Referring to two recent publications, we here propose that clinical reproductive immunology has for decades stagnated because reproductive medicine, including assisted reproduction (AR), has failed to accept embryo implantation as an immune system-driven process, dependent on establishment of maternal tolerance toward the implanting fetal semi-allograft (and complete allograft in cases of oocyte donation). Pregnancy represents a biologically unique period of temporary (to the period of gestation restricted) tolerance, otherwise only known in association with parasitic infections. Rather than investigating the immune pathways necessary to induce this rather unique state of tolerance toward the rapidly growing parasitic antigen load of the fetus, the field, instead, concentrated on irrelevant secondary immune phenomena (i.e., “immunological noise”). It, therefore, does not surprise that interesting recent research, offering new potential insights into maternal tolerance during pregnancy, was mostly published outside of the field of reproductive medicine. This research offers evidence for existence of inducible maternal tolerance pathways with the ability of improving maternal fecundity and, potentially, reducing such late pregnancy complications as premature labor and preeclampsia/eclampsia due to premature abatement of maternal tolerance. Increasing evidence also suggests that tolerance-inducing immune pathways are similar in successful pregnancy, successful organ transplantation and, likely also in the tolerance of “self” (i.e., prevention of autoimmunity). Identifying and isolating these pathways, therefore, may greatly benefit all three of these clinical areas, and research in reproductive immunology should be accordingly redirected.
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NG conceived the concept for this manuscript and wrote the first draft. VAK and DHB contributed to revisions of the manuscript. All authors approved of the final manuscript.
Compliance with ethical standards
No external funds were used in support of this manuscript.
Conflict of interest
NG, and DHB, are co-inventors on a number of pending and already awarded US patents claiming therapeutic benefits from androgen supplementation in women with low functional ovarian reserve (LFOR) and relating to the FMR1 gene in a diagnostic function in female fertility. Both receive royalties from Fertility Nutraceuticals, LLC, in which NG also holds shares. NG, DHB, and VAK also are co-inventors on three pending AMH-related patent applications. They report no conflicts with the reported manuscript.
Wei l, MacDonals T, Shimi S. Association between prior appendectomy and/or tonsillectomy in women and subsequent pregnancy rate: a cohort study. Fertil Steril. 2016;106:1150–6.CrossRefPubMedGoogle Scholar
Robertson SA, Jin M, Yu D, Moldenhauer LM, Davies MJ, Hull L, et al. Corticosteroid-therapy in assisted reproduction—immune suppression is a faulty premise. Hum Reprod 2016; 2164-2172Google Scholar
Zhang YH, Tian M, Tang MX, Liu ZZ, Liao AH. Recent insight into the role of the PD-1/PD-L1 pathway in feto-maternal tolerance and pregnancy. Am J Reprod Immunol. 2015;74:201–8.CrossRefPubMedGoogle Scholar
Chen T, Darrasse-Jèze G, Bergot AS, Courau T, Chriaud G, Valdivia K, et al. Self-specific memory regulatory T cells protect embryos at implantation in mice. J Immunol. 2013;191:2273–81.CrossRefPubMedPubMedCentralGoogle Scholar
Liu Q, Tian FJ, Xie QZ, Zhang J, Liu L, Yang J. Fyn plays a pivotal role in fetomaternal tolerance through regulation of Th17 cells. Am J Reprod Immunol. 2016;75:569–79.CrossRefPubMedGoogle Scholar
Lubbe WF, Butler WS, Palmer S, Liggins GC. Fetal survival after prednisone suppression of maternal lupus-anticoagulant. Lancet. 1983;19(1):1361–3.CrossRefGoogle Scholar
Gleicher N, Friberg J. IgM gammopathy and the lupus anticoagulant syndrome in habitual aborters. JAMA. 1985;253:3278–81.CrossRefPubMedGoogle Scholar
Geva E, Yaron Y, Lessing JB, Yovel I, Vardinon N, Burke M, et al. Circulating autoimmune antibodies may be responsible for implantation failure in vitro fertilization. Fertil Steril. 1994;62:802–6.CrossRefPubMedGoogle Scholar
Gleicher N, Vidali A, Karande V. The immunological “Wars of the Roses”” disagreements amongst reproductive immunologists. Hum Reprod. 2002;17:539–42.CrossRefPubMedGoogle Scholar
Kemeter P, Feichtinger W. Prednisolone supplementation in clomid and gonadotrophin stimulation for in-vitro-fertilization—prospective randomized trial. Hum Reprod. 1986;1:441–4.CrossRefPubMedGoogle Scholar
