Iron overload and immunity

Table 1 Relevant genes/proteins involved in iron homeostasis and iron overload, and their related immunological functions

Genes/Proteins	Main role in iron homeostasis	Related immunological functions
Iron binding, transport and storage
Lactoferrin	Iron chelator	Bactericidal and antiviral[13,14]. Immunoregulatory effects on Th1/Th2 cell activities[15]
Transferrin	Iron transporter	Present in monocyte/machrophages and T lymphocytes[16]
		Required for early T-cell differentiation[17]
Transferrin receptor 1	Cellular iron uptake	Iron uptake by activated lymphocytes and required for DNA synthesis and cell division of T lymphocytes[18]
Ferritin	Iron storage	Synthesised by macrophages and T lymphocytes[19,20]
Nramp1 (SCLA11)	Iron transfer in late phagolysosome	Resistance to infection with intracellular pathogens[21,22]
Nramp2/DMT-1	Iron uptake and transfer in late phagolysosome	Resistance to infection with intracellular pathogens[21,22]
Ferroportin 1 (IREG1)	Cellular iron exporter	TLR4 mediated downmodulation in infection[23]
Lipocalin	Unknown	Limits bacterial growth by sequestering the siderophore[24]
Regulators and modifiers of iron overload
Hepcidin	Key regulator of iron homeostasis[25]. Gene disruption results in hemochromatosis[26]. Mutations associated with severe Juvenile Hemochromatosis (JH)[27]	Liver derived antimicrobial peptide[28]. TLR4 mediated expression in myeloid cells in response to bacterial pathogens[23]
Hemojuvelin	Regulation of hepcidin expression[29,30]. JH associated gene[31]	Unknown
IL-6 and IL-1	Involved in iron deprivation during infection and inflammation, through hepcidin induction and ferroportin down-modulation[32,33]	Derived from macrophages during infection and inflammation[32,33]
Heme-oxygenase 1	Required for mammalian iron reutilization. Targeted Hmox1 mutations induce spontaneous iron overload[34]	High CD4:CD8 ratios with activated CD4+ cells in Hmox1 deficient mice[34]
HFE	Hereditary Hemochromatosis associated gene[35]. HFE gene knockout produces mouse model of hereditary hemochromatosis[36]	Non-classical MHC-class I molecule[37]
β2-Microglobulin	β2m deficiency induces spontaneous iron overload and modifies the phenotype of HFE deficient mice[38,39]	Critical to the folding of MHC-classImolecules and selection of MHC class I molecule-associated peptides[40]
MHC-class I	MHC-class I deficient mice develop hepatic iron overload[41]	Critical molecule for viral peptide presentation[42]