- 1. Dr. Indira Devi PonugotiMD,DGO,FICOG,FIAMS,FCGP. MD.DGO ,
Osmania University, Hyderabad - 1965,1969,1970 FICOG 2009
FAMS2010Professor of Obstetrics and Gyneaecology - Osmania Medical
College 1991--1999Kamineni institute of Medical Sciences HOD 2001 -
06Under and post graduate Examiner 1970 - 2010Chair person womens
wing IMA - Hyderabad2007 - 08Vice President OGSH2007President OGSH
2008 - 2009Coordinator APCOG2008 - 09Vice President IMA HYD 2010 -
11Presented papers at national conferencesChaired the sessions at
national and international conferencesContributed to FOGSI focus on
Maternal NutritionLife member IMA ISOPARB OGAAIAORAOPresentlyState
council member IMA HyderabadOrganizing Co- Chair person & Chair
Person Scientific Committee - AICOG 2011Dean Of Faculty CGP-IMA
2011
2. GreetingsFromHyderabad 3. Dr. P. Indira Devi
MD,DGO,FICOG,FIAMS,FCGP. 4. DefinitionDefined as 3 or more clinical
pregnancies lost before the 20th week of gestation from the last
menstrual periodIncidence 1 2% (3 or more losses) 5% (2 or
morelosses) Only 30% pregnancies result in live birthAlbemann,
SalatBarour 1988 5. SignificanceNo. of previouspregnancy Frequency
losses2 24%--30%3 37%----40% 40%4 6.
EtiologyCauseFrequencyAnatomical 10-15% Chromosomal2-5%Endocrinal
17-20% Autoimmune 20%Infections 0.5-5% Unexplained 40-50% 7.
Reproductive ImmunologyPregnancy is Pregnancy associated an
adaptiveThewith B cells form of principle suppressionwith immunity
target forof humeral &immunoinvolves T cells this human cell
recognitionrecognizeresponse globulinof specificantigen mediated
receptors are theimmunologicantigen &
asMHCrecognizeconferspeptidefunction to antigenic
moleculesaccommodat specificity & bound to expressed position
memory MHC e the semi- of intacton donor allogenic effect by T&
cells(allo-molecules B graft- theMHC) fetus*lymphocyts.Many causes
of RPL- maternal transplant rejection*Thellin& Henwm 8. Normal
ImplantationDepends on Diminishedcontrolled This inturn Decidua
isimmunologictrophoblasticdepends onsupposed to al response
ofinvasion ofuterine large be an the pregnantmaternal
granularimmunologic woman mayendometrium- cells-LGLs &allybe a
cause fordecidua &expression of privilegedsurvival ofspiral 3
of HLAtissue site semi alloarterioles*class genes graft * Meffeh
King- 2002 9. Protective mechanisms in pregnancy The primary
cellular 3 response that developsagainst transplanted The proteins
from HLA 1tissue is directed against major histo genes are not
compatability expressed cocomplex(MHC),proteins dominantlyon donor
tissue.*ontrophoblastcell membrane 2In humans MHCunlike other
proteins are humancell types. leukocyte antigens
(HLA)Tilburg.T,Scherjonsa,Reprod immol,2010;85:58 10. Protective
mechanisms inpregnancyStrict regulation of the expression of
HLAclass 1 molecules in sub population oftrophoblast is supposed to
protect thesemi allograft against immune cells which4 are
programmed to attack cells expressingpaternal HLA class 1
antigens.* Trophoblasts contain indoleamine 2,3 5 disoxynase(IDO ,
inhibits tryptophan metabolism) there by inactivates T
cells*362514Lebo tiller P.Mallet V-HLA G& preg-Reprod
1997;2:7Role of HLA G in Human preg Reprd Bio Endo 2006;4
Supp,1:510 11. Expressions and Reactions At Fetomaternal interphase
by placenta & fetal membranes Endocrine system &Under the
immurne system interact influence of sex closely duringsteroids
,dramatic implantation andincrease occurs in maintenance ofunique
population pregnancy.of lymphocytes Recruitment of Role not clear
uterine natural probably, promote killer cells, ( which growth of
placenta, and are derived from trophoblast ,providingperipheral NK
immune modulation cells * *Dysregulation of above expressions
occurs in RPL 12. Immune Response T cellActivated Tinduce
CDrecognitioncells undergocell + T cell is the clonal
mediatedprimary expansion &cytotoxicity,event
ofinfluenceprovide helpantigeninterleukin 2-for B cell
growthantibodyfactor,production,Signal 1 is provided by the
interaction of T cellSignal 2 by a receptor(TCR)receptor provide
help forwith antigen legendmacrophages to present as ainteraction
oninduce delayedpeptide by T cell/APC cell hypersensitivity antigen
presenting surfacecell(APC). 13. Mechanisms Associated with
