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ABORTUS
dr. Oriza, SpOG
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30%
24%
More than 4
previous
losses
3 previous
losses
2 previous
losses
50- 60%
70%
76%
Regan et al.,your
1989name
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Etiology of RSA
Genetic
Translocation 60.3%
9%
Unexplained
55%
14%
N = 881
(2005. 1.1 - 2009. 12. 31)
14%
5%
4%
Anatomic
Synechia
64.3%
Ut. Septum
14.3%
Autoimmune
ATA
83.3%
APA
16.3%
Endocrine
Hyperthyroidism 71.4%
Infection
Ureaplasma 89.5%
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Karyotyping of
abortus
Parental karyotyping
Genital infection
Cervical culture
Chlamydia
U. Urealyticum
Mycoplasma
Antibiotics
Uterine anomaly?
HSG, MRI
Ovulatory dysfunction?
Allo-immune study
NK number (CD
16,56)
NK cytolytic activity
Hormone therapy
Prednisolone (PDS)
Low molecular weight heparin (LMWH)
IVIG
Auto-immune study
ACA (IgG/IgM)
LAC
Antithyroid Ab
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Hipotesis yg menjelaskan
toleransi maternal terhadap
janin
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PINOPODES
Biochemical
Adhesion
Molecules
P activates
Immuno
modulatory
Cytokines
NK cells
Genetic
expression
HOXA 10
Trophinin
Receptive endometrium
Window of implantation ( 7th 9th post ovulationyour
day)name
Implantation is biomarkers
Apposition
interplay
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HLA-A3
HLA-B5
HLA-Cw7
HLA-A23
HLA-B12
HLA-Cw1
HLA-A11
HLA-B16
HLA-Cw8
HLA-A25
HLA-B40
HLA-Cw2
HLA-A26
HLA-B8
HLA-Cw5
HLA-A2
HLA-B27
HLA-Cw6
HLA-A28
HLA-B17
HLA-Cw5
HLA-A19
HLA-B14
HLA-Cw8
HLA-A19
HLA-B15
HLA-Cw2
HLA-A25
HLA-B12
HLA-Cw1
HLA-A24
HLA-B8
HLA-Cw4
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HLA-G
HLA-E
HLA-F
HLA-G
HLA-E
HLA-F
HLA-G
HLA-E
HLA-F
HLA-G
HLA-E
HLA-F
HLA-G
HLA-E
HLA-F
HLA-G
HLA-E
HLA-F
HLA-G
HLA-E
HLA-F
HLA-G
HLA-E
HLA-F
HLA-G
HLA-E
HLA-F
HLA-G
HLA-E
HLA-F
HLA-G
HLA-E
HLA-F
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HLA in pregnancy
Placenta HLA class Ib
HLA-Gm, -Em, -Fm, -Cm
HLA-Gp, -Ep, -Fp, -Cp
DP
DQ DR
class II
B C
class III
A G F
class I
Chromosome
6
HLA class Ia and II (-A, -B, -C, -DR etc): highly polymorfic
HLA class Ib (-G, -E, -F): nearly monomorphic
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The placenta
Tidak mengekspresikan HLA-A and HLA-B class I
antigen yang polymorphic , hanya mengekspresikan
molekul HLA-C, HLA-G and HLA-E
Loke dan King membagi trophoblast menjadi :
villous trophoblast yg berkontak dengan darah maternal
pada ruang intervillous class I negative
extravillous trophoblast menginvasi desidua uterus
class I positive
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Fungsi HLA-G
Kemungkinan peran HLA-G pada proses implantatsi:
1) Saat melekatnya blastokist ke endometrium
HLA-G*010103
G1 (-92 bp)
G5/G6 (-92 bp)
mRNA isoforms
G1 (+14 bp)
G2/G4 (+14 bp)
G3 (+14 bp)
G5 (+14 bp)
G6 (+14 bp)
G1 (+14 bp)
G2/G4 (+14 bp)
G3 (+14 bp)
G5 (+14 bp)
G6 (+14 bp)
(Hviid et al 2003, Rousseau et al 2003)
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Summary
MHC/HLA in reproduction
Fertilization
Weak evidence for
MHC/HLA-mediated
effects on
spermatogenesis
Heterozygote advantage
Heterozygotes at the
MHC/ HLA loci may provide a
broader immune response
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What are
Cytokines ?
Secreted molecules that regulate the intensity and
duration of the immune response by exerting a variety of
effects on lymphocytes and other immune cells
Cytokines are the messengers of the Immune System
just as
Hormones are the messengers of the Endocrine System
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HLA-G/sHLA-G???
