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Study Question: What is the role of carbohydrates in the binding of human sperm to the zona pellucida (ZP) and what are potential implications for pathogenesis?, Summary Answer: Both lectin-like and protein-protein interactions play an essential role in human gamete interactions., What Is Known Already: Studies in the mouse and human indicate a role for both lectin-like and protein-protein interactions during sperm binding to the ZP., Study Design, Size, Duration: Non-systematic literature review., Main Results and the Role of Chance: Ultrasensitive analysis by mass spectrometry of glycans linked to the human ZP has confirmed that this matrix is coated with a high density of complex type N-glycans terminated with the sialyl-Lewis(x) (sLe(x)) sequence, the universal selectin ligand. Selectins are essential for lymphocyte homing, and they participate in the initial binding of circulating leukocytes to activated endothelium at the sites of infection and tissue injury. Subsequent inhibition studies confirmed that either the sLe(x) tetrasaccharide or neoglycoproteins terminated with this sequence inhibited human sperm-ZP binding by 70% in the hemizona assay. These results support the hypothesis that both lectin-like and protein-protein interactions play an essential role in human gamete interactions. The sLe(x) sequence is also a ligand for siglec-9, a lectin-bearing immunoreceptor tyrosine-based inhibitory motif that transmits inhibitory signals. This siglec is expressed on a wide variety of different types of human leukocytes and lymphocytes. This result is consistent with the hypothesis that human ZP glycans are also being employed for immune recognition of the egg and the histoincompatible embryo prior to blastocyst hatching., Limitations, Reasons for Caution: This field of study is complex and more experimental work is needed to reveal fully the mechanism of sperm-ZP binding and how it varies between species., Wider Implications of the Findings: Knowledge about the glycans involved in sperm-egg binding may be relevant to infertility due to fertilization failure and also to the mother's immune tolerance of the preimplantation embryo., Study Funding/competing Interest(s): Studies focused on human sperm-egg interactions carried out by the author and coworkers have been supported by the Life Sciences Mission Enhancement Reproductive Biology Program funded by the State of Missouri, a Research Board Grant (CB000500) supported by the University of Missouri System and a grant from the Jeffress Memorial Trust of Virginia. Support from the Breeden-Adams Foundation has also been obtained to investigate potential linkages to tumor evasion. The author has no conflict of interest to declare.

Glycodelins are glycoproteins synthesized in various glands, with sequence homology to beta-lactoglobulins, and named according to their unique oligosaccharide structures. We purified, cloned and sequenced endometrium- and seminal plasma-derived glycodelins (GdA and GdS respectively) and found that they are involved in various types of cell-cell communications. These include interactions between the spermatozoon and the egg, and between immune cells and their targets. Endometrial GdA inhibits sperm-egg binding, whereas the differently glycosylated GdS in seminal plasma does not. These observation are of interest for reproductive physiology, detection of causes of infertility, and they also may have potential for contraceptive development.

The mechanisms underlying the protection of the human embryo/fetus from the maternal immune response are poorly understood. Substantial evidence indicates that carbohydrate recognition plays a primary role in the sequestration of leukocytes during inflammatory processes, lymphocyte homing, and initial gamete binding. Our previous studies suggest a possible convergence in the types of carbohydrate sequences recognized during initial human gamete binding and immune/inflammatory cell interactions. Our more recent findings indicate that oligosaccharides participating in such processes are also associated with soluble glycoconjugates found in the human placenta, amniotic fluid, and decidua. We theorize that such glycoconjugates may abrogate the maternal immune/inflammatory response by blocking the primary adhesive interactions required for the expression of such activities. Foreign embryonic cells may also be protected by surface expression of oligosaccharide sequences that suppress immune effector cell action in a manner not dependent upon classical major histocompatibility (MHC) recognition. Glycoconjugates expressing selectin ligands may also manifest a potent contraceptive effect that may also be beneficial for both the mother and the developing embryo/fetus. This hypothesis provides a preliminary framework for understanding how temporally and spatially restricted immunosuppressive effects could be expressed in utero that protect the human embryo/fetus during this period of human development.

Binding of spermatozoa to the zona pellucida is an initial, crucial recognition event leading to fertilization. In the mouse, the best species characterized so far, the zona pellucida protein 3 (ZP3) has a central role as the specific, primary sperm receptor on the zona and as the inducer of the acrosome reaction. This sequence of events is not clearly understood as it relates to human gametes. The ideal test for the evaluation of sperm-zona pellucida interaction is one that can examine these events in a sequential fashion (i.e. binding followed by the acrosome reaction) in a standardized and specific bioassay. Here we have used the hemizona assay as an internally controlled test to examine human sperm-zona pellucida interaction. Results presented show that: (i) the hemizona assay has an excellent predictive power for IVF outcome and for the identification of male infertility; (ii) using a specific anti-ZP3 antiserum in immunocytochemical studies, the hemizona assay allows for the identification of structural/functional anomalies of the protein backbone of human ZP3 (identification of oocyte anomalies); and (iii) glycobiological studies using the hemizona assay model indicate that the initial sperm-zona pellucida binding requires a seletin-like interaction between the human gametes. These efforts may help us to characterize the cellular and molecular mechanisms involved in human gametes and their dysfunctions in infertile patients.