Placental Protein 13 and Decidual Zones of Necrosis: An Immunologic Diversion That May be Linked to Preeclampsia


We evaluated the role of placental protein 13 (PP13; galectin 13) in the process of trophoblast invasion and decidual necrosis. Immunohistochemical analysis for PP13, immune cells, human placental lactogen, cytokeratin, and apoptosis markers was performed on 20 elective pregnancy termination specimens between 6 and 15 weeks of gestation. Placental protein 13 was localized to syncytiotrophoblasts in the chorionic villi and to occasional multinucleated luminal trophoblasts within converted decidual spiral arterioles. Cytotrophoblasts, anchoring trophoblasts, and invasive trophoblasts did not stain for PP13. Extracellular PP13 aggregates were found around decidual veins associated with T-cell-, neutrophil- and macrophage-containing decidual zones of necrosis (ZONEs). We hypothesize that PP13 is secreted into the intervillus space, drains through the decidua basalis veins, and forms perivenous PP13 aggregates which attract and activate maternal immune cells. Thus, syncytiotrophoblast-derived PP13 may create a ZONE that facilitates trophoblast invasion and conversion of the maternal spiral arterioles.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 510

This is the net price. Taxes to be calculated in checkout.


  1. 1.

    Pijnenborg R, Vercruysse L, Hanssens M. Fetal-maternal conflict, trophoblast invasion, preeclampsia, and the red queen. Hypertens. 2008;27(2):183–196.

  2. 2.

    Cudihy D, Lee RV. The pathophysiology of pre-eclampsia: current clinical concepts. J Obstet Gynaecol. 2009;29(7):576–582.

  3. 3.

    Than NG, Sumegi B, Than GN, Berente Z, Bohn H. Isolation and sequence analysis of a cDNA encoding human placental tissue protein 13 (PP13), a new lysophospholipase, homologue of human eosinophil Charcot-Leyden Crystal protein. Placenta. 1999;20(8):703–710.

  4. 4.

    Than NG, Pick E, Bellyei S, et al. Functional analyses of placental protein 13/galectin-13. Eur J Biochem. 2004;271(6):1065–1078.

  5. 5.

    Burger O, Pick E, Zwickel J, et al. Placental protein 13 (PP-13): effects on cultured trophoblasts, and its detection in human body fluids in normal and pathological pregnancies. Placenta. 2004; 25(7):608–622.

  6. 6.

    Chafetz I, Kuhnreich I, Sammar M, et al. First-trimester placental protein 13 screening for preeclampsia and intrauterine growth restriction. Am J Obstet Gynecol. 2007;197(1):35.e31–e37.

  7. 7.

    Gonen R, Shahar R, Grimpel YI, et al. Placental protein 13 as an early marker for pre-eclampsia: a prospective longitudinal study. BJOG. 2008;115(12):1465–1472.

  8. 8.

    Romero R, Kusanovic JP, Than NG, et al. First-trimester maternal serum PP13 in the risk assessment for preeclampsia. Am J Obstet Gynecol. 2008;199(2):122.e1–122.e11.

  9. 9.

    Khalil A, Cowans NJ, Spencer K, Goichman S, Meiri H, Harrington K. First trimester maternal serum placental protein 13 for the prediction of pre-eclampsia in women with a priori high risk. Prenat Diagn. 2009;29(8):781–789.

  10. 10.

    Than NG, Romero R, Goodman M, et al. A primate subfamily of galectins expressed at the maternal-fetal interface that promote immune cell death. Proc Natl Acad Sci U S A. 2009;106(24): 9731–9736.

  11. 11.

    Sekizawa A, Purwosunu Y, Yoshimura S, et al. PP13 mRNA expression in trophoblasts from preeclamptic placentas. Reprod Sci. 2009;16(4):408–413.

  12. 12.

    Balogh A, Pozsgay J, Matko J, et al. Placental protein 13 (PP13/galectin-13) undergoes lipid raft-associated subcellular redistribution in the syncytiotrophoblast in preterm preeclampsia and HELLP syndrome. Am J Obstet Gynecol. 2011;205(2):156.e1–e14.

