• Obstetric pathology due to humoral rejection 
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Obstetric pathology due to humoral rejection 

HEALTH OF WOMAN. 2016.4(110):71–78; doi 10.15574/HW.2016.110.71 

Obstetric pathology due to humoral rejection 

Veropotvelyan Р. N., Veropotvelyan N. P., Tsehmistrenko I. S., Zhuravleva S. A.

The «Inter-provincial center of medical genetics and prenatal diagnosis», Krivoy Rog

Perinatal center, Kiev

In this study was included data of foreign articles and clinical protocols – violation leads to the development of pregnancy pathology, is characterized by the activation of cellular and humoral immune system with the development of clinical manifestations of varying degrees of severity of rejection. The publications expressed the idea of parallels between acute graft rejection, and rejection of the fetus in spontaneous abortion and, in addition, between exclusion and pre-eclampsia.

The cellular mechanisms of rejection of allogeneic transplant or semiallogenic are more studied than humoral in the present period of time. Demonstrated that all types of rejection are with the involvement of different nature antibodies.

Key words: pregnancy, humoral rejection, alloantibodies, autoantibodies, anti-HLA-antibodies, blood group alloantibodies to antigens, embryonic antibodies, agonist antibodies, antiendothelial antibodies.


1. King A, Boocock C, Sharkey AM, Gardner L, Beretta A, Siccardi AG et al. 1996. Evidence for the expression of HLA-C class I mRNA and protein by human first trimester trophoblast. J. Immunol. 156(6):2068–76.

2. Meroni P, Ronda N, Raschi E, Borghi MO. 2005. Humoral autoimmunity against endothelium: theory or reality? Trends Immunol. 25(5):275–81.

3. Jordan SC, Yap HK, Sakai RS, Alfonso P, Fitchman M. 1988. Hyperacute allograft rejection mediated by anti-vascular endothelial cell antibodies with a negative monocyte crossmatch. Transplantation 46(4):585–87. http://dx.doi.org/10.1097/00007890-198810000-00024; PMid:3051566

4. Rose ML. 2004. Role of MHC and non-MHC alloantibodies in graft rejection. Curr. Opin. Organ Transplant. 9:16–22. http://dx.doi.org/10.1097/00075200-200403000-00005

5. Sun Q, Liu Z, Chen J, Chen H, Wen J, Cheng D et al. 2008. Circulating anti-endothelial cell antibodies are associated with poor outcome in renal allograft recipients with acute rejection. Clin. J. Am. Soc. Nephrol. 3(5):1479–86.

6. Sun Q, Cheng Z, Cheng D, Chen J, Ji S, Wen J et al. 2011. De novo development of circulating anti-endothelial cell antibodies rather than pre-existing antibodies is associated with post-transplant allograft rejection. Kidney Int. 79(6):655–62. http://dx.doi.org/10.1038/ki.2010.437; PMid:20980975

7. Yamamoto T, Geshi Y, Kuno S, Kase N, Mori H. 1998. Anti-endothelial cell antibody in preeclampsia: clinical findings and serum cytotoxicity to endothelial cell. Nihon Rinsho Meneki Gakkai Kaishi. 21(5):191–7. http://dx.doi.org/10.2177/jsci.21.191; PMid:11155591

8. Roussev RG, Stern JJ, Kaider BD. 1998. Anti-endothelial cell antibodies: another cause for pregnancy loss? Am. J. Reprod. Immunol. 39(2):89–95.

9. Savage COS. 1994. Endothelial cell antibodies: pathogenetic or epiphenomenon? Nephrol. Dial. Transplant. 9(10):1362–3.

10. Sun Q, Liu Z, Chen J, Chen H, Wen J, Cheng D et al. 2008. Circulating anti-endothelial cell antibodies are associated with poor outcome in renal allograft recipients with acute rejection. Clin. J. Am. Soc. Nephrol. 3(5):1479–86.

