IMMUNOLOGI

ABORTUS
dr. Oriza, SpOG
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Definition of RSA (I)

Traditionally, 3 clinical pregnancy losses before 20
weeks from the last menstrual period
- occurs in about 1/300 pregnancies.
Novak 15th ed., WILCOX et al, 1988

Risk of subsequent pregnancy loss

24% after 2 clinical losses
30% after 3 losses
40~50% after 4 losses
Novak 15th ed., Regan et al, 1989

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Risk for subsequent

pregnancy loss
40 -50%

30%

24%

Pregnancy loss risk

More than 4
previous
losses
3 previous
losses
2 previous
losses

50- 60%
70%

76%

Probability of live birth

Regan et al.,your
1989name

 Pemeriksaan klinis dan terapi yang tepat perlu

dilakukan pada pasangan dengan keguguran spontan
2 kali berturut-turut, khususnya jika ada satu dari
beberapa hal berikut:
Aktivitas jantung embrio telah terdeteksi sebelum
terjadi keguguran
Karyotipe normal pada produk konsepsi keguguran
sebelumnya
Usia pasangan wanita lebih dari 35 tahun
Infertilitas

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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%

Ford HB et al. Rev Obstet Gynecol 2009

Infection
Ureaplasma 89.5%

50% of RSA classified as unexplained

Allo-immune etiology?

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Diagnosis & management protocol of RSA

History taking
Routine lab
Genetic evaluation

Karyotyping of
abortus
Parental karyotyping

Genital infection
Cervical culture
Chlamydia
U. Urealyticum
Mycoplasma

Antibiotics

Ultrasonographic scanning / pelvic exam

PGD

Uterine anomaly?

HSG, MRI

Ovulatory dysfunction?

LH/FSH, E2, PRL, TSH, T3/ freeT4

Uterine anomaly (Septated uterus) Normal

Hysteroscopy
or
Laparoscopy
Surgery
Immunologic evaluation

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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Pada aloimmune abortion,

sistem imun ibu bereaksi
terhadap janin dan
menginvasi trofoblast
melalui reaksi penolakan
allogenik

Pada autoimmune abortion,

perkembangan plasenta dan
janin dipengaruhi oleh
autoantibodi ibu dan sel
autoreaktif akan
mempengaruhi jaringan
desisua dan trofoblast

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IMMUNOLOGY OF RECURRENT ABORTIONS

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Medawar & Billingham,

Nature, 1953
Four hypotheses:
The conceptus lacks immunogenicity
Significant lowering of the immune response
during pregnancy
The uterus is an immunoprivileged site
Barier imun oleh plasenta:
Toleransi sistem imun maternal terhadap janin
yang semi-allogenic melalui mekanisme:
Pencegahan jaringan janin dikenali sebagai benda
asing dan/atau ditolak oleh sistem imun maternal.
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Hipotesis yg menjelaskan
toleransi maternal terhadap
janin

Ekspresi HLA/HLA-G oleh trophoblast

Keseimbangan Th1/Th2
Sel T regulator CD4+CD25+
Lainnya

Leukemia inhibitory factor (LIF)

Indoleamine 2,3-dioxygenase (IDO)
Suppressor macrophages
Hormones
CD95 and its ligand
Annexin II
Lowered complement activity
Hidden trophoblast antigens

(Thellin et al, review 2000)

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SUMMARY OF EVENTS IN ENDOMETRIAL RECEPTIVITY

E2 stimulates
Physiological

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

Co-expression with integrin & LIF

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Nardo & Nikas et al and Aghajanova L, Stavreus-Evers et al Fert.Stert
2003

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HLA dan the semiallogenic janin

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Human Leucocyte Antigen (HLA)

Major Histocompatibility Complex
(MHC)
Several classes of HLA genes:
HLA class Ia (classical HLA class I antigens; on almost
all cells)
HLA-A, HLA-B, HLA-C

HLA class Ib (non-classical HLA class I antigens)

HLA-E, HLA-F, HLA-G

HLA class II (expressed on antigen presenting cells, B

cells)
HLA-DR, HLA-DP, HLA-DQ

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The classical HLA class Ia molecules are

highly polymorphic
HLA-A10
HLA-B12
HLA-Cw5

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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The non-classical HLA class Ib molecules

are
nearly monomorphic
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

HLA-G
HLA-E
HLA-F

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Acceptance of the semi-allogenic

fetus
No expression of polymorfic HLA class Ia and II on fetal
trophoblast cells in the placenta
Expression of non-polymorfic HLA class Ib molecules by
trophoblast: HLA-G (and HLA-E and F)
This expression profile may influence the cytokine profile in
favour of maintaining pregnancy