AlloGraft Rejection Hypothesis Non immunologic Once activated CD4+
Tinjury responses (,induce cells initiatenon specific
inflammation)macrophage mediateddelayed hypersensivity Increased
antigen response & provide help to Bproduction to T cells cells
,for allo antibodyproduction.(by up regulating theexpression of
adhesionmolecules ,Class 11 MHC,Chemokines and cytokines) CD 8
cells induceapoptosis By shedding of intact Jabs WJ etall J .infet
2004;190:1604, Wyburn KR,Jose et,soluble HIA,( which may
all,J.tranplantation,2005;80:164prime the indirect allorecognition
path way.) 14. Alloimmunity and RPLMechanisms - PostulatedImmune
Maternal antimediated and fetal blocking suppressor antibody cell
Sharing of mechanism HLA deficiencyExistence of
immunologicaldifferences among theindividual of the samespecies*
15. OMICS - Studies RPL *Molecular,genomics, These studies possibly
reveal the transcripto genes associated withmics andpathogenesis
witch might occur proteomicsdue to aberrant expression of studies
aregenes and proteins. required tounderstand etiology ofAlso
revealed immune responseRecurrent thrombosis, steroid biopregnancy
synthesis,apoptosis,and angiogenesis loss.related genes*Laird
Smetal 2003.Hum Reprd.update 9,163-174Molecular medicine.vol;13:7
16. Transcriptomic analysis Chromosomally normalchorionic villi
from RPL womenshowed Expression levels of fivegroups of immune
suppression related genesEmbryoOther etiology
relatedattachmentgenes relatedAngiogenesis Apoptosis
relatedrelatedChoi HK et al 2003 Mol Reprd Dev 66,24-31,Back
HH2002.Reprd Fertil dev,14,235-240 ,Lee,J 2005 Fertil Sterl
83,1047-49 17. Proteomic analysis RPL RevealedFollicularaberrant
fluid is Cc3 is expression of identified regulated by C3&
C4thrombophilicwithmembranelevels are factors asdifferentially co
factorfound to fibrinogen expressed protein be high in y&
antiproteins,(MCP) and RPL with 3 thrombinincludingdecaylosess.
which are compliment acceleratingassociatedcomponent factor (DAF)
with RPLC3c. 18. Key mechanisms in RPL 19. Role of cytokines in RPL
When HLA-G expression is down regulated, Th 1 cells are activated
and release cytokines-IFN, TNF-, IL-2 Cytokines inhibit human
placental trophoblast cell growth andmetabolic activity. IFN-
inhibit secretion of (GM-CSF) which promotes growth,
differentiation of trophoblast during normal pregnancy. Ratio of
Th1/Th2 activity is critical for normal pregnancy. Dysregulation of
NK cytotoxicity and cytokine productionmight be involved in
RPL.Expression of natural cytotoxicity receptors (NCRs)- NKp46,
NKp44, NKp30 and A2V-ATPase on CD56 NK cells were up-regulated in
RPL patients. 20. Role of HLA -G in RPL Non classic MHC molecules
Expressed in extravillous cytotrophoblast Invasion of extravillous
cytotrophoblast into the uterus is a vital stage in the
establishment of pregnancy HLA-G polymorphism pregnancy
complications- RPL 21. Possible Immunological Mechanisms Involved
In RPLHLA G molecules of trophoblast cells interact with killer
activator receptor (KAR)of uterine natural killer cells (NK)
Cytokines released from NK cells attacktrophoblast cells. Inter
action of HLA G with killer inhibitory cell ( KIR) has opposite
effect.Th1 cytokines induce cytotoxic activity in uterine NK cells
& cytotoxic T cells.B cells release auto antibodies APA,ANA,ATA
22. Possible Immunological Mechanism Involved In RPLHLA G
moleculesof trophoblast Cytokines releasedcells inter act withfrom
NK cellskiller activator attack trophoblast receptor
(KAR)ofcells.uterine naturalkiller cells (NK)Inter action ofTh1
cytokinesHLA G with killer induce cytotoxic inhibitory cell (
activity in uterineKIR) has oppositeNK cells &effect. cytotoxic
T cells. B cells release auto antibodies APA,ANA,ATA 23. Role of
AngiogenesisExpression levels of Insufficient or
abnormalangiogenesis related gestational angiogenesisgenes
MMP-resulting from aberrant 2,PAI, Integrin, TGF-expression of
angiogenesis, VEGF, FGF were lowerrelated genes lead toin intact
chorionic villi abnormal growth of fetusderived from RPL or
pregnancy loss.patients. 24. Apoptosis Fas ligand (FasL)-Fas
interaction between decidualcells expressing FasL-Fas bearing
leukocytes leads toapoptosis of activated leukocytes down
regulation of production of cytokines TGF- and IL-10 (extravillous