Successful pregnancy more often correlated with a Th2type response than Th1
However, the Th1/Th2 concept may be too simplisticyour name
Immune reaction
during pregnancy
Fetus with
Paternal
antigens
T helper 1
cell response
T helper 2
cell response
Abortion of
The Fetus
Protection of
The Fetus
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Embryo / Fetus
T helper 1 cell response activated
Cascade
Reaction
Abortion of Fetus
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stimulator cell
T cell
receptor
HLADR4
IL-10
TNF-
INF-
responder T cell
HLADR1
Inhibition of
allo-CTL response
HLADR4
HLA-G
(Kapasi et al 2000)
HLA-G
IL-10
TNF-
INF-
Upregulation of the
Th1 response,
downregulation of
Th2:
IL-2
INF-
(TNF-)
Th2 cytokine
production:
IL-4
IL-5
IL-10
IL-13
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Local Immune
suppression
Is there any specific paternal antigen suppressor or
regulatory mechanism ???
Evidence has shown that specific immuno
suppression is directed toward the paternally
encoded MHC antigens
It seems that the mothers T cell assume a
reversible tolerant state during pregnancy in which
the the cells no longer recognize paternal antigens
Tafuri A, Alferink J, Moller P, Hammerling J, Arnold B. T cell awareness of
paternal alloantigens during pregnancy. Science 1995;270:630-3
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Mor G, Gutierrez L, Eliza M, Kahyaoglu F, Arici A. Fas-Fas ligand system induced apoptosis in human placenta and gestational trophoblastic disease. Am J Reprod Immunol 1998;40:89-95.
Bamberger A, Schulte H, Thuneke I, Erdmann I, Bamberger C, Asa S. Expression of the apoptosis-inducing Fas ligand (FasL) in human first and third trimester placenta and choriocarcinoma cells. J Clin Endocrinol Metab
1997;82:3173-5.
your name
Rogers AM, Boime I, Connolly J, Cook JR, Russell JH. Maternal-fetal tolerance is maintained despite transgene-driven trophoblast expression of MHC class I, and defects in Fas and its ligand. Eur J Immunol 1998;28:3479-87.
Huppertz B, Frank HG, Kingdom JC, Reister F, Kaufmann P. Villous cytotrophoblast regulation of the syncytial apoptotic cascade in the human placenta. Histochem Cell Biol 1998;110:495-508.
Apoptosis
High expression
Fas
Apoptosis
genes levels
directly
ofregulate
apoptosis
embryonic
related genes
development during normal pregnancy.
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Decidual NK cells
Decidual NK Cells appear to be
mainly involved in alloimmune
abortion.
Under influence of Th1 cytokines
they damage the trophoblasts.
Patients who abort have increased
NK cell activity and NK cells of
CD3,CD 56,CD 16 types.
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Macrophage
Embryo protective
Immunomodulation
- How is this brought
about?
Normal Pregnancy
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Progesterone-induced
Blocking Factor (PIBF) Link
between the Endocrine and
Immune System
Progesterone
Th2
PIBF
Normally
Progressing
Pregnancy
Progesterone
PIBF
Th1
PIBF
+anti-PIBF
Th1
Miscarriage
Ru 486
Progesterone
Miscarriage
P-receptors in Pregnancy
Lymphocytes
Trophoblast
t
Ac
PIBF
n
io
at
iv
/
PR+
P
P
P
P
Normally
Progressing
Pregnancy
Th2 / Th1
+
Natural
Killer
Cell Activity
Embryo Protective
Immunomodulation What is it?
3 Positive
responses
T helper 2 cell
response
Protective
Cytokines
IL 3
IL 4
IL 5
IL 6
IL 10
IL 13
NK Activity
Asymmetric
Antibodies
No binding with
Antigen
No activation of
Complement Cascade
Protection of Fetus
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T 17 Cells
Wanita dengan RSA didapati jumlah sel Th17 yang lebih ting
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T 17 Cells
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Autoimmune
Systemic Lupus Erythmatosus (SLE)
mengakibatkan risiko abortus 20%
terutama pada 2nd and 3rd trimester kehamilan
dan dihubungkan juga dengan antiphospholipid
antibodies.
Antiphospholipid syndrome (APA)
5 - 15 % of wanita dengan RSA memiliki APA
APA tampaknya menginduksi microthrombus
pada lokasi perlekatan plasenta
mengganggu vaskularitas mempengaruhi
perkembangan embrio menginduksiyour name
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Antiphospholipid
antibodies(APA)
Antiphospholipid
antibodies(APA)
Antiphospholipid syndrome
An Autoimmune disorder having
specific clinical & lab criteria. Sapporo
criteria
Diagnosis requires at least one of
each.
