hiv – fiv - lcmv immune system + viruses tricks of pers. v: t deletion / escape nab delay / escape...
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HIV – FIV - LCMV
• Immune system + viruses• Tricks of pers. V:
T deletion / escapenAb delay / escape
• Re-encountered / persistent antigen maintains nAb (successful vaccines) and act. T (infection immunity: no vaccine) for protection
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LC
MV
blo
od t
iter
(lo
g10
pfu
)
0 50 100 150 200
1
2
3
4
5
67
S7S8
S1S2
S3
S5S6
Tim e dependence of LCM V-virem ia: long-term contro l or escape
LC
MV
blo
od
tite
r (l
og1
0 p
fu)
0 50 100 150 200
1
2
3
4
5
67
S7S8
S1S2
S3
S5S6
LCMV-viremia control or nAb escape
Ciurea, Hunziker et al.
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• Prevent penetration IgA• systemic neutr.-opson.IgM/G• adoptive transferable IgG• IgM 1-2d, regulated by
Ag-dose and structure(no negative selection)
• Control-elim. intracell parasites also in solid organs
• regulate longterm IgG• cause imunopathology
(negative selection)
T
BAb
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glycoprotein: LCMV-GP glycoprotein:IND-G
rLCMV/INDG rVSV/LCMV-GP
reverse genetic glycoprotein exchange between LCMV and VSVPinschewer, de la Torre et al.
LCMV VSV-IND
glycoprotein: LCMV-GPglycoprotein:IND-G
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Only VSVG expressing viruses induce a neutralizing antibody response
3 8 14 20
642
108
12
<1
time after infection (days)
642
108
12
<13 8 14 20
time after infection (days)
VSV-IND neutralization rLCMV/INDG neutralization
3 8 14 20time after infection (days)
642
108
12
<1
rVSV/LCMV-GP neutralization
3 8 14 20time after infection (days)
642
108
12
<1
LCMV-ARM neutralization
2x104 PFU rLCMV/INDG i.v.
2x104 PFU VSV-IND i.v.
2x104 PFU LCMV i.v.
2x104 PFU rVSV/LCMV-GP i.v.
2x107 PFU rVSV/LCMV-GP i.v.
total Ig IgG
LCMV HIS
WEN-3 mAb
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Neutralising Ab: GP structure
early: TH independent IgM, germlinehigh affinity / avidity
late: immunosuppression ?affinity maturation?
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0 10 20 30 40 50 600
5
10
15
20controlanti CD8
CD8 -/-
time after infection (days)
Seru
m Im
mun
glob
ulin
s(%
of t
otal
ser
um p
rote
ins)
Hypergammaglobulinemia Neutralising antibodies
0 10 20 30 40 50 60
<1
anti CD8control
1
2
3
4
5
6
CD8 -/-
time after infection (days)
Neu
tralis
ing
titer
(log
2) X
10
0 10 20 30 40 50 60
<1
WEWE anti CD4 (1 :100)
1
2
3
4
5
6
7
8
time after infection (days)
Neu
tralis
ing
titer
(log
2) X
10
Neutralising antibodies
Hypergammaglobulinemia vs. neutralizing antibodies
Recher, Lang, Hunziker 2004
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Conclusion:
• Many nAb "specificities" control V, if "one" too slow/low: V-escape!
• Hypergammaglobulinemia and polyclonal B cell activation compete with nAb responses and seem to depend upon amount of virus-specific CD4T cells.
• Mechanisms of B cell competition? (Cytokine receptor competition? Anatomic competition in germinal centers? Competition for anti-apoptotic cytokines?).
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Why autoimmune disease inhumans mostly via antibodies?
Why >> !Why all vaccines that function protect via neutr. antibodies?
First infection kills host:no memory needed
Host survives first infection:memory not necessary
Memory vs. Protection
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No protection by Memory B cells but protection by immune serum in
IFN-aBR_/_ against VSV
VSVIND immunespleen cells T+B
LCMV immunespleen cells
VSVIND Ab
Anti-VSVneutr. AB
< 1 : 40
< 1 : 40
< 1 : 2500
% Survivors
0
0
100
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Maintenance of protection
1. Agent persists: TB, leprosy, HIV, HCV, LCMV
Herpes viruses
crippled: measles?
2. Repetitive inf.: polio, bact. toxins
3. Antibody-antigen complex depots in lymph
nodes and spleens
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persistent virusfrom mother
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Poliomyelitis – age distribution in Massachusetts 1912 – 1952
Years Percent0 – 4 years
Percent5 – 9 years
Percent10+ years
1912-1916 70 18 121930-1934 28 38 341948-1952 18 27 55
Modified from: Nathanson,N. Am J Epidemiol 1979; 110:672-692.
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Memory / Pregnant Female
• Academic: earlier + higher (AG –)• Immune against cytopathic infections
otherwise abortions / malformations• MHC-incompatibility – offspring / mother• Maternal antibodies attenuate acute infections
physiological vaccinations (incl. malaria, eggs)• Non-cytophatic infections transferred via placenta / at
birth / after birth (LCMV, HCV, Herpes)• Resistance via T cells: HIV, HTV, TB Lepr. slow• "Emerging" infections
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Conclusions:
Persistent infections numbers / variability
• T cell control – immunopathology – "tolerance"
• nAb essential (affinity maturation?) or escape
• antigen maintains nAb titers and act. T cells (but immunopathology!)
• All successful vaccines: nAbnot successful: should (also) maintainact.T (not achieved yet)
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H. Hengartner
E. Battegay
F. Ciurea
L. Hunziker
M. Recher
U. Steinhoff
B. Odermatt
Th. Leist
K. Lang
L. Pinschewer
J. de la Torre
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IMMUNITY
• “innate resistance“ > 95 %
• Ab in eggs
• protective memory via Ab (vaccines)
• TB: no vaccine
• autoimmunity > 30 y, female > male5 : 1