Breaking of the wall : role of allergy and histamine release
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Breaking of the wall : role of allergy and histamine release
Immunology Unit Institut Pasteur de Madagascar
Immunology Unit Institut Pasteur de Madagascar
Ronan Jambou MD, PhD
Vascular
Immunology
Unit
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Expected decrease of Rural Malaria transmissionExpected decrease of Rural Malaria transmission
Swaziland WHO Report 2006Swaziland WHO Report 2006Kilifi _ Kenya Malaria J 2007Kilifi _ Kenya Malaria J 2007
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Kilifi _ East Africa Mwangi et al JID 2005Kilifi _ East Africa Mwangi et al JID 2005
Changes in transmission modulate Malaria profil Changes in transmission modulate Malaria profil
53%32Saharevo, Madagascar: ≤1 b.i.a./human/year
50%25Pikine, Sénégal: ≤1 b.i.a./human/year
41%62Ndiop, Sénégal: 10-30 b.i.a./human/year
23%43Dielmo, Sénégal: 100-300 b.i.a./human/year
10%25Danané, Côte d'Ivoire: ≥ 300 b.i.a./human/year
% withinadluts
Total Nb of attacks 60 years old
53%32Saharevo, Madagascar: ≤1 b.i.a./human/year
50%25Pikine, Sénégal: ≤1 b.i.a./human/year
41%62Ndiop, Sénégal: 10-30 b.i.a./human/year
23%43Dielmo, Sénégal: 100-300 b.i.a./human/year
10%25Danané, Côte d'Ivoire: ≥ 300 b.i.a./human/year
% withinadluts
Total Nb of attacks 60 years old
Ann
ual N
bof
mal
aria
atta
cks
0
1
2
3
4
5
6
0 5 10 15 20 25 30 35 40 45 50
Age (years)
60A
nnua
l Nb
of m
alar
ia a
ttack
s0
1
2
3
4
5
6
0 5 10 15 20 25 30 35 40 45 50
Age (years)
60
West Africa / Madagascar (meta-analysis)West Africa / Madagascar (meta-analysis)
No clear change in mortalityNo clear change in mortality
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Schofield & Grau 2005
Hunt & Grau 2003
sequestration inflammation
(oedema)pathology
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Major role in: Major role in: Major role in: ECECEC
Vascular permeability
� Diabetes� Dengue fever� Age degenerescence� ARDS� Myocardial infarction� Tumour angiogenesis� Brain injury
� Diabetes� Dengue fever� Age degenerescence� ARDS� Myocardial infarction� Tumour angiogenesis� Brain injury
VVO Junction remodelling
pinocytosis
pathogenspathogenspathogens stimulistimulistimuli
Histamine
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Histamine induces vascular congestion
Guido Majno (1961)
vein
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Histamine
HRF/TCTPbasophiles
cytokine network (IL4, IL2..) eicosanoid pathway
endothelial cells responseto inflammation
platelets / neutrophils
DC response to TH2 typeproduction of IgE
vascular permeability
Cerebral malaria ??
( HR1, HR2, HR3, HR4, HR5 )
IgE AntigenAllergy / helminths
Histamine can modulate endothelial and immune cells func tions
vWFPlatelet + IRBC
adhesion
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PfTCTP is expressed by late trophozoites
PF
TC
TP
T
rans
crip
tRQ
2 8 14 20 3226 38 44 50 hours
0,51
1,52
2,53
3,54
4,5
05
10152025303540
P0 P6 P12 P18 P30P24 P36 P42 P48
- synchronisation + sampling every 6h over 54h = « sampli ng time »
- use of thin smear and timing genes (P David) to define th e « parasite time » (gene8h= MAL8P1.4, gene 12h=PFI1735c- normalisation of mRNA on average of (N1= PFC0255c and N 2=PFA0570), then attime with less mRNA (T44 = 1 for PfTCTP)
Parasite cycle time
Sampling time
gene T8h
gene T12h
Tim
ing
gene
s Pf TCTP
- 38% identity, 53% similarity with hTCTP
- mimics hTCTP in vitro on histamine release
- 0.1 to 1µg/ml in serum from patients with malaria
- totally conserved in 350 P falciparum field isolates => target human cells ??