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HLA in pregnancy
Placenta HLA class Ib
HLA-Gm, -Em, -Fm, -Cm
HLA-Gp, -Ep, -Fp, -Cp

Mother HLA class Ia

HLA-Am, -Bm, -Cm
HLA-Am, -Bm, -Cm

Human Leucocyte Antigen (HLA) system

Major Histocompatibility Complex (MHC)

DP

DQ DR

class II

Fetus HLA class Ia

HLA-Am, -Bm, -Cm
HLA-Ap, -Bp, -Cp
m = maternal
p = paternal

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 berperan pada adhesi cellular (dum et al

1991)

2) Invasi trophoblast pada jatingan uterus dan arteri spiralis

HLA-G diekspresikan oleh sel endovascular

trophoblast cells dan kemungkinan berperan sebagai
modulator angiogenesis (Le Bouteiller et al)

3) Trophoblast berinteraksi dengan sel efektor imun maternal

HLA-G berinteraksi dengan receptors sel imun

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HLA and recurrent

miscarriage (RM)
Many studies have focused on a possible increased
sharing of HLA alleles/haplotypes between the mother
and the father(/the fetus) in RM. However, HLA sharing
is a controversial issue and lacks evidence.
Specific HLA-DR alleles are associated with increased
risk of RM
Meta-analysis (18 published/unpublished case-control studies):
HLA-DRB1*01 risk factor (OR 1.3; 95%CI 1.1-1.6)
(Christiansen et al 1999)

HLA-DRB1*03 risk factor in patients with 4 or more

miscarriages and a significantly increasing trend with
increasing number of previous miscarriages (OR 1.4; 95%CI
1.1-1.9)(Kruse et al 2004)
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HLA-G alleles / alternative

splicing
Genomic DNA
-14 bp
HLA-G*010101

+14 bp 3UTR polymorphism

HLA-G*010102

HLA-G*010103

G1 (-92 bp)
G5/G6 (-92 bp)

mRNA isoforms

G2(/G4) (-92 bp)

G1
G2/G4
G3
G5
G6

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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Levels of sHLA-G in maternal blood

(plasma)
Maternal sHLA-G levels do not change substantially during a
normal course of pregnancy
Soluble HLA-G levels of non-pregnant and pregnant women
seems to be very similar
Therefore, a substantial part of the sHLA-G detected in maternal
circulation may be produced by immunocompetent cells of the
mother
Reduced levels of sHLA-G in maternal plasma may be
associated with pre-eclampsia, spontaneous abortion and
placental abruption (sHLA-G < 9.95 ng/ml RR 7.1; 3 trim)
(Steinborn et al 2003)

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Summary
MHC/HLA in reproduction

Mating preferences seem to be

influenced by MHC/HLA diversity

Fertilization
Weak evidence for
MHC/HLA-mediated
effects on
spermatogenesis

Heterozygote advantage
Heterozygotes at the
MHC/ HLA loci may provide a
broader immune response

Early embryo development and implantation

HLA-G expression associated with cleavage
rate and implantation success

Maternal genome Paternal genome

Balance between foetal/paternal and maternal interests?

Some HLA-G/MHC polymorphisms may work in favour of the
foetus, others in favour of maternal interests?

Foetal growth and survival

Some evidence that HLA haplotypes
and HLA-G polymorphism are
associated with birth weight, risk of
abortion and immuneadaptation
Deficiency of MHC/HLA homozygotes in
isolated populations: frequency of MHC
heterozygotes in human populations higher
than expected

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HLA-G expression in the

blastocyst/embryo
Expression of HLA-G mRNA and sHLA-G has been
associated with an increased cleavage rate, as
compared to embryos lacking HLA-G
The pregnancy rate in women who have embryos
transferred from cultures where sHLA-G is detected
is significantly higher than that in women who have
only embryos transferred from sHLA-G negative
cultures

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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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The Th1/Th2 balance

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

Implantation and Th 1 type / Th 2

type
The normal reproductive woman has a strong tendency to
respond to foreign antigens by developing a Th 1 immune
respons high levels of proinflamatory cytokines
During pregnancy there is a decrease in cellular immunity and
enhancement of humoral immunity high levels of antiinflamatory cytokines
The balance between Th1 and Th2 is believed to be crucial for
determining pregnancy outcome
For the continuous normal development of pregnancy Th1
cytokines will be suppressed whereas Th2 cytokines is
enhanced
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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

Tumor Necrosis Factor

Interleukin2
Natural killer Cells

Lymphokine Activated Killer Cells

Abortion of Fetus

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Role of cytokines in RPL

When HLA-G expression is down regulated,

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Allo-cytotoxic T lymphocyte (CTL) response

Augmentation of the
allo-CTL response

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-

RECURRENT MISCARRIAGE AND PREUNCOMPLICATED PREGNANCY

ECLAMPSIA

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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 T cells were that were specific for fetal antigens were

shown to decrease in number during pregnancy
Jiang SP, Vacchio MS. Multiple mechanism of peripheral T cell tolerance to the fetal allograft. J Immunol 1998;160:3086-90

This reversible tolerant state is caused directly by the

induction of apoptosis of maternal activated T cell by
the Fas/Fas ligand (FasL)

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.

