INTERNATIONAL CONFERENCE ON PARADIGM CHANGES in the Management of Early Pregnancy and Pregnancy Loss (PCMEP) London, UK, February 21-24, 2019 Pregnancy Loss: Sporadic and Recurrent APS-Aetiology Angela Tincani Dipartimento di Scienze Cliniche e Speriimentali Universita degli Studi di Brescia U.O. C Reumatologia e Immunologia Clinica Spedali Civili di Brescia
AGENDA Antiphospholipid Syndrome (APS) and antiphospholipid antibodies (aPL) Animal models of Obstetric APS Pathogenesis of obstetric APS
ANTIPHOSPHOLIPID SYNDROME (APS) CLASSIFICATION CRITERIA CLINICAL CRITERIA • Vascular thrombosis (≥ 1 episode) 1 CLINICAL CRITERIA • Pregnancy morbidity: + 1 LABORATORY CRITERIA • ≥ 3 early consecutive miscarriages (<10 w) • ≥ 1 fetal death (> 10 w) • ≥ 1 premature birth (< 34 w) due to pre-eclampsia/eclampsia/placental insufficiency LABORATORY CRITERIA • aCL (IgG/IgM) (med/high titre) DIAGNOSTIC AND • PATHOGENETIC Anti-b2GPI (IgG/IgM) (med/high titre) ROLE! • LAC (at least one, confirmed 12 weeks apart) Myiakis, et al. JTH; 2006
ANTIPHOSPHOLIPID SYNDROME (APS) THE ANTIBODIES Anti- aCL b 2GPI LA
β ₂ GLYCOPROTEIN I: PHYSIOLOGICAL FUNCTIONS β ₂ GPI deficient individuals are It binds to negatively charged I healthy phospholipids such as CL BUT… β ₂ GPI deficient mice do not II Abundantly present in normal display a clear phenotype plasma III Highly conserved among species during evolution PHYSIOLOGICAL FUNCTIONS V + + + + • Natural Anticoagulant • Modified from Miyakis S, Scavenging protein Thromb Res 2004; 114:335-46 Meroni PL, et al. Lupus; 2016
β ₂ GLYCOPROTEIN I β ₂ GPI can be present on the surface of several cells: extravillous trophoblasts syncytiotrophoblasts decidual endothelial cells β ₂ GPI is the main target Ag ➪ β ₂ GPI-dependent aPL are pathogenic
β ₂ GLYCOPROTEIN I: DOMAINS and ANTIBODIES β ₂ GPI is composed of FIVE “DOMAINS”: different subpopulations of anti- β ₂ GPI may carry a different pathogenic potential In pregnant APS patients Anti-D1 antibodies are a I more specific marker for thrombosis and pregnancy II morbidity III Anti-D4/5 antibodies were described in non-thrombotic, V non-autoimmune conditions + + + + Modified from Miyakis S, Thromb Res 2004; 114:335-46 Chighizzola C, et al. J Autoimm; 2017
AGENDA Antiphospholipid Syndrome (APS) and antiphospholipid antibodies (aPL) Animal models of Obstetric APS Pathogenesis of obstetric APS
ANTIPHOSPHOLIPID SYNDROME (APS) THE ANIMAL MODELS Pathogenetic role of aPL in experimental models: no need of a 2° hit Agostinis C, et al. Blood; 2011 Branch, et al. J Obstetr Gynecol; 1990. Blank, et al. PNAS; 1991. Piona, et al. Sc J Immunol; 1995
ANTIPHOSPHOLIPID SYNDROME (APS) THE ANIMAL MODELS PREGNANT MICE: in vivo distribution of cyanine 5.5- labeled β2GPI The uterine signal was localized at the implantation sites, but was undetectable on the fetuses Specific β2GPI signal in the liver & in the uterus Agostinis C, et al. Blood; 2011
ANTIPHOSPHOLIPID SYNDROME (APS) THE ANIMAL MODELS: Passive infusion models for aPL-mediated fetal loss One shot passive infusion of small amounts Repeated passive injection of large amounts of aPL IgG after mating/ before implantation of aPL IgG after implantation Shoenfeld, et al. Eur J Clin Invest; 2001 Meroni PL et al. Nat Rev Rheumatol; 2011 Piona, et al. Sc J Immunol; 1994. Martinez, et al. PNAS; 2007 Holers, et al. J Immunol; 2002. Girardi, et al. JCI; 2003
AGENDA Antiphospholipid Syndrome (APS) and antiphospholipid antibodies (aPL) Animal models of Obstetric APS Pathogenesis of obstetric APS
OBSTETRIC-APS: PATHOGENESIS histopathologic finding in the placentae of aPL-affected human pregnancies PLACENTAL THROMBOSIS DECREASED TROPHBLAST PROLIFERATION AND DIFFERENTATION IMPARIED SPIRAL ARTERY REMODELLING COMPLEMENT DEPOSITION DEDIDUAL INFLAMMATION Viall CA, et al. Autoimmun Rev; 2015
OBSTETRIC-APS: PATHOGENESIS Placental infarction PLACENTAL THROMBOSIS FETAL SIDE MATERNAL SIDE Decidual inflammation DEFECTIVE PLACENTATION Decreased Increased Imparied spiral vasculosyncytial artery remodelling syncytial knots membranes Viall CA, et al. Autoimmun Rev; 2015