Plasmo-DB
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Allergic response in seasonal transmission area
« The background »
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15°
14°
13°
16°N
Dakar
17°W 16° 15° 14° 13° 12°
SENEGAL
Area of Dakar
Seasonal transmission
4 M inhabitants = 1/3 Senegal
3.5% territory
An arabiensis
Gouly Couly
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Longitudinal study: Gouly couly Longitudinal study: Gouly couly
Nov. 04Baso, IgE
Follow up
EnrolmentJun 04
Jun 05Baso, IgE
july 04IgE
EndJun 06
Rainy season Rainy seasondry season dry seasondry season
Drug resistance study
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CD203Surface marker
activation of basophiles
CD63granule marker
Release
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Low
high
medium
0
20
40
60
80
100
9-19 20-39 40-80
0
2
4
6
8
10
Total IgE ug/L
9-19 20-39 40-80
0
0,5
1
1,5
july 04 Nov 04 July 05
IgE
ug/
mL
0
0,5
1
1,5
2
2,5
IgE
ug/
mL
0
5
10
15
20
25
30
1 2 3
IgE
ug/
mL
% of subjects with > 0.4µg/l
0
5
10
15
20
25
30
35
40
45
9-19 20-39 40-80
% Ig
E_P
f pos
itive
nov_04Jun_05
% of subjects with IgE-Pf
No difference according to age for
high IgE level
Stability of IgE level« High is high »
No change in [IgE] according to season
Higher percent of Pf-IgE during dry
season
IgE responses : Gouly couly IgE responses : Gouly couly
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Basophiles responses : Gouly couly Basophiles responses : Gouly couly
standard antigens
flmpD farinaeD pteronyssinus
0102030405060708090
9-19y 20-39y 40-80y
Per
cent
res
pond
ers
nov jun
Percent of responders maximum during rainy
season
Pf can induce response for 10% of villagers during rainy season
High response for salivary glandsHemozoin
Pf ghostSalivary glands
0
10
20
30
40
50
60
70
80
9-19y 20-39y 40-80y
nov jun nov jun nov jun
Per
cent
res
pond
ers
Mosquitoes can trigger basophiles
activation
Pf antigens
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Mosquitos bites induce mast cells activationJI Demeure (2005)
Mosquitos bites induce mast cells activationJI Demeure (2005)
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No difference according to age for
high IgE level
Stability of IgE level« High is high »
Higher percent of Pf-IgE during dry
season
Percent of responders maximum during rainy
season
Pf can induce response for 10% of villagers during rainy season
High response for salivary glands
Mosquitoes can trigger basophiles
activation
IgE responsesIgE responsesBasophiles responsesBasophiles responses
Anti-IgE present“consummed” ?
Players are there !
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Basophyle activation during Cerebral malaria
« Is it a relevant question ??? »
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Area of Dakar
Patients
Severe malaria (SM) cases were recruited at the Int ensive Care Unit (CHNU)
Mild malaria (MM) matched cases were recruited at t he Saint-Martin Dispensary
Healthy matched subjects attending the laboratory for routine examination
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Mild malaria have = lower basal level of CD203c exp ression
Basal level of CD203c expression
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Cerebral malaria = higher reactivity to IgE-indepen dent stimulation
IgE independant activation of basophiles
HZ hemozoin (malaria pigment)
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Severe malaria=
higher reactivity to IgE-dependent
stimulation+
No over-stimulation
A
B
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Basophiles response to anti-IgE in healthy subjects
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Ex vivo priming with Pf- or h-TCTP increases IgE dependant response and induces over stimulation
hTCTP
Pf-TCTPAnti-IgE 1micro/ml
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Basophiles response to anti-IgE in healthy subjects
Modulation by Pf-TCTP
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(horizontal lines represent median for positive individuals only)
ELISA with Pf-specific monoclonal antibodies
Pf-TCTP / anti Pf-TCTP
Cerebral malaria = higher level of Pf-TCTP
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PfTCTP in serum and response to anti-IgE
Stimulation with anti-IgE 0 (PBS), 0.1, 1 or 10 µg/mL
Presence of PfTCTP is associated with higher IgE depe ndant response
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Anti-PfTCTP in serum and response to IgE
Presence of anti-PfTCTP is associated with protection against excessive IgE dependant response
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Summary
Cerebral malaria is associated with higher basophile response to both IgE independent and dependant
response, without overstimulation
rPf-TCTP enhances basophile response during CM and induces overstimulation in healthy subjects
Presence of PfTCTP in serum enhances IgE dependant response; presence of anti-Pf-TCTP decreases this
response.
