G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
EFFECTS OF IRON ON THE IMMUNE SYSTEM
Gert Mayer
Department of Internal Medicine IV (Nephrology and Hypertension)
Medical University Innsbruck
Austria
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
Conflicts of interest
Research Support: Amgen, Roche, Takeda, Ratiopharm
Honoraria: Amgen, Roche, Takeda, Medice, Astro Pharma, Ratiopharm
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
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
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
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
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
INVESTIGATION OF A RESEARCHERS DEATH DUE TO SEPTICEMIC PLAGUE
BY ATTENUATED YERSINIA PESTIS
Frank KM et al. N Engl J Med 2011
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
Lactoferrin, Transferrin, Ferritin chaperon proteins for iron Haptoglobin chaperon protein for hemoglobin Hemopexin chaperon protein for heme
IRON CHAPERON PROTEINS ARE ACUTE PHASE REACTION PROTEINS
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
HEPCIDIN REGULATION BY IRON AVAILABILITY
AND INFLAMMATION
Babitt JL et al. Am J Kidney Dis 2010
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
MONOCYTE/MACROPHAGE A KEY ROLE IN IRON METABOLISM
AND INFLAMMATION
Ward RJ et al. J Neural Transm 2011
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
Microorganism (auto) immune dysregulation
LPS IFN γ Il-6 Il-1
erythrophagozytosis
M1 macrophage
TNF- α, IL-1, -6, -10, -12,-18 NO, O2-,OH-, H2O2
NUTRITIONAL IMMUNITY (I)
Recalcati S et al. Autoimm Rev 2012
↑DMT 1
Hepcidin
↓ Ferroportin
Hepcidin
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
LPS IFN γ Il-6 Il-1
Iron uptake, storage and release macrophage
IL-4 IL-10 Il-13
NUTRITIONAL IMMUNITY (II)
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
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
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
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
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
MONOCYTE INTRACELLULAR IRON RETENTION AFTER IV IRON IS
DETERMINED BY HEPCIDIN LEVELS
Sonnweber T et al. Nephrol Dial Transplant 2011
intra
cellu
lar f
errit
in c
once
ntra
tion
(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)
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice
Sindrilaru A et al. J Clin Invest 2011
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
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
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE
SYSTEM
Kidney Int 2003
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
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
baseline 3 months p ANOVA over 5me
p difference in trend
Hemoglobin (g/dl)
12.5 +/-‐ 0.8 12.1 +/-‐ 0.8 0.36 0.1
12.3 +/-‐ 0.8 12.5 +/-‐ 1.2 0.28
Ferri5n (ng/ml)
314 +/-‐ 129 160 +/-‐ 97 < 0.001 < 0.001
302 +/-‐ 83 586 +/-‐ 282 < 0.001
Transferrin satura5on (%)
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
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE
SYSTEM
Kidney Int 2003
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
Kidney Int 2003
iron yes no
TNF-α
(ng/
l)
20
10
0 1 8 15 28 90
days
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE
SYSTEM
*
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
Kidney Int 2003
TNF-α
(ng/
l)
IL-4
(ng/
l)
30
20
10
0
150
100
50
0 20 40 60 80 20 40 60 80
TfS, % TfS, %
r=0.56 p=0.008
r=0.43 p=0.02
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE
SYSTEM
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
TH0
TH1 TH2
IL-12 IL-4
IFN-γ IL-2
TNF-α
IL-4, IL-5 IL-10 IL-13
+ - macrophage
TNF- α, IL-1, -6, -10, -12,-18 NO, O2-,OH-, H2O2
- -
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE
SYSTEM
courtesy G. Weiss
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
TH0
TH1 TH2
IL-12 IL-4
IFN-γ IL-2
TNF-α
IL-4, IL-5 IL-10 IL-13
+ - macrophage
TNF- α, IL-1, -6, -10, -12,-18 NO, O2-,OH-, H2O2
- -
Iron
-
-
+
+
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE
SYSTEM
courtesy G. Weiss
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
Sonnweber T et al. Nephrol Dial Transplant 2011
mea
n IL
-6 c
once
ntra
tion
in s
uper
nata
nt
of m
onoc
ytic
cel
l cul
ture
(ng/
ml)
4 3 2 1 0
p=0.01 p=0.04 p=0.26
Control IFN-γ LPS
250
200
150
100
50
0
baseline serum ferritin level
low (<170 ng/ml)
high (>350 ng/ml)
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE
SYSTEM
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
MAYBE NOT ONLY INCREASED IRON AVAILABILITY BUT ALSO IMPAIRED
TH 1 RESPONSE ?
Frank KM et al. N Engl J Med 2011
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
DISTINCT IMMUNOLOGIC EFFECTS OF DIFFERENT INTRAVENOUS IRON PREPARATIONS ON MONOCYTES
Fell LH et al. Nephrol Dial Transplant 2014
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
IRON SUCROSE PROMOTES APOPTOSIS IN
POLYMORPHONUCLEAR LEUCOCYTES
Ichii H et al. Am J Nephrol 2012
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
HIGH DOSE PARENTERAL IRON SUCROSE DEPRESSES NEUTROPHIL INTRACELLULAR KILLING CAPACITY
Deicher R et al. Kidney Int 2003
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
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
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
Kidney Int 2003
TNF-α
(ng/
l
TfS
, %
30
20
10
0
80
60
40
20
0 0 5 10 15 0 5 10 15
POX (µmol/l) POX (µmol/l)
r=0.394 p=0.046
r=0.428 p=0.02
THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE
SYSTEM
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
EFFECT OF DIFFERENT IRON PREPARATIONS ON APOPTOSIS OF
MONONUCLEAR CELLS IN VIVO
Martin-Malo A et al Nephrol Dial Transplant 2012
% a
popt
otic
cel
ls
50
40
30
20
10
0 T0 T1 T2 T3
control iron sucrose iron dextrane
ferric gluconate ferric carboxym
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
SALMONELLA INDUCED INTESTINAL INFLAMMATION IS ATTENUATED IN
Hfe-/- MICE
Wang L et al. J Immunol 2008
G.M. 2014
Innere Medizin IV Nephrologie und Hypertensiologie
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 REGULATORY PROTEINS AND IMMUNE SYSTEM