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Immunologi Abortus-OZA.pptx

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your name IMMUNOLOGI ABORTUS dr. Oriza, SpOG

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dr. Oriza, SpOGyour nameyour name1Definition 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 loss24% after 2 clinical losses30% after 3 losses40~50% after 4 losses Novak 15th ed., Regan et al, 1989

your name 20 3 300 . 2 24%,3 30%, 4 40-50% . 2Risk for subsequent pregnancy lossPregnancy loss riskProbability of live birth24%30%40 -50%76%70%50- 60%3 previous lossesMore than 4 previous losses2 previous lossesRegan et al., 1989your namePemeriksaan 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 keguguranKaryotipe normal pada produk konsepsi keguguran sebelumnyaUsia pasangan wanita lebih dari 35 tahunInfertilitasyour nameEtiology of RSA

Ford HB et al. Rev Obstet Gynecol 2009UnexplainedGenetic Translocation 60.3%Anatomic Synechia 64.3% Ut. Septum 14.3%Endocrine Hyperthyroidism 71.4%Infection Ureaplasma 89.5%N = 881(2005. 1.1 - 2009. 12. 31)50% of RSA classified as unexplained Allo-immune etiology? your name5Diagnosis & management protocol of RSA History takingUltrasonographic scanning / pelvic examNormalGenetic evaluation Karyotyping of abortus Parental karyotypingImmunologic evaluationRoutine labGenital infection Cervical culture Chlamydia U. Urealyticum MycoplasmaHSG, MRILH/FSH, E2, PRL, TSH, T3/ freeT4Uterine anomaly (Septated uterus)Hysteroscopy orLaparoscopyHormone therapyAllo-immune study NK number (CD 16,56) NK cytolytic activity

Auto-immune study ACA (IgG/IgM) LAC Antithyroid AbPGDAntibioticsSurgeryPrednisolone (PDS)Low molecular weight heparin (LMWH)IVIGUterine anomaly?Ovulatory dysfunction?your namePada autoimmune abortion, perkembangan plasenta dan janin dipengaruhi oleh autoantibodi ibu dan sel autoreaktif akan mempengaruhi jaringan desisua dan trofoblastPada aloimmune abortion, sistem imun ibu bereaksi terhadap janin dan menginvasi trofoblast melalui reaksi penolakan allogenikyour nameIMMUNOLOGY OF RECURRENT ABORTIONS

your nameMedawar & Billingham, Nature, 1953Four hypotheses:The conceptus lacks immunogenicitySignificant lowering of the immune response during pregnancyThe 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.your nameHipotesis yg menjelaskan toleransi maternal terhadap janinEkspresi HLA/HLA-G oleh trophoblastKeseimbangan Th1/Th2Sel T regulator CD4+CD25+ LainnyaLeukemia inhibitory factor (LIF)Indoleamine 2,3-dioxygenase (IDO)Suppressor macrophagesHormonesCD95 and its ligandAnnexin IILowered complement activityHidden trophoblast antigens(Thellin et al, review 2000)your name SUMMARY OF EVENTS IN ENDOMETRIAL RECEPTIVITYPhysiologicalBiochemicalImmunomodulatoryGenetic expression PINOPODESAdhesion MoleculesCytokinesNK cellsHOXA 10Trophinin E2 stimulatesP activates Receptive endometrium Window of implantation ( 7th 9th post ovulation day)your nameImplantation is biomarkers interplay Co-expression with integrin & LIF Nardo & Nikas et al and Aghajanova L, Stavreus-Evers et al Fert.Stert 2003 your name

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your nameHLA dan the semi-allogenic janinyour nameHuman 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-CHLA class Ib(non-classical HLA class I antigens)HLA-E, HLA-F, HLA-GHLA class II(expressed on antigen presenting cells, B cells)HLA-DR, HLA-DP, HLA-DQ

your nameThe classical HLA class Ia molecules are highly polymorphicHLA-A10HLA-B12HLA-Cw5HLA-A26HLA-B8HLA-Cw5HLA-A25HLA-B40HLA-Cw2HLA-A11HLA-B16HLA-Cw8HLA-A23HLA-B12HLA-Cw1HLA-A3HLA-B5HLA-Cw7HLA-A2HLA-B27HLA-Cw6HLA-A24HLA-B8HLA-Cw4HLA-A25HLA-B12HLA-Cw1HLA-A19HLA-B15HLA-Cw2HLA-A19HLA-B14HLA-Cw8HLA-A28HLA-B17HLA-Cw5your nameThe non-classical HLA class Ib molecules are nearly monomorphicHLA-GHLA-EHLA-FHLA-GHLA-EHLA-FHLA-GHLA-EHLA-FHLA-GHLA-EHLA-FHLA-GHLA-EHLA-FHLA-GHLA-EHLA-FHLA-GHLA-EHLA-FHLA-GHLA-EHLA-FHLA-GHLA-EHLA-FHLA-GHLA-EHLA-FHLA-GHLA-EHLA-FHLA-GHLA-EHLA-Fyour nameAcceptance of the semi-allogenic fetusNo expression of polymorfic HLA class Ia and II on fetal trophoblast cells in the placentaExpression 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

your nameHLA in pregnancyHLA-Am, -Bm, -CmHLA-Am, -Bm, -Cmm = maternalp = paternalHLA-Am, -Bm, -CmHLA-Ap, -Bp, -CpHLA-Gm, -Em, -Fm, -CmHLA-Gp, -Ep, -Fp, -CpMother HLA class IaFetus HLA class IaPlacenta HLA class Ib

