EFFECTS OF IRON ON THE IMMUNE SYSTEM Gert Mayer Department of Internal Medicine IV (Nephrology and Hypertension) Medical University Innsbruck Austria
Conflicts of interest Research Support: Amgen, Roche, Takeda, Ratiopharm Honoraria: Amgen, Roche, Takeda, Medice, Astro Pharma, Ratiopharm
INTERACTION BETWEEN INFECTION / INFLAMMATION AND IRON METABOLISM EFFECTS OF IRON SUPPLEMENTATION DURING INFECTION / INFLAMMATION EFFECTS OF IRON SUPPLEMENTATION ON THE IMMUNE SYSTEM IN THE ABSENCE OF INFECTION / INFLAMMATION
INTERACTION BETWEEN INFECTION / INFLAMMATION AND IRON METABOLISM EFFECTS OF IRON SUPPLEMENTATION DURING INFECTION / INFLAMMATION EFFECTS OF IRON SUPPLEMENTATION ON THE IMMUNE SYSTEM IN THE ABSENCE OF INFECTION / INFLAMMATION
Drakesmith H et al. Science 2012
INVESTIGATION OF A RESEARCHERS DEATH DUE TO SEPTICEMIC PLAGUE BY ATTENUATED YERSINIA PESTIS Frank KM et al. N Engl J Med 2011
Drakesmith H et al. Science 2012
IRON CHAPERON PROTEINS ARE ACUTE PHASE REACTION PROTEINS Innere Medizin IV Lactoferrin, Transferrin, Ferritin chaperon proteins for iron Haptoglobin chaperon protein for hemoglobin Hemopexin chaperon protein for heme
Ward RJ et al. J Neural Transm 2011
HEPCIDIN REGULATION BY IRON AVAILABILITY AND INFLAMMATION Babitt JL et al. Am J Kidney Dis 2010
MONOCYTE/MACROPHAGE A KEY ROLE IN IRON METABOLISM AND INFLAMMATION Ward RJ et al. J Neural Transm 2011
NUTRITIONAL IMMUNITY (I) Innere Medizin IV Microorganism (auto) immune dysregulation LPS IFN γ Il-6 Il-1 Hepcidin erythrophagozytosis Ferroportin M1 macrophage Hepcidin Recalcati S et al. Autoimm Rev 2012 DMT 1 TNF- α, IL-1, -6, -10, -12,-18 NO, O 2-,OH -, H 2 O 2
NUTRITIONAL IMMUNITY (II) Innere Medizin IV LPS IFN γ Il-6 Il-1 IL-4 IL-10 Il-13 Iron uptake, storage and release macrophage
Anemia of chronic disease (ACD) most frequent anaemia among hospitalised patients mild to moderate, normochromic, normocytic develops in patients with cellular immune activation degree of anaemia correlated to immune activation
INTERACTION BETWEEN INFECTION / INFLAMMATION AND IRON METABOLISM EFFECTS OF IRON SUPPLEMENTATION DURING INFECTION / INFLAMMATION EFFECTS OF IRON SUPPLEMENTATION ON THE IMMUNE SYSTEM IN THE ABSENCE OF INFECTION / INFLAMMATION
MONOCYTE INTRACELLULAR IRON RETENTION AFTER IV IRON IS DETERMINED BY HEPCIDIN LEVELS intracellular ferritin concentration (ng/ml) 300 200 100 0 p = 0.72 p = 0.02 day 0 48 hours prior iron therapy after iron therapy high serum hepcidin (>12 pmol/ml) low serum hepcidin (<12 pmol/ml) Sonnweber T et al. Nephrol Dial Transplant 2011
An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice Sindrilaru A et al. J Clin Invest 2011
INTERACTION BETWEEN INFECTION / INFLAMMATION AND IRON METABOLISM EFFECTS OF IRON SUPPLEMENTATION DURING INFECTION / INFLAMMATION EFFECTS OF IRON SUPPLEMENTATION ON THE IMMUNE SYSTEM IN THE ABSENCE OF INFECTION / INFLAMMATION
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM 31 stable patients on hemodialysis no clinical or routine laboratory signs of infections or inflammation all on ESA therapy, serum ferritin 200-500 µg/l, hemoglobin 11.5-12.5 g/dl, one week after iron withdrawal the subjects were randomized to Group 1: 50-150 IU/kg BW ESA / week Group 2: 50 150 IU ESA/kg BW plus 100 mg iron saccharate / week Kidney Int 2003