OBSTETRIC-APS: PATHOGENESIS 1) THROMBOSIS Possible prothrombotic effects of aPL: • Disruption of Annexin 5 shiel of the trophoblast and endothelial cell monolayers. • Upregulation of Tissue Factor expression. • Interaction with endothelial cells binding to β2GPI ➪ procoagulant and pro-inflammatory endothelial state. • Binding to Ag expressed on platelets ➪ platelet aggregation. • Interference with plasma components of the coagulation cascade inhibiting anticoagulant activity. BUT… Placental thrombosis is NOT the main pathogenic pathway … Rand JH, et al. Blood; 2010. Giannakopoulos B, et al. Blood; 2007. Krone KA, et al. Curr Rheumatol Rep; 2010. Yang, et al. Rheumatology; 2010
OBSTETRIC-APS: PATHOGENESIS 2) INFLAMMATION: CYTOKINES (1) ⇧ IL- 1β and IL -8 • aPL, via TLR-4 and MyD88 , induce trophoblasts to secrete IL- 1β and IL -8 • Downstream of MyD88 is mediated by uric acid which activates NLRP3 inflammasome • Downstream of TLR-4 is mediated by microRNA-146a-3p ⇧ TNF 𝛃 • TNF 𝛃 is a key mediator of strong inflammation in aPL-induced pregnancy loss • link between complement C5a-C5aR activation , pathogenic aPL and fetal damage Fischetti F, et al. Blood; 2005. Pierangeli SS, et al. Ann Rheum Dis; 2007
OBSTETRIC-APS: PATHOGENESIS 2) INFLAMMATION: CYTOKINES (2) ⇩ IL-10 • Related to aPL-induced miscarriages, fetal losses, preterm birth ⇧ IFN 𝛃 • Sensitizing maternal endothelium to the antiangiogenic effects of soluble Flt-1 • Inhibition of transcription of proangiogenic VEGF • Vasculopathic effects of elevated IFNα in active SLE patients Fischetti F, et al. Blood; 2005. Pierangeli SS, et al. Ann Rheum Dis; 2007
OBSTETRIC-APS: PATHOGENESIS 3) COMPLEMENT ACTIVATION • C3 activation is required for aPL-induced fetal loss • C5a key effector: upregulation of tissue factor and neutrophils inflammation • Increased levels of Bb and sC5b-9 , complement activation products, early in pregnancy were significantly associated with adverse pregnancy outcomes (APOs) • Presence of low complement levels during the first trimester is an independent risk factor for fetal loss in patients on conventional treatment (p = 0.02, OR 2.3, CI 95% 1.17 – 9.15) Fredi M, e al Risk Factors for adverse Maternal and Fetal Outcomes in Women With confirmed aPl Positivity: results From a Multicenter study of 283 Pregnancies. Frontiers in Immunology, 2018 . • Protective role of heparin because of anti-complement activity • In mice, prevention of preeclampsia by inhibition of complement activation (animals deficient in complement components or receptors or treated with complment inhibitors) Fischetti F, et al. Blood; 2005. Pierangeli SS, et al. Arthritis Rheum; 2007. Girardi G, et al. J Exp Med; 2006
OBSTETRIC-APS: PATHOGENESIS 3) COMPLEMENT ACTIVATION Complement deposition (C1q, C4d, C3b, C5b-9) was found in placenta tissue from women positive for aPL by immunoproxidase staining PLACENTAL DECIDUA PLACENTAL VILLI Tedesco F, et al. Front Immunol; 2018
OBSTETRIC-APS: PATHOGENESIS 4) DEFECTIVE PLACENTATION MATERNAL SIDE • Inhibition of endometrial angiogenesis both in vitro and in vivo (decreased VEGF) Hypoperfusion and ischemia/reperfusion injury ➪ pregnancy loss, PE, IUGR FETAL SIDE • Inhibition of syncytiotrophoblast differentiation (reduced secretion of hCG) • Impairment of trophoblast invasiveness (inhibition of expression/activity MMPs) • Decrease in trophoblast expression of cadherins and integrins D’Ippolito S, Meroni PL et al, Aut Rev 2014
OBSTETRIC-APS: PATHOGENESIS 4) DEFECTIVE PLACENTATION: aPL EFFECTS ON TROPHOBLASTS • During syncitium formation, phosphatidylserine is expressed in the outer layer of the cell membrane • β 2 GPI is expressed on the cell membrane (perhaps due to binding to phosphatidylserine) • Circulating anti- β 2 GPI antibodies bind β 2 GPI • Antibodies induce cell membrane perturbation INHIBITION OF PROLIFERATION AND INVASIVINESS INDUCTION OF APOPTOSIS Meroni PL et al, Nat Rev 2011
CONCLUSIONS: • Antiphospholipid Antibodies (aPL) are both diagnostic and pathogenetic for APS • Animal models show aPL pathogenic role in fetal loss • Placental thrombosis is not the main pathogenic pathway of obstetric-APS, but different pathways concur: • Decidual inflammation • Imparied spiral artery remodelling • Activation of complement system • Inhibition of proliferation and invasiveness of trophoblasts
Andrea Lojacono Sonia Zatti Francesca Ramazzotto Cristina Zanardini Obstetric Gynecology Mario Motta Neonatal Intensive Care Unit Greeti etings s from om Bres escia cia Rheuma eumato tolog ogy y Unit it
Recommend
More recommend
