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Glycoproteins Presenting Galactose and N-Acetylgalactosamine in Human Seminal Plasma As Potential Players Involved in Immune Modulation in the Fertilization Process

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Glycoproteins Presenting Galactose and N-Acetylgalactosamine in Human Seminal Plasma As Potential Players Involved in Immune Modulation in the Fertilization Process International Journal of Molecular Sciences Article Glycoproteins Presenting Galactose and N-Acetylgalactosamine in Human Seminal Plasma as Potential Players Involved in Immune Modulation in the Fertilization Process Justyna Szczykutowicz 1 , Joanna Tkaczuk-Włach 2,3 and Mirosława Ferens-Sieczkowska 1,* 1 Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-369 Wrocław, Poland; [email protected] 2 Laboratory of Diagnostic Techniques, Medical University of Lublin, 20-081 Lublin, Poland; [email protected] 3 Family Health Centre AB OVO, 20-819 Lublin, Poland * Correspondence: [email protected] Abstract: In light of recent research, there is increasing evidence showing that extracellular semen components have a significant impact on the immune reaction of the female partner, leading to the tolerogenic response enabling the embryo development and implantation as well as further progress of healthy pregnancy. Seminal plasma glycoproteins are rich in the unique immunomodulatory glycoepitopes that may serve as ligands for endogenous lectins that decorate the surface of immune cells. Such interaction may be involved in modulation of the maternal immune response. Among immunomodulatory glycans, Lewis type antigens have been of interest for at least two decades, while the importance of T/Tn antigens and related structures is still far from understanding. In the current work, we applied two plant lectins capable of distinguishing glycoepitopes with terminal GalNAc Citation: Szczykutowicz, J.; and Gal to identify glycoproteins that are their efficient carriers. By means of lectin blotting and Tkaczuk-Włach, J.; lectin affinity chromatography followed by LC-MS, we identified lactotransferrin, prolactin inducible Ferens-Sieczkowska, M. protein as well as fibronectin and semenogelins 1 and 2 as lectin-reactive. Net-O-glycosylation Glycoproteins Presenting Galactose analysis results indicated that the latter three may actually carry T and/or Tn antigens, while in the and N-Acetylgalactosamine in case of prolactin inducible protein and lactotransferrin LacdiNAc and lactosamine glycoepitopes Human Seminal Plasma as Potential were more probable. STRING bioinformatics analysis linked the identified glycoproteins in the Players Involved in Immune close network, indicating their involvement in immune (partially innate) processes. Overall, our Modulation in the Fertilization research revealed potential seminal plasma ligands for endogenous Gal/GalNAc specific lectins with Process. Int. J. Mol. Sci. 2021, 22, 7331. https://doi.org/10.3390/ijms22147331 a possible role in modulation of maternal immune response during fertilization. Received: 18 June 2021 Keywords: infertility; glycome; T/Tn antigens; carbohydrate-protein interaction; maternal tolerance Accepted: 5 July 2021 Published: 8 July 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in Over the last few decades, scientists have been trying to explain the intriguing mystery published maps and institutional affil- in immunology, which is keeping male gametes and a fetus, presenting non-self-paternal iations. antigens, safe from maternal immune reaction. Various hypotheses have been proposed to explain this phenomenon, including fetal antigen immaturity, strong suppression of the mother’s immune system during pregnancy, and strict impermeability of the blood- placenta barrier. None of these hypotheses was fully confirmed. Some recent data indicate Copyright: © 2021 by the authors. the engagement of seminal plasma (SP) components in the interactions involved in the Licensee MDPI, Basel, Switzerland. creation of an appropriate maternal immune balance, allowing selective tolerance for This article is an open access article gametes and developing trophoblast, without inactivation of the effective response to the distributed under the terms and infections [1]. conditions of the Creative Commons According to the fetoembryonic defense hypothesis, the interactions involved in Attribution (CC BY) license (https:// the development of immune tolerance during fertilization and pregnancy are based on creativecommons.org/licenses/by/ recognition of the sugar moieties by the maternal immune system [2–4]. The hypothesis 4.0/). Int. J. Mol. Sci. 2021, 22, 7331. https://doi.org/10.3390/ijms22147331 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 20 Int. J. Mol. Sci. 2021, 22, 7331 2 of 20 According to the fetoembryonic defense hypothesis, the interactions involved in the development of immune tolerance during fertilization and pregnancy