Allergic response is enhanced during CMRelevant with higher histamine detection
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Histamine and brain endothelial cell interaction« to treat or not to treat »
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Opening the junction Opening the junction
(Vandenbrouke et al 2008)
Histamine
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HistamineNRBC IRBC180
200
220
240
260
280
300
320
340
360
380
400
420
440
Sur
face
(pi
xel)
P < 10-5
P < 10-6
NS
Histamine 100µM
IRBC
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ECIS: Electric Cell-substrate Impedance Sensing
Monitoring of cells monolayer impedance to measure jun ction permMonitoring of cells monolayer impedance to measure jun ction perm eabilityeability
HBEC-D3
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HBEC1.5 h
washingHistamine, TNF
Spreading: 5 days 24 h
IRBC, NRBC
TEERAttachment and spreading of the cells
0
5000
10000
15000
20000
0 20 40 60 80 100
Time (hours)
Res
ista
nce
(ohm
s)
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Histamine or platelet supernatant induce opening of junctions
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
29 29.5 30 30.5 31 31.5 32
stimulationHistamine
Control medium
hours
Resistanceohm
LPS
PLT SN
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
23 28 33 38 43
stimulationMedium change
Histamine
Control medium
hours
Resistanceohm
LPS
PLT SN
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H1 receptor mediates histamine effect on HBECsra
tio a
t T0
-0,35
-0,3
-0,25
-0,2
-0,15
-0,1
-0,05
0
0,05
0,1
1 2 3 4 5 6 7 8 10 11 12 13 14 16 17 18 19 20 21 22 23 24 25
his100-anti_H1
histamine100
TNF
hist100-antiH2
control
Anti H1 inhibits histamine effect on HBEC-D3 monola yer
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Histamine 100 µM
Histamine induce calcium mobilization thru HR1Histamine induce calcium mobilization thru HR1
Histamine 1 µM
-100
0
100
200
300
400
500
0 5 10 15 20 25
Time (min)
Ca
(nM
)
Histamine 10 µM
Histamine
Time (min)
0.6
1.6
2.6
3.6
0 20 40 60Time (min)
Nor
mal
ised
Rat
io
Diphenylhydramine (20µM)
Histamine
Cimetidine (40µM)
0.6
1.6
2.6
3.6
4.6
0 20 40 60 80
Nor
mal
ised
Rat
io Histamine
(Pre-incubation 40 min)
H1
H2
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Histamine increases VCAM but not ICAM expression
0
2
4
6
8
10
12
14
16
18
controlHistamine100Histamine100
+ antiH1H2
Histamine_10 Histamine_1
Per
cent
of p
ositi
ve c
ells
*
Histamine 100µM, 10µM, 1µMCimetidine 20µM, diphenylhydramine 20µM,
*Flow cytometry analysis after trypsinization of the HBEC-D3
Anti H1/H2 inhibits histamine effect on VCAM1 expres sion
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The murine model of CM
Score Observation
0 No discernible clinical signs
1 Hunched posture, slightly
ruffled fur
2 Very ruffled fur, incipient
motor impairment
3 Very ruffled fur, severe
motor impairment such
as ataxia, hemiplegia
and paraplegia,
convulsions, fitting and
the Wooley white sign
(CBA only).
4 Very little movement, cold
to the touch
neurological
phase
cerebral
malaria
0 7 14
Blood collected
Platelet-free plasma
hyperparasitaemia
severe
anaemia
21days
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39.
128.
4237.
246.
5.
DPHCiticoline ControlDay post-PbA
infection
ControlCiticholineDiphenyhydramine (anti-H1)
0 7 140
25
50
75
100
Day post-PbA infection
Per
cent
sur
viva
l
Anti_H1 increases survival of P berghei infected mice
Beghdadi et al 2008
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Conclusion Conclusion
Allergy : 20% of population with high IgE level = st ableSeasonal variation of basophiles activation => Impact of mosquitoes bites on histamine release
Anti-histamine = can improve the treatment of CM ?
