Abstract
The ovary does not have a distinct morphologic barrier between the immune system and the developing gametes. This is in contrast to the testis in which the junctional complexes between the Sertoli cells form the blood—testis barrier. Whereas there are numerous factors, including genetic ones, associated with ovarian dysfunction, the immune factors have frequently been implicated in ovarian dysfunction. Much of our knowledge used to evaluate the immune system of the ovary has come from studies on the expression of the zona pellucida (ZP) proteins during ovarian development. Initial studies by Dunbar and colleagues1,2 demonstrated that immunization of rabbits with porcine ZP proteins (but not rabbit ZP proteins) would result in the generation of antibodies that inhibit sperm binding to the ZP and interfere with normal ovarian follicular development.
In contrast to the rabbit and primate models, immunization of mice or rats with porcine ZP proteins does not have an effect on fertility or ovarian function although immunization of certain strains of mice with mouse ZP peptides and immune activator systems has been shown to result in ovarian pathology. Whereas immune inflammatory reactions have been observed in the mouse models, no such immune reactions have been observed in rabbit, guinea pig, or nonhuman primate models.
Subsequent observations in nonhuman primates have shown that immunization of primates with ZP proteins expressed from cDNAs coding for the mouse and rabbit ZP2 (the mouse homologue has 60% amino acid identity with human ZP2) or the mouse ZP3 (the mouse protein has 67% amino acid identity with human ZP3) causes ovarian dysgenesis. In contrast, immunization of primates with recombinant rabbit ZP1 protein (the mouse homologue has 39%o amino acid identity with human ZP1) does not affect nonhuman primate ovarian function or follicular development but will elicit antibodies that inhibit sperm binding to the primate ZP. These studies have collectively provided important information concerning the immunologic status of the ovary and demonstrate the species variations in immune responses to different ovarian immunogens.
Article PDF
Avoid common mistakes on your manuscript.
References
Wood D, Liu C, Dunbar BS. The effect of alloimmunization and heteroimmunization with zonae pellucidae on fertility in rabbits. Biol Reprod 1981;25:439–50.
Skinner SM, Mills T, Kirchick HJ, Dunbar BS. Immunization with zona pellucida proteins results in abnormal ovarian follicular differentiation and inhibition of gonadotropin-induced steroid secretion. Endocrinology 1984;115:2418–32.
Baker TB. Oogenesis and ovulation. In: Austin CR, ed. Reproduction in mammals. 1: Germ cells and fertilization. Cambridge, UK: Cambridge University Press, 1982:17–46.
Dunbar BS. Ovarian antigens and infertility. Am J Reprod Immunol 1989;21:28–31.
Gougeon A. Regulation of ovarian follicular development in primates: Facts and hypothesis. Endocrine Rev 1996;17:121–55.
Erickson GF. Ovarian anatomy and physiology. In: Lobo RA, Kelsey J, Marcus R, eds. Menopause: Biology and pathobiology. New York: Academic Press, 2000:13–28.
Liu C, Litscher ES, Mortillo S, Sakai Y, Kinloch RA, Stewart CL, et al. Targeted disruption of the mZP3 gene results in the production of eggs lacking a zona pellucida and infertility in female mice. Proc Natl Acad Sci U S A 1996;93:5431–6.
Rankin T, Familiari M, Lee E, Ginsberg AM, Dwyer N, Blanchette-Mackie J, et al. Mice homozygous for an insertional mutation in the ZP3 gene lack a zona pellucida and are infertile. Development 1996;122:2903–10.
Rankin T, Prue T, Lee E, Dean J. Abnormal zonae pellucidae in mice lacking ZP1 result in early embryonic loss. Development 1999;126:3847–55.
Dunbar BS, Shivers CS. Immunological aspects of sperm receptors on the zona pellucida of mammalian eggs. Immunol Commun 1976;5:375–86.
Grotenhuis AJ, Philipsen H, de Breet-Grijsbach J, van Duin M. Immunocytochemical localization of ZP3 in primordial follicles of rabbit, marmoset, rhesus monkey and human ovaries using antibodies against human ZP3. J Reprod Fertil 1996;50(Suppl):43–54.
Sinowatz F, Amselgruber W, Topfer-Petersen E, Totzauer I, Calvette J, Plendl J. Immunocytochemical characterization of porcine zona pellucida during follicular development. Anat Embryol 1995;191:41–6.
Totzauer I, Kolle S, Sinowatz F, Plendl J, Amselgruber W, Topfer-Petersen E. Localization of the zona glycoproteins ZPB (ZP3 alpha) and ZPC (ZP3 beta) in the bovine ovary during pre-and postnatal development. Anat Anz 1998;180:37–43.
Prasad S, Skinner SM, Carino C, Wang N, Cartwright J, Dunbar BS. Structure and function of the proteins of the mammalian zona pellucida. Cells Tissues Organs 2000;166:148–64.
Kolle S, Sinowatz F, Boie G, Totzauer I, Amselgruber W, Plendl J. Localization of the zona pellucida ZP3 alpha and its mRNA in the porcine ovary, ooyte and embryo by in situ protein blotting and in situ hybridization. Histochem J 1996;28:441–7.