11. Ziganshina MM, Pavlovich SV, Bovin NV, Suhih GT. 2013. Gumoralnoe ottorzhenie v geneze akusherskoy patologii. Zhurnal Akusherstvo i ginekologiya 6:3-10.

12. Praprotnik S, Blank M, Levy Y, Tavor S, Boffa MC, Weksler B et al. 2001. Anti-endothelial cell antibodies from patients with thrombotic thrombocytopenic purpura specifically activate small vessel endothelial cells. Int. Immunol. 13(2):203–10.

13. Cogert GA, Subherwal S, Wu G et al. 2003. Incidence of non-cellular (humoral) rejection unchanged in the 1990 decade despite a decrease in cellular rejection. J. Heart Lung Transplant. 22:119–142. http://dx.doi.org/10.1016/S1053-2498(02)00837-9

14. Laresgoiti-Servitje E, Gomez-Lopez N, Olson DM. 2010. An immunological insight into the origins of pre-eclampsia. Hum. Reprod. Update. 16(5):510–24.

15. Carter AM. 2011. Comparative studies of placentation and immunology in non-human primates suggest a scenario for the evolution of deep throphoblast invasion and an rxplanation for human pregnancy disorders. Reproduction 141(4):391–6. http://dx.doi.org/10.1530/REP-10-0530; PMid:21273370

16. Ercilla MG, Martorell J. 2010. Immunological study of the donor-recipient pair. Nefrologia. 30(Suppl.2):S60–70.

17. Uchida J, Machida Y, Iwai T, Naquanuma T, Kitamoto K, Iquchi T et al. 2010. Desensitization protocol in highly HLA-sensitized and ABO-incompatible high titre kidney transplantation. Transplant. Proc. 42(10):3998–4002.

18. Samsami Dehaghani A, Doroudchi M, Kalantari T, Pezeshki AM, Ghaderi A. 2005. Heterozygosity in CTLA-4 gene and severe preeclampsia. Int. J. Gynecol. Obstet. 88(1):19–24.

19. Lee J, Romero R, Dong Z, Xu Y, Qureshi F, Jacques S et al. 2011. Unexplained fetal death has a biological signature of maternal anti-fetal rejection: chronic chorioamnionitis and alloimmune anti-human leucocyte antigen antibodies. Histopathology 59(5):928–38. http://dx.doi.org/10.1111/j.1365-2559.2011.04038.x; PMid:22092404 PMCid:PMC3546834

20. Rossini AA, Greiner DL, Mordes JP. 1999. Induction of immunologic tolerance for transplantation. Physiol. Rev. 79(1):99–110.

21. Sumitran-Holgersson S. 2001. HLA-specific alloantibodies and renal graft outcome. Nephrol. Dial. Transplant. 16(5):897–904.

22. Lietz K, John R, Burke E, Schuster M, Roqers TB, Suciu-Foca N et al. 2005. Immunoglobulin M-to-Immunoglobulin G anti-human leukocyte antigen class ІІ antibody switching in cardiac transplant recipients is associated with an increased risk of cellular rejection and coronary artery disease culprit. Circulation 112(6):2468–76. http://dx.doi.org/10.1161/CIRCULATIONAHA.104.485003; PMid:16230499

23. Tinckam KJ, Chandraker A. 2006. Mechanisms and role of HLA and non-HLA alloantibodies. Clin. J. Am. Soc. Nephrol. 1(3):404–14.

24. Bohmig GA, Exner M, Habicht A, Schillinger M, Lang U, Kletzmayr J et al. 2002. Capillary C4d deposition in kidney allografts: a specific marker of alloantibody-dependent graft injury. J. Am. Soc. Nephrol. 13(4):1091–9.