Clinical trial
Cerebral malaria is associated with hyper reactivity of basophiles , without auto-regulationPfTCTP enhances / anti-TCTP decrease, this response
Rapid opening of intercellular junction thru H1R Anti-H1 can inhibit this effect
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University SydneyV Combes
A Sanchez PerezF ElassaadMJ Jambou
GE. Grau
IMTSSA- Le PharoS PelleauD Parzy
Institut Pasteur de Dakar
D AldebertS Pelleau
L Marrama F Diène-Sarr
R PaulIbrahima Dia
B Diop JC Moreau
Institut Pasteur (PF5)
F Nato, P Beguin
Institut Pasteur de Madagascar
RomyTsiry
Emma
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Thanks for your attention
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A B C
IFNg IL10 IFN/IL10
Severe malaria = imbalanced pro/anti-inflammatory r esponse
IFNg / IL10 balance
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Histamine release and HRFsHistamine release and HRFs
Human TCTP (IgE-dependent HRF)
-Gene locus 13q12-q14
- induces histamine release by basophiles of atopic p atients
- in vitro : increase reactivity of basophiles to other stimul us (IgE, ..etc)
- induce proliferation of B cells and activation of e osinophiles
Pf TCTP
- 38% identity, 53% similarity with hTCTP
- mimics hTCTP in vitro on histamine release
- 0.1 to 1µg/ml in serum from patients with malaria
- totally conserved in 350 P falciparum field isolate s => target human cells ??
TCTP
- found in all eukaryotes , with two conserved motifs (microtubules binding domain)
- control cells proliferation, division, and apoptose => overexpression in cancer
Induction of idiopathic allergy ?
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Relative quantity
2
1
-5
20
6
60
ICAM-1 VCAM-1IL-1b
IL-6IL-8
TNFb TLR-2
PfTCTP down regulates expresion of TRL2 and Vcam1 in HMEC
8h of stimulation
Moderate direct effect of recombinant PfTCTP on endothelial cells- Vcam and TRL2 repression- no effect on permeability - no effect on microparticules productions
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sequestration
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Severe Malaria
NewbornfeverdehydrationconvulsionMetabolic disorders= impaired consciousness
ChildSevere anaemia +++High parasitaemia +++Cerebral pathology
AdultRespiratory distresscerebral malarialow parasiteamia= delay in treatment
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29
15 17
53
61
54 55
85 82
42
76
3737
47
74
Monde Afrique Asie Amériquelatine/Caraïbes
Régions plusavancées
1950 2000 2030 (projections)
Source : Nations Unies, Perspectives de la population dans le monde, Edition 2003 (scénario moyen), 2004.
From rural to urban: trends of the population From rural to urban: trends of the population
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Major challenge for the next 10 years
Changes of risks Changes in control strategies
Prevalence of malaria in consultations
0
0,05
0,1
0,15
0,2
0,25
0,3
septembre octobre novembre decembre
00,10,20,30,40,50,6
septembre octobre novembre decembre
00,050,1
0,150,2
0,250,3
0,350,4
sept oct nov dec
part of class of age in the malaria cases
prevalence of severe malaria.
0
200
400
600
800
1000
1200
1400
M F M F M F M F M F0-1 an 1- 4ans 5-14 ans 15- 49 ans 50ans &+
consultations by age
0-1 y1- 4 y5-14 y
15- 49 y> 50 y
From children to adults From children to adults
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brain endothelial cells
TNF plays a major role in sequestrationTNF plays a major role in sequestration
Lucas et al., Eur J Immunol 27: 1719, 1997Lou, Lucas & Grau Clin Microbiol Rev 14: 810, 2001
Stoelcker et al., Infect Immun 70: 5857, 2002
monocyte bindingmonocyte bindingmonocyte bindingmonocyte bindingICAMICAMICAMICAM----1 1 1 1 upregulation upregulation upregulation upregulation
platelet bindingplatelet bindingplatelet bindingplatelet binding
memTNF
TNFR2TNFR2
sol or
memLT
PRBC bindingPRBC bindingPRBC bindingPRBC binding
Functional consequence of TNFR2 upregulation (Functional consequence of TNFR2 upregulation ( mouse modelmouse model , PbA infection), PbA infection)