Human Leucocyte Antigen (HLA) systemMajor Histocompatibility Complex (MHC)Chromosome 6HLA class Ia and II (-A, -B, -C, -DR etc): highly polymorfic

HLA class Ib (-G, -E, -F): nearly monomorphicyour nameThe placentaTidak mengekspresikan HLA-A and HLA-B class I antigen yang polymorphic , hanya mengekspresikan molekul HLA-C, HLA-G and HLA-ELoke dan King membagi trophoblast menjadi :villous trophoblast yg berkontak dengan darah maternal pada ruang intervillous class I negativeextravillous trophoblast menginvasi desidua uterus class I positiveyour name

your nameFungsi HLA-G Kemungkinan peran HLA-G pada proses implantatsi:

1) Saat melekatnya blastokist ke endometriumHLA-G berperan pada adhesi cellular (dum et al 1991)

2) Invasi trophoblast pada jatingan uterus dan arteri spiralisHLA-G diekspresikan oleh sel endovascular trophoblast cells dan kemungkinan berperan sebagai modulator angiogenesis (Le Bouteiller et al)

3) Trophoblast berinteraksi dengan sel efektor imun maternalHLA-G berinteraksi dengan receptors sel imunyour nameHLA 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 RMMeta-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)

your nameHLA-G alleles / alternative splicing

(Hviid et al 2003, Rousseau et al 2003)your name25So it seems that the presence of the 14 bp sequence in exon 8 generates a novel splice mRNA variant with 92 bp of exon 8 spliced out. This is especially observed in the G*01013 allele but also in the G*01012 allele.

Levels of sHLA-G in maternal blood (plasma)Maternal sHLA-G levels do not change substantially during a normal course of pregnancySoluble HLA-G levels of non-pregnant and pregnant women seems to be very similarTherefore, 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)your name

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SummaryMHC/HLA in reproductionyour name28HLA-G expression in the blastocyst/embryoExpression 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

your nameSecreted 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 SystemWhat are Cytokines ? your name30 The Th1/Th2 balance

Successful pregnancy more often correlated with a Th2-type response than Th1

However, the Th1/Th2 concept may be too simplistic

HLA-G/sHLA-G???your nameImplantation and Th 1 type / Th 2 typeThe 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 anti-inflamatory 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 your nameImmune reaction during pregnancyFetus withPaternalantigensT helper 1cell responseAbortion ofThe FetusT helper 2cell responseProtection of The Fetusyour nameEmbryo / FetusT helper 1 cell response activatedTumor Necrosis Factor Interleukin2Natural killer CellsLymphokine Activated Killer CellsAbortion of FetusCascade Reactionyour nameRole of cytokines in RPLyour nameresponder T cellT cellreceptorstimulator cellHLA-DR4HLA-DR4HLA-DR1HLA-GInhibition of allo-CTL response

IL-10 TNF- INF- Allo-cytotoxic T lymphocyte (CTL) responseHLA-GAugmentation of theallo-CTL response

IL-10 TNF- INF- UNCOMPLICATED PREGNANCYRECURRENT MISCARRIAGE AND PRE-ECLAMPSIA Upregulation of the Th1 response,downregulation of Th2: IL-2 INF- (TNF-)(Kapasi et al 2000)Th2 cytokine production:IL-4IL-5IL-10IL-13

your name36Based on in vitro studies by Kapasi and others it can be speculated that high expression of HLA-G during pregnancy may influence the cytokine expression in a direction which is observed during uncomplicated pregnanices (that is a Th2 profile) and an inhibition of the allo-CTL response while low HLA-G expression may be connected with a Th1 cytokine profile which can be seen in pre-eclampsia and certain cases of recurrent spontaneous abortion.

Local Immune suppressionIs 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

your nameT cells were that were specific for fetal antigens were shown to decrease in number during pregnancyJiang 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.

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.your nameApoptosisyour nameCritical process during placental development and differentiation and for maintaining tissue homeostasis 39

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 express FasL.

your nameNatural 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 your name

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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 receptorsExpression of these HLA molecules may confer protection against NK cell-mediated lysis, allowing trophoblastic invasion of the decidua and maintaining cytotoxicity against invading pathogens your nameDecidual NK cellsDecidual 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.

your nameMacrophage

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 your nameEmbryo protective Immunomodulation- How is this brought about?Normal PregnancyProgesterone(P) Receptor Activation Blocks Cascade Reaction, Shift to Th type 2Embryo Protective ImmunomodulationProtection of Embryo / Fetus Progesterone Induced Blocking Factor(PIBF)your nameProgesteronePIBFTh2Normally Progressing PregnancyProgesterone-induced Blocking Factor (PIBF) Link between the Endocrine and Immune SystemProgesteronePIBFTh1MiscarriageRu 486ProgesteronePIBF+anti-PIBFTh1Miscarriage Szekeres - Bartho J et al. Int Immunopharm 2001; 1:1037-1048.your name48Szekeres-Bartho J, Barakonyi A, Par G, Polgar B, Palkovics T, Szereday L. Progesterone as an immunomodulatory molecule. Int Immunopharmacol. 2001 Jun;1(6):1037-48.