  13. 13.

    Rabinovich GA, Toscano MA. Turning ‘sweet’ on immunity: galectin-glycan interactions in immune tolerance and inflammation. Nat Rev Cancer. 2009;9(5):338–352.

  14. 14.

    Liu FT, Rabinovich GA. Galectins: regulators of acute and chronic inflammation. Ann N Y Acad Sci. 2010;1183(2):158–182.

  15. 15.

    Boronkai A, Bellyei S, Szigeti A, et al. Potentiation of paclitaxel-induced apoptosis by galectin-13 overexpression via activation of Ask-1-p38-MAP kinase and JNK/SAPK pathways and suppression of Akt and ERK1/2 activation in U-937 human macrophage cells. Eur J Cell Biol. 2009;88(12):753–763.

  16. 16.

    Yagel S. The developmental role of natural killer cells at the fetal-maternal interface. Am J Obstet Gynecol. 2009;201(4): 344–350.

  17. 17.

    DeSilva JM. A shift toward birthing relatively large infants early in human evolution. Proc Nati Acad Sci U S A. 2011;108(3): 1022–1027.

  18. 18.

    Haig D. Genetic conflicts in human pregnancy. Q Rev Biol. 1993; 68(4):495–532.

  19. 19.

    Linder S, Havelka AM, Ueno T, Shoshan MC. Determining tumor apoptosis and necrosis in patient serum using cytokeratin 18 as a biomarker. Cancer Lett. 2004;214(1):1–9.

  20. 20.

    Protheroe C, Woodruff SA, de Petris G, et al. A novel histologic scoring system to evaluate mucosal biopsies from patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2009;7(7):749–755.e711.

  21. 21.

    Kliman HJ, Feinberg RF, Schwartz LB, Feinman MA, Lavi E, Meaddough EL. A mucin-link glycoprotein identified by MAG (mouse ascites golgi) antibodies. Am J Pathol. 1995;146(1): 166–181.

  22. 22.

    Werwitzke S, Tiede A, Drescher BE, Schmidt RE, Witte T. CD8beta/CD28 expression defines functionally distinct populations of peripheral blood T lymphocytes. Clin Exp Immunol. 2003;133(3):334–343.

  23. 23.

    Rojo JM, Bello R, Portoles P. T-cell receptor. Adv Exp Med Biol. 2008;640:1–11.

  24. 24.

    Hanna J, Goldman-Wohl D, Hamani Y, et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med. 2006;12(9):1065–1074.

  25. 25.

    Le Priol Y, Puthier D, Lecureuil C, et al. High cytotoxic and specific migratory potencies of senescent CD8+ CD57+ cells in HIV-infected and uninfected individuals. J Immunol. 2006; 177(8):5145–5154.

  26. 26.

    Jacobsen EA, Taranova AG, Lee NA, Lee JJ. Eosinophils: singularly destructive effector cells or purveyors of immunoregulation? J Allergy Clin Immunol. 2007;119(6):1313–1320.

  27. 27.

    Vesentini S, Soncini M, Fiore GB, Redaelli A. Mechanisms of polymyxin B endotoxin removal from extracorporeal blood flow: molecular interactions. Contrib Nephrol. 2010;167:45–54.

  28. 28.

    Fox H, Herd ME, Harilal KR. Morphological changes in the placenta and decidua after induction of abortion by extra-amniotic prostaglandin. Histopathology. 1978;2(2):145–151.

  29. 29.

    McCombs HL, Craig JM. Decidual Necrosis in Normal Pregnancy. Obstet Gynecol. 1964;24(3):436–442.

  30. 30.

    Gray CA, Dunlap KA, Burghardt RC, Spencer TE. Galectin-15 in ovine uteroplacental tissues. Reproduction. 2005;130(2):231–240.

  31. 31.

    Weller PF, Goetzl EJ, Austen KF. Identification of human eosinophil lysophospholipase as the constituent of Charcot-Leyden crystals. Proc Natl Acad Sci U S A. 1980;77(12):7440–7443.

  32. 32.