CLINICAL
1) Thrombolic eventsarterial,venous,small vessel
2)Pregnancy loss- 3 losses at <10wks
gestation, fetal death after
10wks,premature birth at <34wks
associated with severe preeclampsiayour
orname
Antiphospholipid antibodi
Antiphospholipid antibodi (APA)
awal implantasi
Rx. membran fosfolipid
Mikrotrombus a.spiralis.
Antibodi di pembuluh darah desidua
kerusakan plasenta RPL
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Antiphospholipid Antibodies
(2%Auto immune )
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Summary
Possible causes for RPL
Secondary immune response due to dysregulation of
HLA Expressions , cytokines and exposed paternal
antigens
Lack of immunological protection to the embryo
Lack of appropriate expression of compliment
regulatory proteins
Apoptosis-inducing TNF super family
members, HLA G or HLA E
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IMMUNOLOGIC FACTORS
Autoimmune
Alloimmune
(directed to self)
(directed to
foreign
tissues/cells)
-Systemic Lupus Erythmatosus
An abnormal
maternal
-Antiphospholipid Syndrome
response to
immune
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Thank you.
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Functions of HLA-G
Several in vitro studies have shown that HLA-G and
HLA-E protect against Natural Killer-mediated cell lysis
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Functions of HLA-G
Suppression of allo-reactive
cytotoxic T cells
Mixed Lymphocyte Reaction (MLR) CD4+ responder
stimulator cell
responder T cell
T cell
receptor
HLADR4
HLADR4
T cell
Secretion of
soluble HLA-G5
HLADR1
inhibitory receptor
(ILT-2, p49 ?)
HLA-G1
K562
Inhibition of T cell
allo-proliferation
(Lila et al
PNAS 2001;
98:12150)
(Carosella et al. Immunol Today 1999; 20:60 / Riteau et al. J Reprod Immunol 1999; 43:203)
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Maternal NK cell
KIR2DL4
CD94/NKG2
ILT-2/(-4)*)
sHLA-G
HLA-E
HLA-C
Maternal monocyte/
macrophage/lymphocyte
IL-10
HLA-G1
HLA-F (?)
Trophoblast cell
FETUS
Cell lysis
HLA-G
(influenced by
HLA-G genotype)
HLA-G
Inhibition of
allo-CTL
response ?
IL-10 ??
TNF-
INF-
TGF-1
VEGF
Augmentation of
allo-CTL response ?
IL-10 ??
TNF-
INF-
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Diagnosis
Antiphospholipid antibody syndrome ACL, APS, API, APE
Anti Nuclear Antibodies ANA
Anti Thyroid Antibodies ATA
Treatment
Heparin and baby aspirin
Prednisone
IViG
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Role of Angiogenesis
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Thrombophilias
Pregnancy a hypercoaguable state
Factor VII, VIII & X shifts the thromboxane &
prostacyclin ratio , vasospasm& platelet aggregation
leading to micro thrombi and placental necrosis.
Deficiency of Protein C ,S & anti thrombin III results in
Platelet aggregation, generation of thromboxane,
lowered platelet reactivity to anti aggregating response
of prostacyclin
Hypercoaguability is aggravated by thrombophilia
RPL
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FETO-PLACENTAL
TISSUES
INJURY
Uterine
CSF-1
GM-CSF
Th2-type
respons
Th1-type
respons
PIBF
LAK
NORMAL
ABNORMAL
Successful Pregnancy
Pregnancy Lost
NK Cells
your name
Anti beta2 GPI antibodies bind and activate through the adherent cofactor beta2 GPI,
likely leading to a procoagulant state. Autoimmune aPL in contrast with infective
aPL, require certain phospholipid binding proteins, such as beta2 GPI
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Recurrent miscarriage
syndrome
and infertility
Antiphospholipid
& Pregnancy
caused by blood coagulation protein or platelet
defects Antiphospholipid isotypes
ACA IgG only
ACA IgM only
ACA IgA only
ACA IgG+IgM
ACA IgG+IgA
ACA IgA+IgM
LA only
ACA + LA
Antiphosphatidylserine
Antiphosphatidylinositol
Antiphosphatididic acid
Antiphosphatidylethanolamine
Antiphosphatidylcholine
Antiphosphatidylglycerol
B2-GPI
Hexagonal phospholipid
37.6
30.7
6.9
5.0
1.0
0.0
2.0
2.0
4.0
2.0
5.0
5.0
6.9
1.0
0.0
0.0
coagulation
Hypercoagulable
state
Annexin V
endothel
Decreased
Endothelial
Cell activity
platelet
activity
fibrinolysis
fibrinolysis
Thrombosis
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5
*362514Lebo tiller P.Mallet V-HLA G& preg-Reprod 1997;2:7
Role of HLA G in Human preg Reprd Bio Endo 2006;4 Supp,1:510
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