25. Colvin RB. 2007. Antibody-mediated renal allograft rejection: diagnosis and pathogenesis. J. Am. Soc. Nephrol. 18(4):1046–56. http://dx.doi.org/10.1681/asn.2007010073

26. Bartel G, Walch K, Wahrmann M, Plis S, Kussel L, Polteranes S et al. 2011. Prevalence and qualitative properties of circulating anti-human leukocyte antigen alloantibodies after pregnancy: no association with unexplained recurrent miscarriage. Hum. Immunol. 72(2):187–92. http://dx.doi.org/10.1016/j.humimm.2010.11.005

27. Lee J, Romero R, Xu Y, Kim JS, Topping V, Yoo W et al. 2011. A signature of maternal anti-fetal rejection in spontaneous preterm birth: chronic chorioamnionitis, anti-human leukocyte antigen antibodies, and C4d. PLoS One. 6(2):e16806.

28. Regan L, Braude PR, Hill DP. 1991. A prospective study of the incidence, time of appearance of anti-paternal lymphocytotoxic antibodies in human pregnancy. Hum. Reprod. 6(2):294–8.

29. Nielsen HS, Witvliet MD, Steffensen R, Haasnoot GW, Goulmy E, Christiansen OB et al. 2010. The presence of HLA-antibodies in recurrent miscarriage patients is associated with a reduced chance of a live birth. J. Reprod. Immunol. 87(1-2):67–73.

30. Lee J, Romero R, Xu Y, Kim JS, Park JY, Kusanovic JP et al. 2011. Maternal HLA panel-reactive antibodies in early gestation positively correlate with chronic chorioamnionitis: evidence in support of the chronic nature of maternal anti-fetal rejection. Am. J. Reprod. Immunol. 66(6):510–26. http://dx.doi.org/10.1111/j.1600-0897.2011.01066.x

31. Kim MJ, Romero R, Kim CJ, Tarca AL, Chhauy S, LaJeunesse С et al. 2009. Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-marernal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal craft-versus-host disease. J. Immunol. 182(6):3919–27.

32. Kim JS, Romero R, Kim MR, Kim YM, Friel L, Espinosa J, Kim CJ. 2008. Involvement of Hofbauer cells and maternal T cells in villitis of unknown aetiology. Histopathology 52(4):457–64. http://dx.doi.org/10.1111/j.1365-2559.2008.02964.x; PMid:18315598 PMCid:PMC2896045

33. Labarrere CA, Faulk WP. 1995. Maternal cells in chorionic villi from placentae of normal and abnormal human pregnancies. Am. J. Reprod.Immunol. 33(1):54–9.

34. Redline RW, Patterson P. 1993. Villitis of unknown etiology is associated with major infiltration of fetal tissue by maternal inflammatory cells. Am. J. Pathol. 143(2):473–79.

35. Cohen F, Zuelzer WW, Gustafson DC, Evans MM. 1964. Mechanisms of isoimmunization. I. The transplacental passage of fetal erythrocytes in homospecific pregnancies. Blood. 23:621–46.

36. Sebring ES, Polesky HF. 1990. Fetomaternal hemorrhage: incidence, risk factors, time of occurrence, and clinical effects. Transfusion 30(4):344–57. http://dx.doi.org/10.1046/j.1537-2995.1990.30490273444.x

37. Wilczyсski JR. 2006. Immunological analogy between allograft rejection, recurrent abortion and preeclampsia – the same basic mechanism? Hum. Immunol. 67(7):492–511.

38. Erlebacher A. 2013. Mechanisms of T cell tolerance towards the allogenic fetus. Nat. Rev. Immunol. 13(1):23–33.

39. Carp Howard JA, ed. 2007. Reccurent pregnancy loss: causes, controversies and treatment. Informa UK Ltd:290.

40. Raghupathy R. 2009. The immune system in pregnancy: Friend or foe? Kuwait Med. J. 41(2):93–102.

41. Yarilin AA. 2010. Immunologiya: uchebnik. M, GEOTAR-Media:752.

42. Holt S, Donaldson H, Hazlehurst G, Varghese Z, Contreras M, Kingdon E et al. 2004. Acute transplant rejection induced by blood transfusion reaction to the Kidd blood group system. Nephrol. Dial.Transplant. 19(9):2403–6.