Increased progesterone sensitivity of pregnancy lymphocytes is due to activation-induced appearance of progesterone binding sites in the lymphocytes. Following recognition of fetally derived antigens gamma/delta TCR+ cells develop progesterone receptors. Progesterone binding results in the synthesis of a mediator protein named the progesterone-induced blocking factor (PIBF). PIBF by acting on the phospholipase A2 enzyme interferes with arachidonic acid metabolism, induces a Th2 biased immune response, and by controlling NK activity exerts an anti-abortive effect.

P-receptors in Pregnancy LymphocytesTrophoblastActivation/PR+P PP PPIBF+ Szekeres-Bartho J et al. Int Immunopharm 2001; 1:10371-1048./ Natural Killer Cell Activity

Th2 / Th1 +Normally Progressing Pregnancyyour name49The P-receptors on the pregnancy lymphocytes, CD56+ cells and PBMC, are not regulated by steroids but are rather up-regulated by immune mechanisms. After trophoblastic invasion into the endometrium, the pregnancy lymphocytes are activated by exposure to fetal antigens. This leads to an up-regulation of P-receptors. Once the P-receptors are activated by progesterone, PIBF is produced. This leads to at Th2 dominance and decrease the NKcells which gives an anti-abortive effect.Szekeres-Bartho J, Barakonyi A, Par G, Polgar B, Palkovics T, Szereday L. Progesterone as an immunomodulatory molecule. Int Immunopharmacol. 2001 Jun;1(6):1037-48. Increased progesterone sensitivity of pregnancy lymphocytes is due to activation-induced appearance of progesterone binding sites in the lymphocytes. Following recognition of fetally derived antigens gamma/delta TCR+ cells develop progesterone receptors. Progesterone binding results in the synthesis of a mediator protein named the progesterone-induced blocking factor (PIBF). PIBF by acting on the phospholipase A2 enzyme interferes with arachidonic acid metabolism, induces a Th2 biased immune response, and by controlling NK activity exerts an anti-abortive effect.

Embryo Protective Immunomodulation What is it? Raghupathy et al., (2000): Cytokine production by maternal lymphocytes during normal human pregnancy and in unexplained recurrent spontaneous abortion. Hum. Reprod. 15(3); 713-18. 3 Positive responsesT helper 2 cell responseNK Activity Asymmetric Antibodies No binding with AntigenNo activation of Complement CascadeProtection of FetusProtective CytokinesIL 3IL 4IL 5IL 6IL 10IL 13

your name50Peran Treg dalam keberhasilan kehamilanRegulatory T-cell (Treg) suatu kelompok T-cell yang berfungsi untuk menjaga toleransi terhadap antigen tidak berbahaya dengan mekanisme inhibisi T-cell SitotoksikBeberapa penelitian terbaru mendapatkan adanya interaksi antara jumlah populasi Treg dengan keberhasilan implantasi embrio, yaitu menurunnya jumlah Treg pada kegagalan kehamilanpeningkatan jumlah Treg pada keberhasilan implantasipenurunan Treg kembali pada masa post-partum.

51your namePeran Treg dalam keberhasilan kehamilanPenelitian pada wanita fertile non pregnant didapati Peningkatan jumlah sel Treg pada fase folikuler akhir uterus siap untuk menerima embrio sehingga dibutuhkan penurunan respon inflamasiDiikuti dengan penurunan drastis pada fase sekresi implantasi suatu proses inflamasiyour namePeran Treg dalam keberhasilan kehamilanPada suatu keberhasilan kehamilan, keberadaan Treg berperan untuk menghambat serangan sistim imun maternal yang ditujukan pada fetal antiallogen.Treg berperan menjaga homeostasis immunMekanisme inhibisi Treg dijalankan dengan beberapa cara yaitu dengan:mensekresi IL-10 dan TGF-b1 limfokin yang berfungsi sebagai immunosuppressant yang akan menghambat proliferasi T-cell yang akan menyerang fetusmerangsang 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.

53your nameT 17 Cellsyour nameT 17 Cellsyour nameAutoimmuneSystemic 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 menginduksi abortusyour name

your nameAntiphospholipid 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.

your nameAntiphospholipid 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 membraneAPA 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 phospholipid epitopes

your nameAntiphospholipid syndrome An Autoimmune disorder having specific clinical & lab criteria. Sapporo criteria Diagnosis requires at least one of each. CLINICAL 1) Thrombolic events-arterial,venous,small vessel 2)Pregnancy loss- 3 losses at