trophoblast invasion) High expression levels of apoptosis
relatedgenes caspase 3,6,7,8,9,10,12,BAD, BAX, BID, FasL, Fas in
women with RPL.Apoptosis genes directly regulate
embryonicdevelopment during normal pregnancy. 25. Regulatory T
Cells (Tregs)*Women with RPL showedlow no. and
functionallydeficient T regs at both thefollicular,and luteal
phases Immunity related genes, those encoding PP14, HCG, mucin 1
were aberrantly expressed in intact chorionic villi from RPL
patients 26. Type 2 T Helper cellsIL-4 a growthfactor for B Th1
tocell T cellTh 2 Type 17 Producantibodye IL- production 3 cytokin
T cells subsee may4,5,10,1 ,alsot express contribu3 andinhibits
Tion iste to help B cell TH17 associa allograft cell maturation
secret ted withrejectiofunctioninto Th1 . pathes IL- allograft n is
not 17 toleranc clear.way(Clearseparasitic infections inmammals)
27. HLA Class 11 Contains genes encoding HLA molecule region
HLA-DR,DQ &DP These are expressed on B cells ,dendrite
&monocytes can be induced during inflammation. Also contain
alpha & B chains on MHC. 28. Genetic predisposition
RPLPredisposition to venous thrombosis -specific single
nucleotidepolymorphism s(SNPs)in theElevation ofhomocysteinvenous
genes coding levels thrombosis & for factor v attributed
toelevation inLeiden& mutation in homocysteinprothrombin- MTHFR
in levels G20210A particular to C677T SNP*Nelen 1998,Lissak 1999,
Finan 2002 Wang 2004, 29. Antiphospholipid Antibodies(2%Auto immune
)Incidence of APA 2%LA, ACl in RPL15-20%Prevent trophoblast
proliferation,cause early fetal loss bycomplement activationCause
thrombosis by interruptingfibrinolysis, inhibits theanticoagulant
pathway, causes LA& aCLAthrombin generationelevated require
plasma protein co factors Interact with placental interphase
resulting in decidual vasculopathy ,deposition of immune complexes
leading to lowered 30. Thrombophilias Pregnancy a hypercoaguable
state Factor VII, VIII & X shifts the thromboxane
&prostacyclin ratio , vasospasm& platelet
aggregationleading to micro thrombi and placental necrosis.
Hypercoaguability is aggravated by thrombophilia RPL Deficiency of
Protein C ,S & anti thrombin III results in Platelet
aggregation, generation of thromboxane, lowered platelet reactivity
to anti aggregating responseof prostacyclin 31. Schematic
representation of the coagulation pathway.The circles depict
theprothrombinconvertasecomplex (FVa + FXa) that drivescoagulation
by convertingprothrombin into thrombin. Thrombin converts
fibrinogento fibrinand this is stabilized by thecrosslinking of
fibrin polymers byFXIII.Thrombin is inactivated byantithrombin III
(ATIII). Blackarrows indicate modification,white arrows indicate
catalyticor modifying effects and the 32. Thyroid Disease & RPL
*Pain less thyroiditis Positive TPO one year afterantibody
ispregnancy loss canassociated with cause immunological high
incidence of changes and RPL.hypothyroidism20% of TPO + will Auto
antibodiesdevelop subclinicalmight causehypothyroidism by term
growth inhibition of if untreated. trophoblast and
thrombosis.*Investigation RPL Fertil,Steril,2005;83:821. 33.
Summary Programming the uterus for semi allo genicpregnancy my
occur with introduction ofsemen* Possible causes for RPL Secondary
immune response due to dysregulation of HlA Expressions , cytokines
andexposed paternal antigens .are the. Lack of immunological
protection to the embryo Lack of appropriate expression of
complimentregulatory proteins , Apoptosis-inducing TNF super family
members,HLA G or HLA E . 34. Summary Extraordinary variation in
upstream regulatory regions of HLA G explains the fetal loss rates
and polymorphism. Polymorphism -725 C/G allele in both partners has
increased the rates of fetal loss. Increased pro inflammatory
cytokines and up regulated thrombophilic tendency a 35. Conclusion
With introduction of OMIC studies RPLetiology has become more
complex thanthought earlier. Functional analysis of genes and or
theirproducts will help to recognize thepregnancy with RPL A
definitive approach to etiologic cal factorand immune modulators
may help. Understanding the agony ,counseling,assurance on future
with sympathy, arenecessary for better out come. 36. The gift of
life is a marvel of divinity, and no words can expressthe awesome
moment of its creation.