43. Tasaki M, Nakajima T, Imai N, Nakagawa Y, Saito K, Takahashi K et al. 2010. Detection of allogeneic blood group A and B enzyme activities in patients with ABO incompatible kidney transplantation. Glycobiology 20(10):1251–8. http://dx.doi.org/10.1093/glycob/cwq086; PMid:20542872

44. Eastlund T. 1998. The histo-blood group ABO system and tissue transplantation. Transfusion. 38(10):975–88. http://dx.doi.org/10.1046/j.1537-2995.1998.381098440863.x; PMid:9767749

45. Dahlseide AL. 2005. Succcessful ABO incompatible organ transplantation. Univ. Alberta Health Sci. J. 2(1):17–20.

46. Garratty G, Telen MJ, Petz LD. 2002. Red cell antigens as functional molecules and obstacles to transfusion. Hematology Am. Soc. Hematol. Educ. Program:445–62.

47. Gote SV, Tsirulnikova OM, Ammosov AA, Lure YuE, Moysyuk YaG, Poptsov VN i dr. 2011. Opyit AVO-nesovmestimyih transplantatsiy pecheni. Vestnik transplantologii i iskusstvennyih organov. 13(2):21–8.

48. Anstee DJ. 2010. The relationship between blood groups and disease. Blood. 115(23):4635–43. http://dx.doi.org/10.1182/blood-2010-01-261859

49. Bolton-Maggs PH. 2013. Bullet points from SHOT: key messages and recommendations from the Annual SHOT Report 2013. Transfus Med 23(4):215–6.

50. Ghasemi N, Sheikhha MH, Davar R, Soleimanian S. 2011. ABO bloods group incompatibility in recurrent abortion. Iran. J. Pediatr. Hematol. Oncol. 29(1):62–6.

51. Saldanha SG, Costa AR. 1979. Genetic counseling in two cases of possible ABO incompatibility. Rev. Brasil. Genet. 2(3):191–8.

52. Lurie S, Ben-Aroya Z, Eldar S, Sadan O. 2003. Association of Lewis blood group phenotype with preterm premature rupture of membranes. J. Soc. Gynecol. Investig. 10(5):291–93.

53. Hudson KE, Lin E, Hendrickson JE. 2010. Regulation of primary alloantibody response through antecedent exposure to a microbial T-cell epitope. Blood 115(19):3989–96. http://dx.doi.org/10.1182/blood-2009-08-238568; PMid:20086249 PMCid:PMC2869558

54. Pozsonyi E, Gyorgy B, Berki T, Banlaki Z, Buzas E, Rajczy K et al. 2009. HLA-association of serum levels of natural antibodies. Mol. Immunol. 46(7):1416–23.

55. Poletaev AB, Morozov SG. 2000. Changes of maternal serum natural antibodies of IgG class to proteins МВ^ S100, ACBP14/18 and MP65 and embryonic misdevelopments in humans. Human Antibody 9:4:216–222.

56. Finkenzeller D, Fischer B, McLaughlin J, Schrewe H, Ledermann B, Zimmermann W. 2000. Trophoblast cell-specific carcinoembryonic antigen cell adhesion molecule 9 is not required for placental development or a positive putcome of allotypic pregnancies. Molecular and Cellular Biology 20:19:7140–7145. http://dx.doi.org/10.1128/MCB.20.19.7140-7145.2000

57. Tong ZB, Gold L, De Pol A, Vanevski K, Dorward H, Sena P, Palumbo C, Bondy CA, Nelson LM. 2004. Developmental expression and subcellular localization of mouse MATER, an oocyte-specific protein essential for early development. Endocrinology 145:1427–1434. http://dx.doi.org/10.1210/en.2003-1160; PMid:14670992

58. Landor M. 1995. Maternal-fetal transfer of immunoglibulins. Ann. Allergy, Asthma a. Immunology 474;4:279–283.

59. Xia Y, Kellems RE. 2009. Is preeclampsia an autoimmune disease? Clin. Immunol. 133(1):1–12.

60. Dragun D. 2007. Agonistic antibody-triggered stimulation of angiotensin ІІ type 1 receptor and renal allograft vascular pathology. Nephrol. Dial. Transplant. 22(7):1819–22.