are based on recog- nition of the sugar moieties by the maternal immune system [2–4]. The hypothesis as- assumessumes that that these these protein–carbohydrate protein–carbohydrate bindings bindings in in the the female female reproductive reproductive tract in thethe post-coitalpost-coital periodperiod areare similarsimilar toto thethe mechanismmechanism exploitedexploited byby pathogenspathogens andand metastaticmetastatic cancercancer cellscells toto escapeescape fromfrom thethe controlcontrol ofof hosthost immuneimmune systemsystem [[3,5].3,5]. BothBoth pathogenspathogens andand cancer cellscells presentpresent surfacesurface glycanglycan antigens that are normallynormally absentabsent (or extremelyextremely rare)rare) inin thethe glycoproteinsglycoproteins ofof healthyhealthy humanhuman bodybody fluids.fluids. Surprisingly,Surprisingly, similarsimilar carbohydratescarbohydrates are abundant on the sperm surface and in seminalseminal plasma glycoproteins of healthy, fertilefertile men [[4,6].4,6]. So far, thethe researchresearch relatedrelated toto thethe analysisanalysis ofof semensemen glycosylationglycosylation patternpattern hashas been focused on on the the glycoepitopes glycoepitopes containing containing fucose fucose and and sialic sialic acid, acid, considered considered to be to im- be immunomodulatorymunomodulatory [7–12]. [7–12 ].Such Such terminal terminal glycoe glycoepitopespitopes can can be be presented presented on on both N- andand O-glycans. To date, muchmuch moremore researchresearch concernsconcerns thethe N-glycomeN-glycome becausebecause ofof itsits relativerelative technical ease. This approach, however, removes from the field of interest an important technical ease. This approach, however, removes from the field of interest an important category of truncated O-glycans, including T and sialo T/Tn antigens, though they are also category of truncated O-glycans, including T and sialo T/Tn antigens, though they are also assigned with an immunomodulatory role (Figure1)[13–15]. assigned with an immunomodulatory role (Figure 1) [13–15]. FigureFigure 1.1. TheThe schematicschematic representationrepresentation ofof seminalseminal plasmaplasma glycanglycan structures,structures, highlightinghighlighting thethe antigensantigens analyzedanalyzed inin thisthis study.study. ImagesImages were were taken taken from from Servier Servie Medicalr Medical Art Art (https://smart.servier.com (https://smart.servier.com (accessed (accessed on on 14 14 June June 2021)) 2021)) and and modified modified by theby the authors authors under under the the following following terms: terms: Creative Creative Commons Commons Attribution Attribution 3.0 Unported3.0 Unported License. License. Thomsen–Friedenreich related antigens, T (Galβ1-3GalNAcα1-R), Tn (T precursor, GalNAcα1-R) and and sialyl-Tn sialyl-Tn (NeuAc (NeuAcαα2-6GalNAc2-6GalNAcαα1-R)1-R) are are known known as ascancer cancer associated associated an- antigens.tigens. Such Such antigens antigens are present are present in approximately in approximately 90% of 90% all ofcancers. all cancers. Though Though T-antigen T- antigenmay be mayalso expressed be also expressed in the normal in the normalepitheli epithelium,um, Tn seems Tn to seems be strictly to be strictlycancer-related cancer- related[16–20].[ 16Thomsen–Friedenreich–20]. Thomsen–Friedenreich related related antigens antigens have been have correlated been correlated with withcancer cancer pro- progressiongression and and poor poor prognosis prognosis [13,21–24]. [13,21– 24Interestingly,]. Interestingly, it has it hasbeen been also alsosuggested suggested that thatpre- predominancedominance of Tn of over Tn over T is Tassociated is associated with with a high a high metastatic metastatic potential potential of carcinoma, of carcinoma, thus thusresulting resulting in more in more effective effective evasion evasion from from the immune the immune system system control control [17–19]. [17– 19 ]. Mucin-type glycosylation was confirmedconfirmed in seminal plasma components by Miluti- novi´cetnović etal. al. [ 25[25]] and and different different O-glycan O-glycan structures, structures, including including T antigen, T antigen, were were earlier earlier reported re- byported Pang by et Pang al. [4 et]. al. There [4]. isThere no informationis no information to show to show whether whether T/Tn T/Tn antigens antigens may may be the be nextthe next category category of glycospecies of glycospecies important important for immunomodulationfor immunomodulation during during fertilization. fertilization. In theIn the current current work, work, the the two two plant plant lectins, lectins,Vicia Vicia villosa villosa(VVL) (VVL) and andMaclura Maclura pomiferapomifera (MPL),(MPL), werewere used to to detect detect truncated truncated O-glycans O-glycans and and related related structures structures in the in theseminal seminal
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