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM Hemoglobin (g/ dl) baseline 3 months p ANOVA over 5me p difference in trend 12.5 +/- 0.8 12.1 +/- 0.8 0.36 0.1 Ferri5n (ng/ml) Transferrin satura5on (%) 12.3 +/- 0.8 12.5 +/- 1.2 0.28 314 +/- 129 160 +/- 97 < 0.001 < 0.001 302 +/- 83 586 +/- 282 < 0.001 21.5 +/- 8.6 18.4 +/- 10.2 0.31 0.08 24.8 +/- 8.8 38.1 +/- 19.9 0.01 iron supplementation iron supplementation iron supplementation Kidney Int 2003
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM 20 TNF-α (ng/l) 10 * iron yes no 0 1 8 15 28 90 days Kidney Int 2003
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM 30 150 TNF-α (ng/l) 20 10 r=0.56 p=0.008 IL-4 (ng/l) 100 50 r=0.43 p=0.02 0 0 20 40 60 80 20 40 60 80 TfS, % TfS, % Kidney Int 2003
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM IL-12 TH0 IL-4 TH1 - - TH2 IFN-γ IL-2 TNF-α IL-4, IL-5 IL-10 IL-13 + - macrophage courtesy G. Weiss TNF- α, IL-1, -6, -10, -12,-18 NO, O2 -,OH -, H 2 O 2
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM IL-12 TH0 IL-4 TH1 - - + TH2 Iron - IFN-γ IL-2 TNF-α - + - macrophage + IL-4, IL-5 IL-10 IL-13 courtesy G. Weiss TNF- α, IL-1, -6, -10, -12,-18 NO, O2 -,OH -, H 2 O 2
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM 4 250 mean IL-6 concentration in supernatant of monocytic cell culture (ng/ml) 3 2 1 p=0.01 p=0.04 p=0.26 200 150 100 50 baseline serum ferritin level low (<170 ng/ml) high (>350 ng/ml) 0 0 Control IFN-γ LPS Sonnweber T et al. Nephrol Dial Transplant 2011
MAYBE NOT ONLY INCREASED IRON AVAILABILITY BUT ALSO IMPAIRED TH 1 RESPONSE? Frank KM et al. N Engl J Med 2011
DISTINCT IMMUNOLOGIC EFFECTS OF DIFFERENT INTRAVENOUS IRON PREPARATIONS ON MONOCYTES Fell LH et al. Nephrol Dial Transplant 2014
IRON SUCROSE PROMOTES APOPTOSIS IN POLYMORPHONUCLEAR LEUCOCYTES Ichii H et al. Am J Nephrol 2012
HIGH DOSE PARENTERAL IRON SUCROSE DEPRESSES NEUTROPHIL INTRACELLULAR KILLING CAPACITY Deicher R et al. Kidney Int 2003
EFFECTS OF INFECTION / INFLAMMATION ON IRON METABOLISM EFFECTS OF IRON SUPPLEMENTATION DURING INFECTION / INFLAMMATION EFFECTS OF IRON SUPPLEMENTATION ON THE IMMUNE SYSTEM IN THE ABSENCE OF INFECTION / INFLAMMATION
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM 30 80 TNF-α (ng/l 20 10 r=0.394 p=0.046 TfS, % 60 40 20 r=0.428 p=0.02 0 0 0 5 10 15 0 5 10 15 POX (µmol/l) POX (µmol/l) Kidney Int 2003
EFFECT OF DIFFERENT IRON PREPARATIONS ON APOPTOSIS OF MONONUCLEAR CELLS IN VIVO 50 control iron sucrose iron dextrane 40 ferric gluconate ferric carboxym % apoptotic cells 30 20 10 0 T0 T1 T2 T3 Martin-Malo A et al Nephrol Dial Transplant 2012
SALMONELLA INDUCED INTESTINAL INFLAMMATION IS ATTENUATED IN Hfe -/- MICE Wang L et al. J Immunol 2008
IRON REGULATORY PROTEINS AND IMMUNE SYSTEM Innere Medizin IV Lactoferrin weak iron chelator Immunoregulator effects on Th1/Th2 cell activities Transferrin iron transporter present on monocytes, macrophages, T lymphocytes, required for early T cell differentiation Transferrin receptor 1 cellular iron uptake iron uptake by activated lymphocytes, required for DNA synthesis and cell division of T lymphocytes Ferroportin cellular iron exporter toll-like gate receptor 4 mediates downregulation in infection etc. Ward RJ et al. J Neural Transm 2011
IRON INHIBITS IFN γ ACTIVITY IN HUMAN MONOCYTES/MACROPHAGES Innere Medizin IV desferrioxamine GTP IFN- γ + - Fe +2 Fe +3 transferrin/fe tryptophan GTP-CH IDO neopterin TNF- α MHC class II kynurenine Weiss et al. Exp Hematol 1992, J Exp Med 1994