Kolle S, Sinowatz F, Boie G, Totzauer I, Amselgruber W, Plendl J. Localization of the mRNA encoding the zona protein ZP3α in the porcine ovary, oocyte and embryo by non radioactive in situ hybridization. Histochem J 1996;28:441–7.
Wolgemuth DJ, Celenza J. Bundman DS, Dunbar BS. Formation of the rabbit zona pellucida and its relationship to ovarian follicular development. Dev Biol 1984;106:1–14.
Lee VH, Dunbar BS. Developmental expression of the rabbit 55-kDa zona pellucida protein and messenger RNA in ovarian follicles. Dev Biol 1993;155:371–82.
Prasad SV, Wilkins B, Skinner SM, Dunbar BS. Evaluating zona pellucida structure and function using antibodies to 55kDa ZP protein expressed in baculovirus expression system. Mol Reprod Dev 1996;43:519–29.
Lee VH. Expression of rabbit zona pellucida-1 messenger ribonucleic acid during early follicular development. Biol Reprod 2000;63:401–8.
Maresh GA, Timmons T, Dunbar B. Effects of extracellular matrix on the expression of specific ovarian proteins of cultured primary ovarian follicles. Biol Reprod 1990;43:965–76.
Lee VH, Dunbar BS. Developmental expression of the rabbit 55-kDa zona pellucida protein and messenger RNA in ovarian follicles. Dev Biol 1993;155:371–82.
Philpott CC, Ringuette MJ, Dean J. Oocyte-specific expression and developmental regulation of ZP3, the sperm receptor of the mouse zona pellucida. Dev Biol 1987;121:568–75.
Millar SE, Lader E, Liang L, Dean J. Oocyte-specific factors bind a conserved upstream sequence required for mouse zona pellucida promoter activity. Mol Cell Biol 1991;11:6197–204.
Epifano O, Liang L, Familari M, Moos MC, Dean J. Coordinate expression of the three zona pellucida genes during mouse oogenesis Development 1995;121:1947–56.
Richards J, Fitzpatric S, Clemens J, Morris J, Alliston T, Sirois J. Ovarian cell differentiation: A cascade of multiple hormones, cellular signals, and regulated genes. Recent Progr Hormone Res 1995;50:223–54.
Eppig JJ. Mammalian oocyte development. In: Hillier SG, ed. Ovarian endocrinology. Oxford: Blackwell Scientific, 1991:107–31.
Kumar T, Wang Y, Lu N, Matzuk M. Follicle stimulating hormone as required for ovarian follicle maturation but not male fertility. Nat Genet 1997;15:201–4.
Cattanach B, Iddon C, Charlton H, Chiappa S, Fink G. Gonadotrophin-releasing hormone deficiency in a mutant mouse with hypogonadism. Nature 1977;269:338–40.
Elvin JA, Matzuk MM. Mouse models of ovarian failure. Rev Reprod 1998;3:183–95.
Manova K, Huang EJ, Angeles M, De Leon V, Sanchez S, Pronovost SM, Besmer P, et al. The expression pattern of the c-Kit ligand in gonads of mice supports a role for the c-kit receptor in oocyte growth and in proliferation of spermatogonia. Dev Biol 1993;157:85–99.
Carabatsos MJ, Elvin JA, Matzuk MM, Albertini D. Characterization of oocyte and follicle development in growth differentiation factor-9-deficient mice. Dev Biol 1998;204:373–84.
Hayashi M, McGee EA, Min G, Klein C, Rose UM, van Duin M, et al. Recombinant growth differentiation factor-9 (GDF-9) enhances growth and differentiation of cultured early ovarian follicles. Endocrinology 1999;140:1236–44.
Aaltonen J, Laitinen MP, Vuojolainen K, Jaatinen R, Horelli-Kuitunen N, Seppa L, et al. Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B are expressed in oocytes during early folliculogenesis. J Clin Endocrinol Metab 1999;84:2744–50.
Elvin JA, Changning Y, Pei W, Katsuhiko N, Matzuk M. Molecular characterization on the follicle defects in the growth differentiation factor 9-deficient ovary. Mol Endocrinol 1999;13:1018–34.
Elvin JA, Clark AT, Wang P, Wolfman NM, Matzuk MM. Paracrine actions of growth differentiation factor in the mammalian ovary. Mol Endocrinol 1999;13:1035–48.
Shivers CA, Dunbar BS. Autoantibodies to zona pellucida: A possible cause of infertility in women. Science 1977;197:1082–4.
Coulam C. The prevalence of autoimmune disorders among patients with primary ovarian failure. Am J Reprod Immunol Microbiol 1983;4;63–6.
Bosquet D, Jacques S, Roberts IKS, Chapdelaine A, Bleau G. Zona pellucida antibodies in a group of women with idiopathic infertility. Am J Reprod Immunol Microbiol 1982;2:73–8.
Horesjsi J, Martinek J, Novakova D, Madar J, Brandejska M. Autoimmune antiovarian antibodies and their impact on the success of an IVF/ET program. Ann NY Acad Sci 2000;900:351–6.
