tolleranza immunitaria madre-feto

Maternal “Immune Tolerance”

Maternal “Immune Tolerance” does not increase the risk of pregnancy infections.

One of the immunological questions concerning the obstetrician’s mind is the so-called ‘tolerance’ of the mother towards the product of conception. It is feared that the need to ‘accept’ the foetus will lead to a decrease in the immune system in the mother, and that this will expose her to an increased risk of infections: but in reality this increase does not occur. It is undoubtedly true that the foetal genetic component of paternal origin constitutes an extraneous element that maternal immunity cannot recognize as ‘self’; it is therefore true that she should theoretically expel the foetus, as occurs in the well-known ‘rejection reaction’ of a transplanted but ‘incompatible’ organ. So why doesn’t this happen? The chapter on maternal tolerance has never been organically addressed, but the research of the last decades provides important clarifying elements of this mystery. To address this issue, one must first consider that there are two forms of immunity: humoral and cellular. Humoral immunity is mainly achieved through the so-called ‘antigen-antibody reaction’. It provides that the immune-competent cells, encountering a foreign element, called antigen, produce an antibody that binds to it neutralizing it. However, this type of immune reaction is not compromised in the mother, on her encounter with the foetal antigenic component of paternal origin. In fact, it is triggered in the antigenic incompatibility between the blood group of the foetus and that of the mother. In practice this happens: if the mother is ‘Rh negative’ (i.e. if her red blood cells do not contain the Rh antigen), while the foetus is Rh positive (i.e. he inherited the paternal Rh antigen), then the maternal immunocompetent cells produce ‘anti Rh’ antibodies that cross the placenta and destroy the red blood cells of the foetus, causing it to die. However, this intact and efficient defense system also protects the foetus, which receives maternal antibodies together with pathogens through the placenta. If therefore the mother maintains her humoral immunity unchanged, why does she not use it to ‘reject’ the product of conception? The answer is simple: because the ‘rejection reaction’ of an incompatible transplant does not take place through the antigen-antibody reaction, but through an inflammatory reaction, (i.e. through cellular, not humoral immunity). Regarding humoral immunity, it must therefore be concluded that it is not compromised in pregnancy, and does not justify the fear of an increased risk of infection. In fact, although any pregnant women may contract infections, these are not at all to a greater extent compared to other categories of healthy individuals. This evidence is there for all to see, and I can confirm it based on my clinical experience gained in the Sant’Anna Hospital of Ferrara from 1972 to 2014. In fact, the cases of viral infectious diseases that came to our observation in that period were extremely rare. Over the course of 42 years, I remember only one case of measles in a pregnant woman at the eighth month, who was isolated in the infectious diseases ward, where she gave premature birth to a healthy baby, indicating that the passage of maternal antibodies through the placenta had protected the foetus as well.

A further demonstration of the substantial parity of the risk of infection of pregnant women in comparison with other healthy individuals can also be deduced from the recent studies of professor Tognon, professor Martini and their coworkers, at the University of Ferrara, a research group to which I am honoured to belong. In a series of recently published papers, our group has shown that in successful pregnancies the amount of some viruses in the chorionic villi and in the monocytes of maternal blood is the same as that of cases that end in abortion; specific antibodies against the same viruses in the maternal blood behave in the same way. Logically, however, if the tested viruses were the cause of abortion, and if humoral immunity was compromised by pregnancy, the concentration of viral DNA should be higher, and that of antibodies lower, in cases with spontaneous abortion: such a result therefore indicates a protective action against infection, exerted by the maternal immune system during pregnancy. Research by the group of Professor Tognon has also shown that the viruses themselves with their specific antibodies are freely and early transmitted from the mother to the foetus, without any difference between favourable cases and spontaneous abortions.
For all the above reasons, it can therefore be stated:

  • that maternal humoral immunity is not compromised by pregnancy;
  • that viruses freely cross the placental barrier;
  • that usually they are not a cause of abortion;
  • that maternal antibodies are transferred together with the viruses, and they can therefore exert their protective action on the foetus.

