needs elucidation. Rodent studies indicate that the brain acquires iron by diferric transferrin, since hypo-transferrinemia in mice affects neurologic development. 101 However, other mice studies suggest that NTBI, acquired by ZIP8, DMT1 and possibly other, still unidentified NTBI iron transporters, appears to be the main source of iron for astrocytes, oligodendrocytes, and microglia, since these cell types do not express transferrin receptors. 13 Iron and the immune system The human immune system is a dynamic system that varies with age refelecting the different challenges during the different phases of fetal life, childhood and adulthood, a concept known as immune ontogeny. 102 The immune system in early life is programmed to tolerate foreign antigenic influences of the mother in utero but has to adapt rapidly to a functional system that is able to distuinguish harmful pathogens from helpful microbes right after birth. 102 This ability is thought to be critical for health and failure to regulate these responses may result in recurrent infections, auto- inflammatory diseases and allergies. 103,104 Because the intestine houses the majority of lymphocytes and other immune effector cells of the human body, nutritional status and also iron is very likely to contribute to the education of the immature immune system, by directly influencing the function of the intestinal immune cells 103,105 and by indirectly modifying the intestinal microbiota. 106 Apart from the developmental aspects, both the innate 107-109 and adaptive 110 immune system need iron in order to mount a proper response against pathogens. Regarding the innate immune system, iron is essential for the antimicrobial oxidative burst inside neutrophils, the binding activity of pro-inflammatory transcription factors and the polarisation and differentiaton of macrophages during infections. 107,111-113 For the adaptive immune sytem, in vitro studies and anecdotal data indicate that the proliferation and function of lymphocytes also depend on iron. 110,114 Impaired cellular iron acquisition of lymphocytes caused by a defect of TfR1 caused compromised T and B cell proliferation and subsequent antibody class switching, resulting in a severe immunodeficiency with life threatening and even fatal infections in two affected families in the Middle East. 110,114 This is clinically important since ID is highly prevalent in young