Immunology Prof MUDr Zdenka Ulcova Gallova DrSc Genetics Pilsen and Department of Gynecology and Obstetrics of Charles University Pilsen Czech Republic wwwulcovagallovacz ID: 544841
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Slide1
Reproductive Immunology
Prof. MUDr. Zdenka
Ulcova
-Gallova, DrSc.
Genetics
–
Pilsen
and Department
of
Gynecology
and
Obstetrics
of
Charles University,
Pilsen
, Czech Republic
www.ulcovagallova.cz
Ulcova
-Gallova
@email.czSlide2Slide3
Screening for reproductive
immunology
(RI)
Sperm
antibodies
Zona
pellucida
antibodies
Panel of
various
antiphospholipid
antibodies
(
eight
)
Embryocytotoxic
cytokines
Intraacrosomal
proteins
Endometrial
Ab
Antitrophoblast
antibodies
aTSH
,
aTPO
HLA-I a HLA II
HLA-G
AMH
Inhibin
(A, B)
Local
CD56+/CD16+
Detailed
immunological
profile
according
to basic dg.(CD56/CD16)Slide4
RI
Men
Women
BothSlide5
Immunological origin in unknown
/
known
cause
of
infertility
Repeated
spontaneous
abortion
or
missed
abortion
Repeated
IVF
failure
Patients
with
autoimmune
or
oncological
diseases
Endometri
osis
,
preeclampsia
, PCO
, POF,
HELLP…..
Andrological
factorSlide6
Zona
pellucida
antibodies
Sperm
antibodiesSlide7
Anti-sperm antibodies (ASA)
History
Incidence in
men
,
women
Methods
of
measurement
„
Treatment
“Slide8
Rich history of ASA
Animals
: 1899 by
Landsteiner
and
Metchnikoff
Metalnikoff
1932
Baskin
Human
studies:Rumke
1954, Bronson, Shulman (1991), Dondero, Hendry, Fjallbrandt, Hjort,
Isojima
,
Mori
,
Koyama
,Kutteh
,
Moghissi
,
Nakov
,
Bratanov
,
Lenzi
,
Mathur
,
Ingerslev
,
Clark,Mettler
,
Ulcova
-Gallova (1985),
Bohring
,
etc
.
Multicentric
study -1994-2010,
comparison
of
various
tests
for
detection
of
ASASlide9
Origin of ASA in men
Damage
of
blood
testis-barrier
Genetic
predisposition
HLA A-28, B-22Slide10
Origin of ASA in women
Ascendent
immunisation
(but
other
way
is
possible
)Slide11
Sperm antibodies inhibit from:
Sperm transport
Bloking
ZP
penetration
Sperm capacitation
Acrosomal
reaction
E
arly
fertilization
P
ostfertilization effectSlide12
ExaminationSerum
Semen
OCM
Peritoneal
fluid
Folicular
fluidSlide13
Detection of free ASA
Gelatin
agglutination
tests
(GAT-
Kibrick
)
Tube-
Slide
Agglutination testTray
agglutination test (TAT-Friberg)Sperm-immobilization test(Isojima)Mixed reaction anti-
immunoglobulin
tests
(MAR-test)
Immunobead
technique
ELISA (
poor
correlation
with
infertility)
RIASlide14
ASA
IgG
IgM
IgA
, s
IgA
(i
IgE
)Slide15
ASA and significance
Sperm-agglutinating
Sperm-immobilising
Sperm-cytotoxicSlide16
Prof. Isojima S.
Publication
Science
AJRI, 1988-2004Slide17
Kibrick test
Shulman,1985Slide18
Capillary test (Fjallebrandt)
Shulman,1985Slide19
Sperm-agglutination head to head -TATSlide20
Direct /indirect MAR testor
immunobead
testSlide21
OCMThe
Miller-
Kurzrok
Test
)
The
Sperm
Cervical
Mucus
Contact TestKremer
test Slide22
Kremer test
Slide23
Antizonal antibodies (aZP
)
Block sperm
adherention
and sperm penetration into oocyte
Postfertilization
effectSlide24
Zona pellucida
Animal
models
(
Oikawa
,
Yanagimachi
,
Kamada
,
Mori
,
Aitken, Hasegawa,
Koyama, Isojima, Inoue, Yamasaki, Clark, et al.) Importance of
ZP
ZP
epitopesSlide25
ZPHuman
ZP X
porcine
ZP
(
Sacco
, 1977) Slide26
AJRIUlcova
-Gallova Z.,
Mardesic
T.:
Does
In Vitro
Fertilization
( IVF ) Influence
the
Levels
of Sperm
and Zona Pellucida ( ZP ) Antibodies in Infertile Women? Amer
. J.