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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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On other hand, it has long been know that

certain sites in the body, for example, the
eye, the testes and the brain are immune
privileged".
They are protected from attack by the
immune system. Many factors are
involved in immune privilege, such as
tight junctions between the cells of the
tissue, little expression of class I
histocompatibility molecules, and
expression of FasL.
For instance, the corneal epithelium and
the retina of the eye, Sertoli cells of the
testis and the trophoblast of the placenta
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express FasL.

Natural Killer Cell

Animal studies have suggested a supportive role for NK cells in pregnancy

through production of cytokines that may stimulate placental growth. Uterine
NK cells may have a key role in the immunology of implantation and in the
regulation of decidualization.
Studies in
mice have implicated a role for uterine NK cell-derived IFN- in the
formation and maintenance of the decidua
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Such protection of the trophoblast against NK cell-mediated lysis seems to occur

through the ability of the HLA class I molecules expressed by the trophoblast to
trigger more inhibitory, rather than stimulatory, NK cell signals.
Uterine NK cells express subtypes of killer inhibitory receptors and killer activator
receptors
Expression of these HLA molecules may confer protection against NK cell-mediated
lysis, allowing trophoblastic invasion of the decidua and maintaining cytotoxicity
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against invading pathogens

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

Hunt and co-workers implied that maternal macrophages assist in

the tissue remodeling that is necessary to accommodate expansion
of extraembryonic tissue, however, macrophages are scavengers of
dying cells and also actively orchestrate apoptosis of unwanted cells
during tissue remodeling.
Macrophages synthesize and secrete cytokines and growth factors,
which govern the local cellular and tissue interactions
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Embryo protective
Immunomodulation
- How is this brought
about?
Normal Pregnancy

Progesterone(P) Receptor Activation

Progesterone Induced Blocking Factor(PIBF)

Blocks Cascade Reaction, Shift to Th type 2

Embryo Protective Immunomodulation

Protection of Embryo / Fetus

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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

Szekeres - Bartho J et al. Int Immunopharm

2001;
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1:1037-1048.

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

Szekeres-Bartho J et al. Int Immunopharm 2001;

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1:10371-1048.

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

Raghupathy et al., (2000): Cytokine production by maternal lymphocytes during normal

human pregnancy and in unexplained recurrent spontaneous abortion. Hum. Reprod. 15(3);
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713-18.

Peran Treg dalam

keberhasilan
kehamilan
Regulatory
T-cell (T ) suatu kelompok Treg

cell yang berfungsi untuk menjaga toleransi

terhadap antigen tidak berbahaya dengan
mekanisme inhibisi T-cell Sitotoksik
Beberapa penelitian terbaru mendapatkan
adanya interaksi antara jumlah populasi Treg
dengan keberhasilan implantasi embrio, yaitu

menurunnya jumlah Treg pada kegagalan

kehamilan
peningkatan jumlah Treg pada keberhasilan
implantasi
penurunan Treg kembali pada masa post-partum.
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Peran Treg dalam

keberhasilan
kehamilan

Penelitian pada wanita fertile non pregnant

didapati
Peningkatan jumlah sel Treg pada fase folikuler
akhir uterus siap untuk menerima embrio
sehingga dibutuhkan penurunan respon inflamasi
Diikuti dengan penurunan drastis pada fase
sekresi implantasi suatu proses inflamasi

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Peran Treg dalam

keberhasilan kehamilan
Pada suatu keberhasilan kehamilan, keberadaan Treg
berperan untuk menghambat serangan sistim imun
maternal yang ditujukan pada fetal antiallogen.
Treg berperan menjaga homeostasis immun
Mekanisme inhibisi Treg dijalankan dengan beberapa
cara yaitu dengan:
mensekresi IL-10 dan TGF- limfokin yang berfungsi
sebagai immunosuppressant yang akan menghambat
proliferasi T-cell yang akan menyerang fetus
merangsang sel dendritik untuk menghasilkan IDO yang
mampu melakukan katabolisme tryptophan, sehingga secara
tidak langsung juga mencegah proliferasi T-cell.
interaksi cell-to-cell antara Treg dan T-cell Helper dan T-cell
Sitotoksik sehingga menghambat respon imun terhadap 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

