Journal: International Journal of Biological Sciences
Article Title: The Different Immune Responses by Age Are due to the Ability of the Fetal Immune System to Secrete Primal Immunoglobulins Responding to Unexperienced Antigens
doi: 10.7150/ijbs.67203
Figure Lengend Snippet: Suggested Primal Immune System as a Self Defense Mechanism of Fetal Stem Cells before the establishment of innate and adaptive immune systems. Since virus invasion and infection into host cells are affected by the host's innate and adaptive immune responses, it was recognized that the fetus was very susceptible to viral infection before forming innate and adaptive immune systems. However, our results for FSCs in early pregnancy suggest that the fetus possesses very complicated and sophisticated self-defense mechanisms (primal immune system) at the cellular level exist in addition to the protective function of the placental TBC, which was considered as the only barrier to protect the fetus from external infections so far. (A) Extracellular defense mechanism by secretion of NAbs and complement proteins. Our results show that FSCs in early pregnancy can produce and secrete various NAbs, including IgP (fetal IgG3) polyreactive to unexperienced antigens, along with complement proteins to eliminate external pathogens immediately by CDC and ADCC, before umbilical cord generation, the main delivery route of maternal IgG, and before the complete development of B cells. In particular, IgP secreted from early pregnancy FSCs was proved to have the primal Ig repertoire that can instantly recognize various antigenic epitopes pathogens. Furthermore, IgP has the most outstanding Fc effector function to induce ADCC by binding with the highest affinity to Fcγ receptor of NK cells. These functions of IgP may contribute to much effective removal of the infectious agents. Also, we demonstrated that itPG-FSCs could secrete various NAbs such as IgP, IgM, and IgA as they contained factors, including Igll1, Pax5, and Cstf, that promote the secretion of soluble Igs. This finding may indicate that the primal immune system can establish the protective mechanism against various infection routes such as the upper respiratory tract in addition to the placenta and maternal blood. (B) The defense mechanism in the cellular and endosomal membranes to inhibit virus entry and replication by IFN-inducing proteins. Over the past decade, several IFN-inducible proteins, including interferon-inducible transmembrane family (IFITMs), ArfGAP with dual pleckstrin homology (PH) domains 2 (ADAP2), gamma-interferon-inducible lysosome/endosome-localized thiolreductase (GILT), and LY6E, have been known to regulate the infectious entry of various viruses . Still, few studies have been performed on the fetus during pregnancy. However, we proved through new ex-vivo culture conditions containing HSC/UCB-MSC CO -EVs that the expressions of IFN-inducible proteins such as IFITM3, LY6E, and HLA-G were increased in fetal stem cells by increased IFN stimulation. Our results that itPG-FSC-EVs contained a higher level of LY6E and IFITM3 than FSC-EVs suggest that FSCs also have a sophisticated self-protection mechanism that suppresses the viral infection by LY6E mainly expressed in the plasma membrane at the beginning of virus entry and by IFITM3 expressed in the endosomal membrane after cell entry. In addition, membrane-bound HLA-G, whose expression is increased by IFN stimulation, may inhibit the relative expression of receptors that can be used as entry pathways of viruses and protect infected host cells by inducing delayed immune response through trogocytosis by contact with immune cells . (C) Intercellular defense mechanism to inhibit virus transmission by activating anti-viral autophagy. Transient Receptor Potential Mucolipin Subfamily (TRPMLs) are proteins constituting endosome cation channels and perform various physiological functions. TRPML1 is receiving attention as a target molecule that inhibits the fusion of the SARS-CoV-2 envelopes and endosomes , and a novel role of TRPML2, only expressed in the recycled endosome, in the innate immune response was recently revealed , but there is still little study on fetal stem cells during pregnancy. From our results, the expression of TRPML2 was increased in itPG-FSC EVs. We intend to suggest a new mechanism that the viral antigen information degraded by IFITMs upregulated by interferon stimulation acts as a pattern recognition receptor (PRR), thereby increasing TRPML2 expression , . In addition, upregulated TRPML2 may contribute to the intracellular protective mechanism that can prevent the replication of infected inhibits virus by binding to the endosomes containing the virus entering the cell, thereby inhibiting the entry of the virus into the cell nucleus and by inducing the degradation through anti-viral autophagy (lysosomal degradation).
Article Snippet: FSCs were harvested and stained with anti-Human CD73 APC (Invitrogen by Thermo Fisher Scientific, Waltham, MA, USA), anti-Human CD90 APC (Invitrogen), anti-Human CD105 APC (Invitrogen), anti-Human SSEA-4 AF488 (Invitrogen), anti-HLA-G 87G APC (BioLegend, San Diego, CA, USA), anti-HLA-G 2A12 FITC (Invitrogen), anti-Human IgG Fc AF488 (BioLegend), anti-Human IgG3 Hinge AF555 (SouthernBiotech, Birmingham, AL, USA), anti-Human IgG3 AF488 (Novus Biologicals, Centennial, CO, USA), and anti-Human IgM AF647 (BioLegend) Abs for 30 min at room temperature.
Techniques: Virus, Infection, Binding Assay, Ex Vivo, Clinical Proteomics, Membrane, Expressing, Transmission Assay
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