BackgroundA long-term existing schistosome infection can aid in maintaining immuno-homeostasis, thus providing protection against various types of autoimmune diseases to the infected host. Such benefits have often been associated with acute or egg stage infection and with the egg-induced Th2 response. However, since schistosome infection undergoes different stages, each associated with a specific induction of Th responses, the requirements for the ability of the different stages of schistosome infection to protect against autoimmune disease has not been elucidated. The present study was designed to study whether different stages of schistosome infection offer unique protection in collagen-induced arthritis and its mechanisms.ResultsArthritis susceptible strain DBA/1 male mice were infected with Schistosoma japonicum for either 2 weeks resulting in early stage infection or for 7 weeks resulting in acute or egg stage infection. Following Schistosoma japonicum infection, collagen II was administered to induce collagen-induced arthritis, an animal model for human rheumatoid arthritis. Infection by Schistosoma japonicum significantly reduced the severity and the incidence of experimental autoimmune collagen-induced arthritis. However, this beneficial effect can only be provided by a pre-established acute stage of infection but not by a pre-established early stage of the infection. The protection against collagen-induced arthritis correlated with reduced levels of anti-collagen II IgG, especially the subclass of IgG2a. Moreover, in protected mice increased levels of IL-4 were present at the time of collagen II injection together with sustained higher IL-4 levels during the course of arthritis development. In contrast, in unprotected mice minimal levels of IL-4 were present at the initial stage of collagen II challenge together with lack of IL-4 induction following Schistosoma japonicum infection.ConclusionThe protective effect against collagen-induced arthritis provided by Schistosoma japonicum infection is infection stage-dependent. Furthermore, the ability of schistosomiasis to negatively regulate the onset of collagen-induced arthritis is associated with a dominant as well as long-lasting Th2 response at the initiation and development of autoimmune joint and systemic inflammation.
Human amniotic fluid stem cells (hAFSCs) can be readily isolated from human amniotic fluid and display multi-differentiation potential and immunomodulatory properties. The mechanism of hAFSCs immunoregulation has not been defined. Here, we explore the immunomodulatory effects of hAFSCs derived from human amniotic fluid and evaluate the role of IL-10 and the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) in mediating the immunosuppressive actions of hAFSCs. Flow cytometry showed that hAFSCs were positive for the mesenchymal stem cell markers CD29, CD44, CD105, HLA-ABC, and more than 84% of the hAFSCs were positive for SSEA-4, which is a typical marker of embryonic stem cell (ESCs), and negative for HLA-DR. The RT-PCR and immunostaining results revealed that the multipotent stem cells expressed OCT-4, Nanog, CD44, SOX2 and SSEA-1. In vitro differentiation assays demonstrated that hAFSCs underwent osteogenic differentiation. We examined the immunomodulatory function of hAFSCs using a co-culture system with phorbol 12-myristate 13-acetate (PMA) stimulated peripheral blood mononuclear cells (PBMCs). PBMC proliferation was suppressed by the hAFSCs in a dose-dependent manner. The inhibitory effect was caused by increased IL-10 and IDO induction after co-culture. Neutralizing the IL-10 activity or blocking the function of IDO partially abolished the immunosuppressive action of the hAFSCs. In conclusion, these results suggest that the hAFSCs possess immunomodulatory properties, and IL-10 and IDO are involved in immunosuppression by hAFSCs.
Purpose Tubulin beta eight class VIII (TUBB8) is essential for oogenesis, fertilization, and pre-implantation embryo development in human. Although TUBB8 mutations were recently discovered in meiosis-arrested oocytes of infertile females, there is no effective therapy for this gene mutation caused infertility. Our study aims to further reveal the infertility-causing gene mutations in the patient's family and to explore whether the infertility could be rescued by optimizing the conditions of embryo culture and finally achieve the purpose of making the patient pregnant. Methods Whole-exome sequence analysis and Sanger sequencing were performed on patients' family members to screen and identify candidate mutant genes. Construction of plasmids, in vitro transcription, microinjection of disease-causing gene cRNA, and immunofluorescence staining were used to recapitulate the infertility phenotype observed in patients and to understand the pathogenic principles. Simultaneously, overexpression of mutant and wild-type cRNA of the candidate gene in mouse oocytes at either germinal vesicle (GV) or metaphase II (MII) stage was performed in the rescue experiment. Results We first identified a novel heritable TUBB8 mutation (c.1041C>A: p.N347K) in the coding region which specifically affects the first mitosis and causes the developmental arrest of early embryos in a three-generation family. We further demonstrated that TUBB8 mutation could lead to abnormal spindle assemble. And moreover, additional expression of wild-type TUBB8 cRNA in the mouse oocytes in which the mutant TUBB8 were expressed can successfully rescue the developmental defects of resulting embryo and produce full-term offspring. Conclusions Our study not only defines a novel mutation of TUBB8 causing the early cleavage arrest of embryos, but also provides an important basis for treating such female infertility in the future.
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