LAUSR

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.