61. Xia Y, Ramin SM, Kellems RE. 2007. Potential roles of angiotensin receptor-activating autoantibody in the pathophysiology of preeclampsia. Hypertension. 50(2):269–75. http://dx.doi.org/10.1161/HYPERTENSIONAHA.107.091322; PMid:17576854 PMCid:PMC3261616

62. Dechend R, Gratze P, Wallukat G, Shagdarsuren E, Plehm R, Brдsen JH et al. 2005. Agonistic autoantibodies to the AT1 receptor in a transgenic rat model of preeclampsia. Hypertension. 45(4):742–46. http://dx.doi.org/10.1161/01.HYP.0000154785.50570.63; PMid:15699466

63. LaMarca B, Parrish M, Fournier L, Murphy SR, Roberts L, Glover P et al. 2009. Hypertension in response to autoantibodies to the angiotensin ІІ type 1 receptor (AT1-AA) in pregnant rats. Hypertension. 54(4):905–9. http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.137935; PMid:19704104 PMCid:PMC2785498

64. Walther T, Wallukat G, Jank A, Bartel S, Schultheiss HP, Faber R et al. 2005. Angiotensin ІІ type 1 receptor agonistic antibodies reflect fundamental alterations in the uteroplacental vasculature. Hypertension. 46(6):1275–79. http://dx.doi.org/10.1161/01.HYP.0000190040.66563.04; PMid:16260641

65. Hubel CA, Wallukat G, Wolf M, Herse F, Rajakumar A, Roberts JM et al. 2007. Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia. Hypertension. 49(3):612–17. http://dx.doi.org/10.1161/01.HYP.0000256565.20983.d4; PMid:17210828

66. Xia Y, Zhou CC, Ramin SM, Kellems RE. 2007. Angiotensin receptors, autoimmunity, andpreeclampsia. J. Immunol. 179(6):3391–95.

67. Fitzgerald B, Shannon P, Kingdom J, Keating S. 2011. Rounded intraplacental haematomas due to decidual vasculopathy have a distinctive morphology. J. Clin. Pathol. 64(8):729–32.

68. Wehner J, Morrell CN, Reynolds T, Rodriguez ER, Baldwin WM. 3rd. 2007. Antibody and complement in transplant vasculopathy. Circ. Res. 100(2):191–203.

69. Keswani SC, Chauhan N. 2002. Antiphospholipid syndrome. J. Roy. Soc. Med. 95(7):336–41.

70. Lim W, Growther MA, Eikelboom JW. 2006. Management of antiphospholipid antibody syndrome. JAMA. 295(9):1050–57.

71. Rand JH. 2002. Molecular pathogenesis of the antiphospholipid syndrome. Circ. Res. 90(1):29–37.

72. Аржанова ОН, Шляхтенко ТН, Сельков СА. 2002. Роль антифосфолипидных антител (АФА) в патогенезе невынашивания беременности. Журнал акушерства и женских болезней 50(2):18–23.

73. Макацария АД, Шаховская ЕН. 2008. Профилакика повторных репродуктивных потерь при антифосфолипидном синдроме. Врач 10:89–91.

74. Rai R. 2000. Obstetric management of antiphospholipid syndrome. J. Autoimmun. 15(2):203–7. http://dx.doi.org/10.1006/jaut.2000.0417; PMid:10968910

75. Cervera R. 2012. European forum on antiphospholipid antibodies: brief history report and governance document. Lupus. 21(7):699–703. http://dx.doi.org/10.1177/0961203312436865; PMid:22635206

76. Devreese K, Hoylaerts MF. 2010. Challenges in the diagnosis of the antiphospholipid syndrome. Clin. Chem. 56(6):930–40.

