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Reproductive Immunology

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.cz. Neuro- hormonal - immu - influences.

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Reproductive Immunology

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  1. ReproductiveImmunology Prof. MUDr. Zdenka Ulcova-Gallova, DrSc. Genetics –Pilsen and Department ofGynecology and Obstetricsof Charles University, Pilsen, Czech Republic www.ulcovagallova.cz Ulcova-Gallova@email.cz

  2. Neuro-hormonal-immu- influences

  3. Screeningforreproductiveimmunology (RI) • Spermantibodies • Zonapellucidaantibodies • Panel of variousantiphospholipidantibodies (eight) • Embryocytotoxiccytokines • Intraacrosomalproteins • Endometrial Ab • Antitrophoblastantibodies • aTSH, aTPO • HLA-I a HLA II • HLA-G • AMH • Inhibin (A, B) • Local CD56+/CD16+ • Detailedimmunological profile according to basic dg.(CD56/CD16)

  4. RI Men Women Both

  5. Immunologicalorigin in unknown/known cause of infertility • Repeatedspontaneousabortionormissedabortion • Repeated IVF failure • Patientswithautoimmuneoroncologicaldiseases • Endometriosis, preeclampsia, PCO, POF, HELLP….. • Andrologicalfactor

  6. Zonapellucidaantibodies Spermantibodies

  7. Anti-spermantibodies (ASA) • History • Incidence in men, women • Methodsofmeasurement • „Treatment“

  8. Richhistoryof ASA • Animals: 1899 by Landsteiner and MetchnikoffMetalnikoff 1932 Baskin Humanstudies: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, comparisonofvarioustestsfordetectionof ASA

  9. Originof ASA in men • Damageofbloodtestis-barrier • Geneticpredisposition HLA A-28, B-22

  10. Originof ASA in women • Ascendent immunisation (but otherwayispossible)

  11. Sperm antibodies inhibit from: • Sperm transport • Bloking ZP penetration • Sperm capacitation • Acrosomal reaction • Early fertilization • Postfertilization effect

  12. Examination • Serum • Semen • OCM • Peritoneal fluid • Folicular fluid

  13. Detectionof free ASA • Gelatinagglutinationtests (GAT-Kibrick) • Tube-SlideAgglutination test • Trayagglutination test (TAT-Friberg) • Sperm-immobilization test(Isojima) • Mixedreaction anti-immunoglobulintests (MAR-test) • Immunobeadtechnique • ELISA (poorcorrelationwith infertility) • RIA

  14. ASA • IgG • IgM • IgA, s IgA • (i IgE)

  15. ASA and significance • Sperm-agglutinating • Sperm-immobilising • Sperm-cytotoxic

  16. Prof. Isojima S. • Publication • Science • AJRI, 1988-2004

  17. Kibrick test Shulman,1985

  18. Capillary test (Fjallebrandt) Shulman,1985

  19. Sperm-agglutination head to head -TAT

  20. Methods • Direct i i-MAR-test (indirectmixedantiimmunoglobulinreaction test forIgG, IgA ( IgM, IgE) /orimmunobead test 49% Ig H-H

  21. OCM • The Miller-Kurzrok Test) • TheSpermCervicalMucusContact Test • Kremer test

  22. Kremertest

  23. Antizonal antibodies (aZP) • Block sperm adherention and sperm penetration into oocyte • Postfertilization effect

  24. Zonapellucida • Animal models (Oikawa, Yanagimachi, Kamada, Mori, Aitken, Hasegawa, Koyama, Isojima, Inoue, Yamasaki, Clark, et al.) • Importanceof ZP • ZP epitopes

  25. ZP • Human ZP X porcine ZP (Sacco, 1977)

  26. AJRI • Ulcova-Gallova Z., Mardesic T.: Does In Vitro Fertilization ( IVF ) Influence theLevelsofSperm and ZonaPellucida ( ZP ) Antibodies in InfertileWomen? Amer. J. Reprod. Immunol. 1996, 36, p.216-219 • Very important!!!

  27. ZP antigens • Porcineoocytes ZP1 –ZP4 epitopes (60 kDa, Hasegawa et al. 1995) Mice –ZP 1- ZP3 Monoclonalantibodies

  28. Koyama, Hasegawa, Mochida, Colongos, 2005-2015 • Inductionoffolliculardysfunction by ZP • E.g. ↑aZP in POF • Et al.

  29. ExaminationofaZPantibodies • Passive haemmagglutination tests • ELISA

  30. Antiphospholipid antibodies Interference with membrane phospholipid 1. Prae-conceptionally 2 .Post-conceptionally

  31. APA (IgG, IgA, IgM) • Ph-L-serine • ph-L-glycerol • ph-L-inositol • ph-ethanolamine -annexin V • ph-acid • cardiolipin • b2-GP

  32. Criteriaof APA sy • -primary • -secondary(withautoimmunedisease) In general: • aPls • Thrombosis (thrombocytopenie?) • Failure in reproduction

  33. For instance • Immuno-histologicaldetection a-annexin V Ab

  34. Červeně: apoptotic.buňky Zeleně: mrtvé buňky

  35. Detectionofintracrosomalenzymes • IF (monoclonalantibodies)

  36. Immunological tolerance • Mother X foetus

  37. Dr. Peter Medawar a prof.MilanHasek

  38. Nidation and implantation

  39. Mother -immunotolerance • Barier of decidua • Blockadeantibodies • Immunotolerance to foetusantigens • Pregnancyspecificproteins (Bohn p.) • HCG, E, P • Anti-idiotypeantibodies • Immunosuppressivecells (spec., non-sp.) • Othermechan.

  40. Foetus -immunotolerance • Throphoblastbariereof placenta • Sialomucinglycocalixlayer • Lowexpressionof MHC • Damping elements:e.g. α FP, PGE, … • C system

  41. Ab -detection • Anti-foetus • Anti-placental • Anti-paternal

  42. Development of a particular immune response which enhances embryo acceptance Recognition by decidual cells Th2 Trophoblast antigens HLA-G? CD46? R80k? CD1? γδTcells? Th2 RESPONSE Th2 • Immunoabsorbent placenta • Trophoblast resistant • to NK cell lysis • Local hormone-dependent immunosuppression FACILITATION REACTION IMMUNOTROPHISM growth, maturation of the placenta Blocking antibodies  BLOCKAGE of cytotoxic reactions ? ΑΝΤΙΓΟΝΑ ΤΡΟΦΟΒΛΑΣΤΗΣ HLA-G; CD46; R80k; CD1; ; «ÔÇ2»

  43. Rh-incompatibility(ery-C,D,E,c,d,e) • Rh negative mother • Rh positive foetus • Treatment: anti D (to 72 hours) • ABO –incomp.veryrare • Keely, Lewinetc.

  44. CAVE! • - foetuserytroblastosis • 1. Anaemianeonatorum • 2. Icterusneonati gravis • 3. Hydrops fetus universalis

  45. 15-20% ofinfertilecouple • Clearimmunological cause of infertility orcombinewithothercauses

  46. FERTILITY and RI • biologicagingofthehypothalamic-pituitary-ovarian axis in elderwomen • →changes in endocrinology, immunity, psychology • Tests in RI withereason

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