    So, if humoral immunity is not compromised in pregnancy, what can be said about cellular immunity? Now, it is necessary to know that it is fully functional in the whole maternal organism, and that its natural tendency is to hinder the implantation of the embryo in the most effective way: the successful outcome of the physiological pregnancy is a consequence of the local release of anti-inflammatory mediators, rather than a result of impaired maternal cellular immunity. In fact, at the uterine-placental level there is a real challenge between the foetus and the mother: the chorionic villi release substances capable of inducing in the uterine vessels the changes necessary for foetal development, while the mother triggers inflammation and coagulation in order to repair the breakdown of blood vessels. We can therefore say that the outcome of this struggle depends mainly on the foetus. It is true that there are cases of particularly pronounced maternal intolerance, in which therefore abortion is more frequent: nevertheless, even in these patients a foetus particularly efficient in the production of anti-inflammatory mediators, will be able to survive up to the end of pregnancy. Fortunately, in the majority of cases, maternal reactivity is not enhanced: it can therefore be said that the cause of the majority of abortions lies in the inability of the foetus itself to produce the right mediators for its sustenance. From all the above, it must be concluded that, as both humoral and cellular maternal immunity are perfectly efficient, there is no indication to subject pregnant women to the so-called anti-flu, nor to any other vaccination. It is not easy for official medical science to understand these concepts, despite the fact that they are evident from the literature of the last 40 years. The articles reported below deal with the following topics:

  • the passage of pathogens and antibodies from the mother to the foetus (1, 2, 3, 4, 5, 20);
  • the role of inflammation in the physiological and pathological events of pregnancy (9, 10, 11, 12, 17, 19, 23, 27, 28, 29, 31, 33, 35);
  • the function mediators of the chorionic villi (6);
  • the substantial analogy between the pathogenic mechanism of aneuploid and euploid abortion (14, 15, 16, 26);
  • the anti-inflammatory therapy of pregnancy complications (7, 8, 13, 18, 21, 22, 24, 25, 30, 32, 34, 36).

1) Mother-to-child transmission of oncogenic polyomaviruses BKPyV, JCPyV and SV40.
Mazzoni E, Pellegrinelli E, Mazziotta C, Lanzillotti C, Rotondo JC, Bononi I, Iaquinta MR, Manfrini M, Vesce F, Tognon M, Martini F
J Infect. 2020 Feb 22. pii: S0163-4453(20)30091-8. doi: 10.1016/j.jinf.2020.02.006. [Epub ahead of print]
2) Droplet-digital PCR assay to detect Merkel cell polyomavirus sequences in chorionic villi from spontaneous abortion affected females.
Tagliapietra A, Rotondo JC, Bononi I, Mazzoni E, Magagnoli F, Gonzalez LO, Contini C, Vesce F, Tognon M, Martini F.
J Cell Physiol. 2020 Mar;235(3):1888-1894. doi: 10.1002/jcp.29213. Epub 2019 Sep 23.

3) Footprints of BK and JC polyomaviruses in specimens from females affected by spontaneous abortion.
Tagliapietra A, Rotondo JC, Bononi I, Mazzoni E, Magagnoli F, Maritati M, Contini C, Vesce F, Tognon M, Martini F.
Hum Reprod. 2019 Mar 1;34(3):433-440. doi: 10.1093/humrep/dey375.

4) Investigation on silent bacterial infections in specimens from pregnant women affected by spontaneous miscarriage.
Contini C, Rotondo JC, Magagnoli F, Maritati M, Seraceni S, Graziano A, Poggi A, Capucci R, Vesce F, Tognon M, Martini F.
J Cell Physiol. 2018 Jan;234(1):100-107. doi: 10.1002/jcp.26952. Epub 2018 Aug 5.
5) Serum IgG Antibodies from Pregnant Women Reacting to Mimotopes of Simian Virus 40 Large T Antigen, the Viral Oncoprotein.
Mazzoni E, Di Stefano M, Fiore JR, Destro F, Manfrini M, Rotondo JC, Casali MV,Vesce F, Greco P, Scutiero G, Martini F, Tognon MG.
Front Immunol. 2017 Apr 10;8:411. doi: 10.3389/fimmu.2017.00411. eCollection 2017.
6) Control of human trophoblast function.
Lunghi L, Ferretti ME, Medici S, Biondi C, Vesce F. Reprod Biol Endocrinol. 2007 Feb 8;5:6
7) Use of glucocorticoids in pregnancy.
Lunghi L1,Pavan B,Biondi C,Paolillo R,Valerio A,Vesce F, Patella A.
Curr Pharm Des. 2010;16(32):3616-37
8) The role of glucocorticoids in pregnancy: four decades experience with use of betamethasone in the prevention of pregnancy loss.
Vesce F, Giugliano E, Cagnazzo E., Bignardi S., Mossuto E., Servello T., Marci R.
In “Glucocorticoids. New recognition of our familiar friend”. Edited by Xiaoxiao Qian, INTECH, November 2012, Croatia, pag 407-48