77. Nъсez-Бlvarez CA, Cabiedes J. 2011. Pathogenic mechanisms of the anti-phospholipid antibodies. Reumatol. Clin. 7(1):72–6.

78. Hughes GR, Khamashta MA. 2003. Seronegative antiphospholipid syndrome. Ann. Rheum. Dis. 62(12):1127.

79. Miret C, Cervera R, Reverter JC, Garcнa-Carrasco M, Ramos M. 1997. Antiphospholipid syndrome without antiphospholipid antibodies at the time of the thrombotic event: transient “seronegative” antiphospholipid syndrome. Clin. Exp. Rheumatol. 15:541–4.

80. Castaneda Ospina SA, Cardona Maya WD, Bueno Sanchez JC, Cadavid Jaramillo AP. 2003. Pregnancy outcome in women with antiphospholipid syndrome and alloimmunity: a case report. Sao Paulo Med. J. 121(6):248–50.

81. Thi Thuong DL, Tieulie N, Costedoat N, Andreu MR, Wechsler B, Vauthier-Brouzes D et al. 2005. The HELLP syndrome in the antiphospholipid syndrome: retrospective study of 16 cases in 15 women. Ann. Rheum. Dis. 64(2):273–78. http://dx.doi.org/10.1136/ard.2003.019000

82. Ritis K, Doumas M, Mastellos D, Micheli A, Giaglis S, Magotti P et al. 2006. A novel C5a receptor-tissue factor cross-talk in neutrophilis links innate immunity to coagulation pathways. J. Immunol. 177(7):4794–801.

83. Redecha P, Tilley R, Tencati M, Salmon JE, Kirchhofer D, Mackman N et al. 2007. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody-induced fetal injury. Blood. 110(7):2423–31. http://dx.doi.org/10.1182/blood-2007-01-070631

84. Bokarewa MI, Morrissey JH, Tarkowsky A. 2002. Tissue factor as a proinflammatory agent. Arthr. Res. 4(3):190–5.

85. Matsuyama M, Yoshimura R, Akioka K, Okamoto M, Ushigome H, Kadotani Y et al. 2003. Tissue factor antisense oligonucleotides prevent renal ischemia-reperfusion injury. Transplantation 76(5):786–91. http://dx.doi.org/10.1097/01.TP.0000079630.68668.C2; PMid:14501854

86. Varela C, de Haro J, Bleda S, Esparza L, de Maturana IL, Acin F. 2011. Anti-endothelial cell antibodies are associated with peripheral arterial disease and markers of endothelial dysfunction and inflammation. Interact. Cardiovasc. Thorac. Surg. 13(5):463–7.

87. Praprotnik S et al. 2001. Anti-endothelial cell antibodies from patients with thrombotic thrombocytopenic purpura specifically activate small vessel endothelial cells. Intern. Immunol. 13(2):203–210.

88. Varela C. 2011. Anti-endothelial cell antibodies are associated with peripheral arterial disease and markers of endothelial dysfunction and inflammation. Interact Cardiovasc Thorac Surg. 13(5):463–7. http://dx.doi.org/10.1510/icvts.2011.275016; PMid:21852269

89. Cieњlik P. 2008. Vasculopathy and vasculitis in systemic lupus erythematosus. Pol Arch Med Wewn. 118(1–2):57–63.

90. Youinou P. 2005. New target antigens for anti-endothelial cell antibodies. Immunobiology. 210(10):789–97.

91. Kovalchuk LV. 2011. Klinicheskaya immunologiya i allergologiya s osnovami obschey immunologii: uchebnik. M, GEOTAR – Media:640.

92. Haitov RM. 2011. Immunologiya: ucheb. dlya studentov med. vuzov. M, GEOTAR-Media:311.

93. Osidak LV i soavt. 2009. Metod. posobie dlya vrachey. Sankt-Peterburg:58.94. Abul Abbas K et al. 2015. Basic Immunology: Functions and Disorders of the Immune System. 5th edition, Elsevier.