The Different Immune Responses by Age Are due to the Ability of the Fetal Immune System to Secrete Primal Immunoglobulins Responding to Unexperienced Antigens.

Among numerous studies on coronavirus 2019 (COVID-19), we noted that the infection and mortality rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) increased with age and that fetuses known to be particularly susceptible to infection were better protected despite various mutations. Hence, we established the hypothesis that a new immune system exists that forms before birth and decreases with aging. Methods: To prove this hypothesis, we established new ex-vivo culture conditions simulating the critical environmental factors of fetal stem cells (FSCs) in early pregnancy. Then, we analyzed the components from FSCs cultivated newly developed ex-vivo culture conditions and compared them from FSCs cultured in a normal condition. Results: We demonstrated that immunoglobulin M (IgM), a natural antibody (NAb) produced only in early B-1 cells, immunoglobulins (Igs) including IgG3, which has a wide range of antigen-binding capacity and affinity, complement proteins, and antiviral proteins are induced in FSCs only cultured in newly developed ex-vivo culture conditions. Particularly we confirmed that their extracellular vesicles (EVs) contained NAbs, Igs, various complement proteins, and antiviral proteins, as well as human leukocyte antigen G (HLA-G), responsible for immune tolerance. Conclusion: Our results suggest that FSCs in early pregnancy can form an independent immune system responding to unlearned antigens as a self-defense mechanism before establishing mature immune systems. Moreover, we propose the possibility of new solutions to cope with various infectious diseases based on the factors in NAbs-containing EVs, especially not causing unnecessary immune reaction due to HLA-G.

Study of immune-tolerized cell lines and extracellular vesicles inductive environment promoting continuous expression and secretion of HLA-G from semiallograft immune tolerance during pregnancy.

An immune reaction is a protector of our body but a target to be overcome for all non-self-derived medicine. Extracellular Vesicles (EVs), noted as a primary alternative to cell therapy products that exhibit immune rejection due to mismatching-major histocompatibility complex (MHC), were discovered to have excellent curative effects through the delivery of various biologically active substances. Although EVs are sure to incur immune reaction by immunogenicity due to alloantigens from their parental cells, their immune rejection is rarely known. Hence, to develop cell lines and EVs as medicines with no immune rejection, we noted the immune tolerance where the foetus, as semi-allograft, is perfectly protected from the maternal immune system. We designed the ex-vivo culture systems to simulate in-vivo environmental factors inducing extravillous trophoblast (EVT)-specific Human Leukocyte Antigen-G (HLA-G) expression and secretion of HLA-G-bearing EVs at the mother-foetus interface. Using them, we confirmed that immune-tolerized stem cells (itSCs) continuously expressing and secreting HLA-G like EVTs during pregnancy can be induced. Also, EVs secreted from itSCs are verified as immune-tolerized EVs (itSC-EVs) containing HLA-G and not causing immune rejection through various analytical methods. These findings can provide a new perspective on the local and extensive immune tolerance environment where HLA-G is expressed and secreted by pregnancy-related hormones and different biological conditions. Furthermore, they show the new way to develop itSCs-EVs-based therapeutics that are free from time, space, and donor limitation causing immune rejection. ABBREVIATIONS: CFSE: carboxyfluorescein succinimidyl ester; DC: dendritic cells; ELISA: enzyme-linked immunosorbent assay; EV: extracellular vesicles; EVT: extravillous trophoblast; FSH: follicle stimulating hormone; HA: hyaluronic acid; hCG: human chorionic gonadotropin; HLA-G: human leukocyte antigen G; iPSC: induced pluripotent stem cells; itSC-EVs: immune-tolerized extracellular vesicles from itSCs; itTBC-EVs: immune-tolerized extracellular vesicles from itTBCs; itSCs: immune tolerized stem cells; itTBCs: immune-tolerized trophoblast cells; LH: luteinizing hormone; MHC: major histocompatibility complex; MSC: mesenchymal stem cells; NK: natural killer cells; NTA: nanoparticle tracking analysis; PBMC: peripheral blood mononuclear cells; PHA: phytohemagglutinin; SP-IRIS: single particle interferometric reflectance imaging sensing; STB: syncytiotrophoblast.

Food protective effects of Periploca sepium oil and its active component against stored food mites.

The aim of this study was to examine the acaricidal activity of Periploca sepium oil and its active component against Tyrophagus putrescentiae. Based on its 50% lethal dose (LD(50) ) value, P. sepium oil (8.45 µg/cm(2)) was highly active against T. putrescentiae. The active constituent of P. sepium was isolated by chromatographic techniques and identified as 2-hydroxy-4-methoxybenzaldehyde. In the comparison with synthetic acaricides, the acaricidal activity of 2-hydroxy-4-methoxybenzaldehyde (0.94 µg/cm(2)) against T. putrescentiae was 12.2- and 31.2-fold greater than those of benzyl benzoate (11.45 µg/cm(2)) and N,N-diethyl-m-toluamide (29.33 µg/cm(2)), respectively. To establish structure-activity relationships, the acaricidal activities of 2-hydroxy-4-methoxybenzaldehyde and its derivatives against T. putrescentiae were determined by using an impregnated fabric disk bioassay. On the basis of LD(50) values, 4-methoxybenzaldehyde (0.48 µg/cm(2)) was the most effective against T. putrescentiae, followed by 3-methoxybenzaldehyde (0.82 µg/cm(2)), 2-hydroxy-5-methoxybenzaldehyde (0.92 µg/cm(2)), 2-methoxybenzaldehyde (0.95 µg/cm(2)), 2-hydroxybenzaldehyde (0.97 µg/cm(2)), and 2-hydroxy-3-methoxybenzaldehyde (2.35 µg/cm(2)). These results indicate that the introduction of a hydroxyl and/or methoxy group into the benzaldehyde skeleton increased the acaricidal activity. Therefore, 2-hydroxy-4-methoxybenzaldehyde and its derivatives could potentially be used as potent mite control agents.