Th17 dapat berubah menjadi Th1, Th2 dan Treg kemungkina

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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)

APA adalah antibodi heterogen yang terdapat pada

sirkulasi darah perifer dan cairan peritoneal
berikatan dengan phospholipids pada membran
platelet membrane serta serum factors lainnya , seperti
Factor III, prothrombin, Factors Xa and V and calcium
Antiphospholipid antibodies (APA) are acquired IgG,
IgM and/or IgA immunoglobins or monoclonal
antibodies directed against negatively charged
phospholipids associated with a slow progressive
thrombosis and infarction in the placenta
APA dapat mempengaruhi kehamilan sejak dari masa
blastocyst/ trophoblast stage sampai persalinan.
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Antiphospholipid
antibodies(APA)

Antigen APA antigens bervariasi berupa PE

phophatidylethanolamine) dan PS (phosphatidylserine)
antigens yang merupakan komponen utama membran
plasma sementara cardiolipin (CL) terbatas ditribusinya
hanya pada inner mitochondrial membrane
APA yang sering dihubungkan dengan kegagalan
kehamilan adalah lupus anticoagulant (LA) and
anticardiolipin (aCL).
aCL akan menyerang CL antigen complexed melalui
plasma protein co-factor, b2-glycoprotein I (b2-GPI)
APA berikatan dengan phospholipids seperti
prothrombin, Factor Xa, protein C or S APA
merupakan campuran antibodi terhadap b2-GPI dan
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phospholipid epitopes

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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Schematic representation of the coagulation pathway .

The circles depict the

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Possible Immunological Mechanisms Involved

In RPL
HLA G molecules of

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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-

Influence, interact with or modulate

Secretion of the specific factor

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Recurrent pregnancy loss

autoimmunity and pregnancy loss

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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Recurrent pregnancy loss

Alloimmunity: pregnancy
as an allograft
Immunosuppression in pregnancy
Role of NK-cells
TH1 vs. TH2 response
HLA-G, Progesterone Blocking Factor
Diagnosis
Embryo toxic factor
Immunophenotype and NK-cell activity
Cytoxicity
HLA
Treatment
IViG
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LIT

Thyroid Disease & RPL

*Painless

*Investigation RPL Fertil,Steril,2005;83:821.

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Role of Angiogenesis

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So what does HLA-G do?

Alloimmune Protection

One function is to decrease or prevent the maternal

alloimmune attack on the fetus' paternally inherited MHC
HLA-G inhibits both the antigen-specific cytotoxic
lymphocyte (CTL) response and decreases NK cell function
Thus, the low variability may be sufficient to present antigen
fragments
In comparison to MHC-I and MHC-II molecules, there has
been little evolutionary pressure for HLA-G to evolve greater
variability because of the limited number of pathogens, and
there has been pressure to not evolve variability, to avoid
maternal autoimmune reactions to the fetus
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So what does HLA-G do?

Autoimmune Protection

Autoimmune reaction occurs when the appropriate

proportion of CD4:CD8 is disrupted (Beer and
Kwak, 1999)
Changes in the proportion of CD4:CD8 inhibit NK
cell adhesion to HLA-G producing an
autoimmune response to the placental
trophoblast and termination of the developing
conceptus (Beer and Kwak, 1999).
Such losses are usually repetitive (Beer and
your name
Kwak, 1999).

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

Maternal immune system

Immunoregulatory
placental factors

Uterine
CSF-1
GM-CSF

Th2-type
respons

Th1-type
respons

PIBF

IFN-, TNF-, IL-2., IL-12

IL-3, IL-4, IL-10

LAK

NORMAL

ABNORMAL

Successful Pregnancy

Pregnancy Lost

NK Cells

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Arthritis and Rheumatism

Volume 40 Number 3 March 1997
Copyright @ 1997 American College of
Rheumatology

Human Polyclonal and Monoclonal Anti beta 2

Glycoprotein I Antibodies React In Vitro With
Endothelial Cells Through Adherent beta 2
Glycoprotein I and Induce Endothelial Activation
Del Papa N, Guidali L, Sala A, Buccellati C, Khamashta MA, Ichikawa K, et al.

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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your name

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

Bick RL. Clin Appl Throm

Hemostat 2000; 63: 115your
-125
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Mechanisme of thrombosis in APS

APS

coagulation

Hypercoagulable
state

Annexin V

endothel

Decreased

Endothelial
Cell activity

platelet

activity

fibrinolysis

fibrinolysis

Thrombosis
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your name

your name

Protective mechanisms in pregnancy

Strict regulation of the expression of HLA class 1 molecules i

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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