EFFECTS OF IRON ON THE IMMUNE SYSTEM · Recalcati S et al. Autoimm Rev 2012 ↑DMT 1 Hepcidin ↓ Ferroportin Hepcidin . G.M. 2014 Innere%Medizin%IV% Nephrologie%und%Hypertensiologie%

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


Conflicts of interest

Research Support: Amgen, Roche, Takeda, Ratiopharm

Honoraria: Amgen, Roche, Takeda, Medice, Astro Pharma, Ratiopharm

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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

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INFLAMMATION


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Drakesmith H et al. Science 2012

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INVESTIGATION OF A RESEARCHERS DEATH DUE TO SEPTICEMIC PLAGUE

BY ATTENUATED YERSINIA PESTIS

Frank KM et al. N Engl J Med 2011

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Drakesmith H et al. Science 2012

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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

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Ward RJ et al. J Neural Transm 2011

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HEPCIDIN REGULATION BY IRON AVAILABILITY

AND INFLAMMATION

Babitt JL et al. Am J Kidney Dis 2010

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MONOCYTE/MACROPHAGE A KEY ROLE IN IRON METABOLISM

AND INFLAMMATION


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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

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LPS IFN γ Il-6 Il-1

Iron uptake, storage and release macrophage

IL-4 IL-10 Il-13

NUTRITIONAL IMMUNITY (II)

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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

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INFLAMMATION


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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)

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An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice

Sindrilaru A et al. J Clin Invest 2011

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INFLAMMATION


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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

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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




SYSTEM

Kidney Int 2003

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Kidney Int 2003

iron yes no

TNF-α

(ng/

l)

20

10

0 1 8 15 28 90

days


SYSTEM

*

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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


SYSTEM

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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

- -


SYSTEM

courtesy G. Weiss

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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

-

-

+

+


SYSTEM

courtesy G. Weiss

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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)


SYSTEM

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MAYBE NOT ONLY INCREASED IRON AVAILABILITY BUT ALSO IMPAIRED

TH 1 RESPONSE ?

Frank KM et al. N Engl J Med 2011

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DISTINCT IMMUNOLOGIC EFFECTS OF DIFFERENT INTRAVENOUS IRON PREPARATIONS ON MONOCYTES

Fell LH et al. Nephrol Dial Transplant 2014

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IRON SUCROSE PROMOTES APOPTOSIS IN

POLYMORPHONUCLEAR LEUCOCYTES

Ichii H et al. Am J Nephrol 2012

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HIGH DOSE PARENTERAL IRON SUCROSE DEPRESSES NEUTROPHIL INTRACELLULAR KILLING CAPACITY

Deicher R et al. Kidney Int 2003

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EFFECTS OF INFECTION / INFLAMMATION ON IRON METABOLISM


INFLAMMATION


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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


SYSTEM

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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

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SALMONELLA INDUCED INTESTINAL INFLAMMATION IS ATTENUATED IN

Hfe-/- MICE

Wang L et al. J Immunol 2008

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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.


IRON REGULATORY PROTEINS AND IMMUNE SYSTEM

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IFN- γ

GTP-CH

GTP

neopterin

IDO

tryptophan

kynurenine TNF- α MHC class II

desferrioxamine Fe+2

Fe+3

transferrin/Fe + -

Weiss et al. Exp Hematol 1992, J Exp Med 1994

IRON INHIBITS IFN γ ACTIVITY IN HUMAN MONOCYTES/MACROPHAGES

Documents

EFFECTS OF IRON ON THE IMMUNE SYSTEM · Recalcati S et al. Autoimm Rev 2012 ↑DMT 1 Hepcidin ↓ Ferroportin Hepcidin . G.M. 2014 Innere%Medizin%IV% Nephrologie%und%Hypertensiologie%