    Ackerman SJ, Corrette SE, Rosenberg HF, et al. Molecular cloning and characterization of human eosinophil Charcot-Leyden crystal protein (lysophospholipase). Similarities to IgE binding proteins and the S-type animal lectin superfamily. J Immunol. 1993;150(2):456–468.

  33. 33.

    Pantanowitz L, Balogh K. Charcot-Leyden crystals: pathology and diagnostic utility. Ear Nose Throat J. 2004;83(7):489–490.

  34. 34.

    Dunphy JL, Barcham GJ, Bischof RJ, Young AR, Nash A, Meeusen EN. Isolation and characterization of a novel eosinophil-specific galectin released into the lungs in response to allergen challenge. J Biol Chem. 2002;277(17):14916–14924.

  35. 35.

    Yang QS, Ying K, Yuan HL, et al. Cloning and expression of a novel human galectin cDNA, predominantly expressed in placenta(1). Biochim Biophys Acta. 2002;1574(3):407–411.

  36. 36.

    Than NG, Kim SS, Abbas A, et al. Chorioamnionitis and increased galectin-1 expression in PPROM–an anti-inflammatory response in the fetal membranes? Am J Reprod Immunol. 2008;60(4):298–311.

  37. 37.

    Than NG, Romero R, Erez O, et al. Emergence of hormonal and redox regulation of galectin-1 in placental mammals: implication in maternal-fetal immune tolerance. Proc Natl Acad Sci U S A. 2008;105(41):15819–15824.

  38. 38.

    McDonald B, Pittman K, Menezes GB, et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science. 2010;330(6002):362–366.

  39. 39.

    Formigli L, Papucci L, Tani A, et al. Aponecrosis: morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis. J Cell Physiol. 2000;182(1):41–49.

  40. 40.

    Zeiss CJ. The apoptosis-necrosis continuum: insights from genetically altered mice. Vet Pathol. 2003;40(5):481–495.

  41. 41.

    Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: mechanisms and significance. Annu Rev Physiol. 2010;72:19–44.

  42. 42.

    McCarthy JV. Apoptosis and development. Essays Biochem. 2003;39:11–24.

  43. 43.

    Anversa P, Kajstura J, Leri A, Bolli R. Life and death of cardiac stem cells: a paradigm shift in cardiac biology. Circulation. 2006; 113(11):1451–1463.

  44. 44.

    Graham A, Koentges G, Lumsden A. Neural crest apoptosis and the establishment of craniofacial pattern: an honorable death. Mol Cell Neurosci. 1996;8(2–3):76–83.

  45. 45.

    Rieder C, Bajer AS. Heat-induced reversible hexagonal packing of spindle microtubules. J Cell Biol. 1977;74(3):717–725.

  46. 46.

    Sun M, Liu Y, Gibb W. Distribution of annexin I and II in term human fetal membranes, decidua and placenta. Placenta. 1996; 17(2–3):181–184.

  47. 47.

    Calafat J, Janssen H, Knol EF, Weller PF, Egesten A. Ultrastructural localization of Charcot-Leyden crystal protein in human eosinophils and basophils. Eur J Haematol. 1997;58(1):56–66.

  48. 48.

    Lewis SK, Farmer JL, Burghardt RC, et al. Galectin 15 (LGALS15): a gene uniquely expressed in the uteri of sheep and goats that functions in trophoblast attachment. Biol Reprod. 2007; 77(6):1027–1036.

  49. 49.

    Kliman HJ, Nestler JE, Sermasi E, Sanger JM, Strauss JF. Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology. 1986;118(4): 1567–1582.

  50. 50..

    Kliman HJ. Trophoblast to Human Placenta. Encyclopedia of Reproduction. San Diego, CA: Academic Press; 1999:834–846.

  51. 51.

    Orendi K, Gauster M, Moser G, Meiri H, Huppertz B. Effects of vitamins C and E, acetylsalicylic acid and heparin on fusion, beta-hCG and PP13 expression in BeWo cells. Placenta. 2010;31(5): 431–438.

  52. 52.

    Kao LC, Wu S, Strauss JF, Caltabiano S, Kliman HJ. The human villous cytotrophoblast-interactions with extracellular-matrix proteins, endocrine function, and cytoplasmic differentiation in the absence of syncytium formation. Dev Biol. 1988;130(2): 693–702.