Tucker MJ, Cohen J, Massey JB, Mayer MP, Wiker SR, Wright G. Partial dissection of the zona pellucida of frozen-thawed human embryos may enhance blastocyst hatching, implantation and pregnancy rates. Am J Obstet Gynecol. 1991;165:341–4.CrossRefPubMedGoogle Scholar
Deglincerti A, Croft GF, Pietila LN, Zernicka-Goetz M, Siggia ED, Brivanlou AH. Self-organization of the in vitro attached human embryo. Nature. 2016;533:251–4.CrossRefPubMedGoogle Scholar
Shahbazi MN, Jedrusik A, Vuoristo S, Recher G, Hupalowska A, Bolton V, et al. Self-organization of the human embryo in the absence of maternal tissues. Nat Cell Biol. 2016;18:700–8.CrossRefPubMedPubMedCentralGoogle Scholar
Enderby C, Keller CA. An overview of immunosuppression in solid organ transplantation. A J Manag Care. 2015;21(1 Suppl):s12–23.Google Scholar
Hobelka E, Nielsen PJ, Medgyesi D. Signaling mechanisms regulating B-lymphocyte activation and tolerance. J Mol Med (Berl). 2015;93:145–58.Google Scholar
Shehadri S, Sunkara SK. Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis. Hum Reprod Update. 2014;20:429–38.CrossRefGoogle Scholar
Blackwell AD, Tamayo MA, Beheim B, Trumble BC, Stiglitz J, Hopper PL, et al. Helminth infection, fecundity, and age of first pregnancy in women. Science. 2015;350:970–2.CrossRefPubMedGoogle Scholar
Velasquez-Manoff M. The parasite underground. The New York Times Magazine, June 16, 2016.Google Scholar
Lin H, Mosmann TR, Guilbert L, Tuntipopipat S, Wegman TG. Synthesis of T helper 2-type cytokines at the maternal-fetal interface. J Immunol. 1993;151:4562–73.PubMedGoogle Scholar
Wortman AC, Casey BM, McIntire DD, Sheffield JS. Association of influenza vaccination on decreased stillbirth rate. Am J Perinatol. 2015;32:571–6.CrossRefPubMedGoogle Scholar
Sheffield JS, Greer LG, Rogers VL, Roberts SW, Lytle H, McIntire DD, et al. Effect of influenza vaccination in the first trimester of pregnancy. Obstet Gynecol. 2012;120:532–7.CrossRefPubMedGoogle Scholar
Bratton KN, Wardle MT, Orenstein WA, Omer SB. Maternal influenza immunization and birth outcomes of stillbirth and spontaneous abortion: a systematic review and meta-analysis. Clin Infect Dis. 2015;60:e11–9.CrossRefPubMedGoogle Scholar
Olsen SJ, Mirza SA, Vonglokham P, Khanthamaly V, Chitry B, Pholsena V, et al. The Effect of Influenza vaccination on birth outcomes in a cohort of pregnant women in Lao PDR, 2014-2015. Clin Infect Dis. 2016;63:487–94.CrossRefPubMedPubMedCentralGoogle Scholar
Regan AK, Moore HC, de Klerk N, Omer SB, Shellam G, Mak DB, et al. Seasonal trivalent influenza vaccination during pregnancy and the incidence of stillbirth: population-based retrospective cohort study. Clin Infect Dis. 2016;62:1221–7.CrossRefPubMedGoogle Scholar
Ibrahim SA, Ackerman 4th WE, Summerfield TL, Lockwood CJ, Schatz F, Kniss DA. Inflammatory gene networks in term human decidual cells define a potential signature for cytokine-mediated parturition. Am J Obstet Gynecol. 2016;214:284. e1—284 e47.CrossRefPubMedGoogle Scholar
Gleicher N. Does the immune system induce labor? Lessons from preterm deliveries in women with autoimmune diseases. Clin Rev Allergy Immunol. 2010;39:194–206.CrossRefPubMedGoogle Scholar
Clark CE, Fay MP, Chico ME, Sandoval CA, Vaca MG, Boyd A, et al. Maternal helminth infection is associated with higher infant immunoglobulin A titers to antigen in orally administered vaccines. J Infect Dis. 2016;213:1996–2004.CrossRefPubMedGoogle Scholar
ACOG. Committee opinion No 468: influenza vaccination during pregnancy. Obstet Gynecol. 2010;116:1006–7.CrossRefGoogle Scholar
Samy A, El-Enbaawy M, El-Sanousi AA, Nasef SA, Hikono H, Saito T. Initiation of regulation of immune responses to immunization with whole inactivated vaccines prepared from two genetically and antigenically distinct lineages of Egyptian influenza A virus subtype H5N1. Arch Virol. 2016;161:2797–806.CrossRefPubMedGoogle Scholar
Ppadatou I, Piperi C, Alexandraki K, Kattamis A, Theodoridou M, Spoulou V. Antigen-specific B-cell response to 13-valent pneumococcal conjugate vaccine in asplenic individuals with ß-thalasemia previously immunized with 23-valent pneumococcal polysaccharide vaccine. Clin Infect Dis. 2014;59:862–5.CrossRefGoogle Scholar
Goltz D, Huss S, Ramadori E, Büttner R, Diehl L, Meyer R. Immunomodulation by splenectomy or by FRY720 protects the heart against ischemia reperfusion injury. Clin Exp Pharmacol Physiol. 2015;42:1168–77.CrossRefPubMedGoogle Scholar
Gershovitz M, Sergienko R, Friedler JM, Wiznitzer A, Zlotnik A, Sheiner E. Pregnancy outcome in women following splenectomy. J Womens Health (Larchmt). 2011;20:1233–7.CrossRefGoogle Scholar