Lou Y, Park K, Agersborg S, Alard P, Tung K. Retargeting T cell-mediated inflammation: A new perspective on autoantibody action. J Immunol 2000;164:5251–7.
Ushiogoe K, Irahara M, Fukumochi M, Kamada M, Aono T. Production and regulation of cytokine-induced neutrophil chemoattractant in rat ovulation. Biol Reprod 2000;63:121–6.
Kol S, Wong K, Ando M, Ben-Shlomo I, Adashi E. Rat ovarian interleukin-lalpha:interleukin-1-dependent in vitro expression. Endocrine 1999;11:269–75.
Taguchi O, Nishizuka Y, Sakakura T, Kojima A. Autoimmune oophoritis in thymectomized mice: Detection of circulating antibodies against oocytes. Clin Exp Immunol 1980;40:540–53.
Dunbar BS. Role of ovarian antigens in fertility and infertility. In: Kurpisz M, Fernandez N, eds. Immunology of human reproduction. Oxford, UK: BIOS Scientific Ltd., 1995:115–32.
Skinner S, Prasad S, Ndolo R, Dunbar B. Zona pellucida antigens: Targets for contraceptive vaccines. Fertil Steril J Reprod 1996;35(Suppl):163–74.
Skinner S, Timmons T, Schwoebel E, Dunbar BS. The role of zona pellucida antigens in fertility and infertility. Immunol Allergy Clin North Am 1990;10:185–97.
Jones GR, Sacco AG, Subramanian MG, Kruger M, Zhang S, Yurewicz EC, et al. Histology of ovaries of female rabbits immunized with deglycosylated zona pellucida macromolecules of pigs. J Reprod Fertil 1992;95:513–25.
Kerr PJ, Jackson RJ, Robinson AJ, Swan J, Silvers L, French N, et al. Infertility in female rabbits (Oryctolagus cunicultis) alloimmunized with the rabbit zona pellucida protein ZPB either as a purified recombinant protein or expressed by recombinant myxoma virus. Biol Reprod 1999;61:606–13.
Lee VH, Soch, JF, Dunbar BS. Effects of immunization with zona pellucida (ZP) proteins on ovarian development in the guinea pig. (Abstract #321) Biol Reprod 1992;46:131.
Mahi Brown CA, Yanagimachi R, Nelson ML, Yanagimachi H, Palumbo N. Ovarian histopathology of bitches immunized with porcine zonae pellucidae. Am J Reprod Immunol Microbiol 1988;18:94–103.
VandeVoort CA, Schwoebel ED, Dunbar BS. Immunization of monkeys with recombinant cDNA expressed zona pellucida proteins. Fertil Steril 1995;64:838–47.
Paterson M, Thillai Koothan P, Morris KD, O’Byrne KT, Braude P, Williams A, Aitken RJ. Analysis of the contraceptive potential of antibodies against native and deglycosylated porcine ZP3 in vivo and in vitro. Biol Reprod 1992;46:523–34.
Aitken RJ, Paterson M, van Duin M. The potential of the Zona pellucida as a target for immunocontraception. Am J Reprod Immunol 1996;35:175–80.
Sacco AG, Pierce DL, Subramanian MG, Yurewicz EC, Dukelow WR. Ovaries remain functional in squirrel monkeys (Saimiri sciureus) immunized with procine zona pellucida 55,000 macro-molecule. Biol Reprod 1987;36:481–90.
Sacco AG, Yurewicz EC, Subramanian MG, Ye L, Dukelow WR. Immunologic response and ovarian histology of squirrel monkeys (Saimiri sciureus) immunized with porcine zona pellucida ZP3 (Mr = 55,000) macromolecules. Am J Primatol 1991;24:15–28.
Dunbar BS, Lo C, Stevens V. Effect of immunization with purified porcine zona pellucida proteins on ovarian function in baboons. Fertil Steril 1989;52:311–8.
Govind CK, Gupta SK. Failure of female baboons (Papio anubis) to conceive following immunization with recombinant non-human primate zona pellucida glycoprotein-B expressed in Escherichia coli. Vaccine 2000;18:2970–8.
Sacco AG, Subramanian MG, Yurewicz EC. Active immunization of mice with porcine zonae pellucidae: Immune response and effect on fertility. J Exp Zool 1981;218:405–18.
Millar SE, Chamow SM, Baur AW, Oliver C, Robey I, Dean J. Vaccination with a synthetic zona pellucida peptide produces long term contraception in the mouse. Science 1989;246:935–8.
Lou YH, Tung KK. T cell peptide of a self protein elicits autoantibody to the protein antigen. J Immunol 1.993;151:5790–9.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by the Mellon Foundation, Contraceptive Research and Development Program (CONRAD), and NIHCHD12547. This research was also sponsored by NICHD/NIH through cooperative agreement UA5 HD-07495 as part of the Specialized Cooperative Centers Program, in Reproduction Research.
Rights and permissions
This article is published under an open access license. Please check the 'Copyright Information' section either on this page or in the PDF for details of this license and what re-use is permitted. If your intended use exceeds what is permitted by the license or if you are unable to locate the licence and re-use information, please contact the Rights and Permissions team.