9) Th1-type immunity is incompatible with successful pregnancy.
Raghupathy R1. Immunol Today. 1997 Oct;18(10):478-82
10) Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions. Makhseed M1, Raghupathy R, Azizieh F, Omu A, Al-Shamali E, Ashkanani L.
Hum Reprod. 2001 Oct;16(10):2219-26
11) A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition.
Romero R1, Gomez R, Ghezzi F, Yoon BH, Mazor M, Edwin SS, Berry SM.
Am J Obstet Gynecol. 1998 Jul;179(1):186-93.
12) The fetal inflammatory response syndrome.
Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. Am J Obstet Gynecol. 1998 Jul;179(1):194-202.
13) Successful pregnancy outcome following 19 consecutive miscarriages: case report.
Queenby S, Farquharson R, Young M, Vince G. Hum Reprod (2003)18:2562-4
14) Cytokine imbalance in pregnancies with fetal chromosomal abnormalities.
Vesce F, Scapoli C, Giovannini G, Tralli L, Gotti G, Valerio A, Piffanelli A. Hum Reprod. 2002 Mar;17(3):803-8.
15) Plasminogen activator system in serum and amniotic fluid of euploid and aneuploid pregnancies.
Vesce F, Scapoli C, Giovannini G, Piffanelli A, Geurts- Moespot A, Sweep FC. Obstet Gynecol. 2001 Mar;97(3):404-8

16) Raised level of amniotic endothelin in pregnancies with fetal aneuploidy.
Vesce F, Farina A, Jorizzo G, Tarabbia C, Calabrese O, Pelizzola D, Giovannini G, Piffanelli A. Fetal Diagn Ther. 1996 Mar-Apr;11(2):94-8
17) An immunological insight into the origins of pre-eclampsia. Laresgoiti-Servitje E1, Gómez-López N, Olson DM. Hum Reprod Update. 2010 Sep-Oct;16(5):510-24
18) Corticosteroids in pregnancy
Sidhu R. K. In Drugs and Pregnancy, Edited by D. F. Hawkins. Chapter 11, 166-79 CHURCHILL LIVINGSTONE 1987
19) Tumor necrosis factors: pivotal components of pregnancy? Hunt J S, Chen H L, Miller l. Biol Reprod 1996; 54 (3):554-63.
20) Serum IgG Antibodies from Pregnant Women Reacting to Mimotopes of Simian Virus 40 Large T Antigen, the Viral Oncoprotein.
Mazzoni E, Di Stefano M, Fiore JR, Destro F, Manfrini M, Rotondo JC, Casali MV,Vesce F, Greco P, Scutiero G, Martini F, Tognon MG.
Front Immunol. 2017 Apr 10;8:411. doi: 10.3389/fimmu.2017.00411. eCollection 2017.
21) Influence of vaginal lactoferrin administration on amniotic fluid cytokines and its role against inflammatory complications of pregnancy.
Maritati M, Comar M, Zanotta N, Seraceni S, Trentini A, Corazza F, Vesce F, Contini C.
J Inflamm (Lond). 2017 Feb 15;14:5. doi: 10.1186/s12950-017- 0152-9. eCollection 2017.