Reprod
.
Immunol
. 1996, 36, p.216-219
Very
important
!!!Slide27
ZP antigens
Porcine
oocytes
ZP1 –
ZP4
epitopes
(60
kDa
,
Hasegawa
et al. 1995)
Mice –ZP 1- ZP3
Monoclonal antibodiesSlide28Slide29
Koyama, Hasegawa, Mochida
,
Colongos
, 2005-2015
Induction
of
follicular
dysfunction
by ZP
E.g
. ↑aZP in POFEt al.Slide30
Examination
of
aZP
antibodies
Passive haemmagglutination tests
ELISASlide31Slide32Slide33
Antiphospholipid antibodies
Interference with membrane phospholipid
1.
Prae-conceptionally
2 .Post-
conceptionallySlide34
APA (IgG, IgA, IgM)
Ph
-L-serine
ph
-L-glycerol
ph
-L-inositol
ph
-ethanolamine
-
annexin
V
ph
-acidcardiolipinb2-GPSlide35
Criteria of APA sy
- are not
sufficiant
for
infertility
In
general
:
aPls
Thrombosis
(
thrombocytopenie
?)Failure in reproductionSlide36
For instanceSlide37
Analysis of 2965 infertile women(
Ulcova
-Gallova et
al.AJRI
,
2005 Aug;54(2):112-7
.)
P
<
0,001Slide38
For instance
Immuno-histological
detection
a-
annexin
V AbSlide39
Červeně:
apoptotic.buňky
Zeleně: mrtvé buňkySlide40
Detection of intracrosomal
enzymes
IF (
monoclonal
antibodies
)Slide41Slide42
Immunological tolerance
Mother
X
foetusSlide43
Dr. Peter Medawar
a
prof.Milan
HasekSlide44
Nidation and implantationSlide45
Mother -immunotolerance
Barier
of
decidua
Blockade
antibodies
Immunotolerance
to
foetus
antigens
Pregnancy
specific proteins (Bohn p.)HCG, E, P Anti-
idiotype
antibodies
Immunosuppressive
cells
(
spec
., non-
sp
.)
Other
mechan
.Slide46
Foetus -immunotolerance
Throphoblast
bariere
of
placenta
Sialomucinglycocalix
layer
Low
expression
of MHCDamping elements:e.g. α FP, PGE, …C systemSlide47
Ab -detection
Anti-
foetus
Anti-
placental
Anti-
paternalSlide48
ΑΝΤΙΓΟΝΑ ΤΡΟΦΟΒΛΑΣΤΗΣ
HLA-G; CD46; R80k; CD1;
;
«ÔÇ
2
»
Recognition
by decidual cells
Trophoblast antigens
HLA-G? CD46? R80k? CD1?
γδ
Tcells?
FACILITATION
REACTION
IMMUNOTROPHISM
growth, maturation
of the placenta
Blocking
antibodies
BLOCKAGE
of cytotoxic reactions
Immunoabsorbent placenta
Trophoblast resistant
to NK cell lysis
Local hormone-dependent immunosuppression
Th2
Th2
Th2 RESPONSE
?
Development of a particular immune response which enhances embryo acceptanceSlide49
Rh-incompatibility (
ery-C,
D
,E,c,d,e
)
Rh
negative
mother
Rh
positive
foetus
Treatment
: anti D (to 72
hours)ABO –incomp.very rareKeely
,
Lewin
etc
.Slide50
CAVE!-
foetus
erytroblastosis
1.
Anaemia
neonatorum
2.
Icterus
neonati
gravis
3. Hydrops fetus
universalisSlide51
15-20% of infertile couple
Clear
immunological
cause
of
infertility
or
combine
with
other
causes Slide52
FERTILITY and RI
biologic
aging
of
the
hypothalamic-pituitary-ovarian
axis in
elder
women→changes
in endocrinology, immunity, psychologyTests in RI
withe
reasonSlide53
Immunological screening for
reproductive
failure
Sperm
antibodies
Zona
pellucida
antibodies
Panel of various antiphospholipid antibodies (
eight
)
Embryocytotoxic
cytokines
Intraacrosomal
proteins
Endometrial
Ab
Inhibin
(A, B)
Antitrophoblast
antibodies
aTSH
,
aTPO
HLA-I a HLA II
HLA-G
AMH
Local
CD56+/CD16+
Detailed
immunological
profile
according
to basic dg.(CD56/CD16)Slide54
Other future in RI
Antigens
of
Sperm
, ZP, beta HCG
etc
. -
contraceptive
vaccine
Ways, means
of influencing of fertility