  53. 53.

    Orendi K, Gauster M, Moser G, Meiri H, Huppertz B. The choriocarcinoma cell line BeWo: syncytial fusion and expression of syncytium-specific proteins. Reproduction. 2010; 140(5):759–766.

  54. 54.

    Wang JL, Gray RM, Haudek KC, Patterson RJ. Nucleocytoplasmic lectins. Biochim Biophys Acta. 2004;1673(1–2):75–93.

  55. 55.

    Nakahara S, Hogan V, Inohara H, Raz A. Importin-mediated nuclear translocation of galectin-3. J Biol Chem. 2006;281(51): 39649–39659.

  56. 56.

    Khalil A, Cowans NJ, Spencer K, Goichman S, Meiri H, Harrington K. First trimester markers for the prediction of pre-eclampsia in women with a priori high risk. Ultrasound Obstet Gynecol. 2010;35(6):671–679.

  57. 57.

    Grimpel YI, Kivity V, Cohen A, et al. Effects of calcium, magnesium, low-dose aspirin and low-molecular-weight heparin on the release of PP13 from placental explants. Placenta. 2011;32(suppl):S55–S64.

  58. 58.

    Wortelboer EJ, Koster MP, Kuc S, et al. Longitudinal trends in feto-placental biochemical markers, uterine artery Doppler flow velocities and maternal blood pressure during the first-trimester of pregnancy. Ultrasound Obstet Gynecol. 2011;38(4):383–388.

  59. 59.

    Zhou CC, Zhang Y, Irani RA, et al. Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice. Nat Med. 2008;14(8):855–862.

  60. 60.

    Gebhardt S, Bruiners N, Hillermann R. A novel exonic variant (221delT) in the LGALS13 gene encoding placental protein 13 (PP13) is associated with preterm labour in a low risk population. J Reprod Immunol. 2009;82(2):166–173.

  61. 61.

    Antczak DF, Allen WR. Maternal immunological recognition of pregnancy in equids. J Reprod Fertil Suppl. 1989;37:69–78.

  62. 62.

    Flaminio MJ, Antczak DF. Inhibition of lymphocyte proliferation and activation: a mechanism used by equine invasive trophoblast to escape the maternal immune response. Placenta. 2005; 26(2–3):148–159.

  63. 63.

    Adams AP, Antczak DF. Ectopic transplantation of equine invasive trophoblast. Biol Reprod. 2001;64(3):753–763.

  64. 64.

    Huber MJ, Roser JF, Riebold TW, Schmotzer WB, Grubb TL, Crisman RO. Effect of surgical removal of endometrial cups on concentrations of chorionic gonadotrophin and subsequent fertility in the mare. Equine Vet J. 1993;25(2):110–114.

  65. 65.

    Enders AC, Meadows S, Stewart F, Allen WR. Failure of endometrial cup development in the donkey-in-horse model of equine abortion. J Anat. 1996;188(pt 3):575–589.

  66. 66.

    Enders AC, King BF. Early stages of trophoblastic invasion of the maternal vascular system during implantation in the macaque and baboon. Am J Anat. 1991;192(4):329–346.

  67. 67.

    Enders AC. Trophoblast differentiation during the transition from trophoblastic plate to lacunar stage of implantation in the rhesus monkey and human. Am J Anat. 1989;186(1):85–98.

  68. 68.

    Haig D, Graham C. Genomic imprinting and the strange case of the insulin-like growth factor II receptor. Cell. 1991;64(6):1045–1046.

Download references

Author information

Correspondence to Harvey J. Kliman MD, PhD.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kliman, H.J., Sammar, M., Grimpel, Y.I. et al. Placental Protein 13 and Decidual Zones of Necrosis: An Immunologic Diversion That May be Linked to Preeclampsia. Reprod. Sci. 19, 16–30 (2012) doi:10.1177/1933719111424445

Download citation


  • PP13
  • galectin 13
  • trophoblast
  • preeclampsia
  • pregnancy
  • placenta
  • necrosis