22) Vaginal Lactoferrin Modulates PGE2, MMP-9, MMP-2, and TIMP-1 Amniotic Fluid Concentrations.
Trentini A, Maritati M, Cervellati C, Manfrinato MC, Gonelli A, Volta CA,Vesce F, Greco P, Dallocchio F, Bellini T, Contini C.
Mediators Inflamm. 2016;2016:3648719. Epub 2016 Oct 31.
23) The behaviour of the peripheral natural killer cells in the foetal growth restriction.
Vesce F, Cagnazzo E, Giugliano E, Mossuto E, Marci R.
Eur Rev Med Pharmacol Sci. 2014 Aug;18(16):2248-52.
24) Vaginal lactoferrin administration before genetic amniocentesis decreases amniotic interleukin-6 levels.
Vesce F, Giugliano E, Bignardi S, Cagnazzo E, Colamussi C, Marci R, Valente N, Seraceni S, Maritati M, Contini C. Gynecol Obstet Invest. 2014;77(4):245-9. doi: 10.1159/000358877. Epub 2014 Mar 7.
25) Low dose of betamethasone throughout the whole course of pregnancy and fetal growth: a clinical study.
Vesce F, Giugliano E, Cagnazzo E, Mossuto E, Marci R.
Eur Rev Med Pharmacol Sci. 2014;18(4):593-8.
26) Downregulation of A(1) and A(2B) adenosine receptors in human trisomy 21 mesenchymal cells from first-trimester chorionic villi.
Gessi S, Merighi S, Stefanelli A, Mirandola P, Bonfatti A, Fini S, Sensi A, Marci R, Varani K, Borea PA, Vesce F.
Biochim Biophys Acta. 2012 Nov;1822(11):1660-70. doi: 10.1016/j.bbadis.2012.07.013. Epub 2012 Jul 31.

27) Betamethasone, progesterone and RU-486 (mifepristone) exert similar effects on connexin expression in trophoblast- derived HTR-8/SVneo cells.
Cervellati F, Pavan B, Lunghi L, Manni E, Fabbri E, Mascoli C, Biondi C, Patella A, Vesce F.
Reprod Fertil Dev. 2011;23(2):319-28. doi: 10.1071/RD10077.
28) Evidence for the presence of N-formyl-methionyl-leucyl- phenylalanine (fMLP) receptor ligands in human amniotic fluid and fMLP receptor modulation by physiological labour. Biondi C, Pavan B, Dalpiaz A, Valerio A, Spisani S, Vesce F.
J Reprod Immunol. 2005 Dec;68(1-2):71-83. Epub 2005 Oct 19.
29) Prostaglandin E2 inhibits proliferation and migration of HTR-8/SVneo cells, a human trophoblast-derived cell line. Biondi C, Ferretti ME, Pavan B, Lunghi L, Gravina B, Nicoloso MS, Vesce F, Baldassarre G.
Placenta. 2006 Jun-Jul;27(6-7):592-601. Epub 2005 Sep 12
30) Inhibition of amniotic interleukin-6 and prostaglandin E2 release by ampicillin.
Vesce F, Pavan B, Lunghi L, Giovannini G, Scapoli C, Piffanelli A, Biondi C.
Obstet Gynecol. 2004 Jan;103(1):108-13.
31) Formyl-methionyl-leucyl-phenylalanine induces prostaglandin E2 release from human amnion-derived WISH cells by phospholipase C-mediated [Ca+]i rise.
Biondi C, Pavan B, Ferretti ME, Corradini FG, Neri LM, Vesce F.
Biol Reprod. 2001 Mar;64(3):865-70.

32) Effect of different classes of antibiotics on amniotic prostaglandin E release.
Vesce F, Pavan B, Buzzi M, Pareschi MC, Bianciotto A, Iorizzo G, Biondi C.
Prostaglandins Other Lipid Mediat. 1999 Jun;57(4):207-18.
33) Does formyl-methionyl-leucyl-phenylalanine exert a physiological role in labor in women?
Buzzi M, Vesce F, Ferretti ME, Fabbri E, Biondi C.
Biol Reprod. 1999 May;60(5):1211-6.
34) Inhibition of amniotic prostaglandin E release by ampicillin.
Vesce F, Buzzi M, Ferretti ME, Pavan B, Bianciotto A, Jorizzo G, Biondi C.
Am J Obstet Gynecol. 1998 Apr;178(4):759-64.
35) Increased incidence of preeclampsia in pregnancies complicated by fetal malformation.
Vesce F, Farina A, Giorgetti M, Jorizzo G, Bianciotto A, Calabrese O, Mollica G.
Gynecol Obstet Invest. 1997;44(2):107-11.

36) Betamethasone-induced lecithin release in vitro from the fetal membranes.
Vesce F, Pareschi MC, Travagli S, Tarabbia C, Pansini F, Salvatorelli G, Gulinati AM, Grandi E, Biondi C.
Gynecol Obstet Invest. 1992;33(3):134-7.

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