Excretory and secretory products (ESPs) of nematode contain various proteins which are capable of inducing the instigation or depression of the host immune response and are involved in the pathogenesis of the worms. In the present study, Haemonchus contortus excretory and secretory products (HcESPs) were collected from the adult worms. Binding of HcESPs to goat peripheral blood mononuclear cells (PBMCs) was confirmed by immune-fluorescence assay. Effects of the HcESPs on cytokine production, cell proliferation, cell migration and nitric oxide (NO) production of PBMCs were checked by co-incubation of HcESPs with goat PBMCs. The results indicated that the production of IL-4 and IFN-γ were significantly decreased by HcESPs in dose dependent manner. On the contrary, the production of IL-10 and IL-17 were increased. Cell migration was significantly enhanced by HcESPs, whereas, HcESPs treatment significantly suppressed the cell proliferation and NO production. These results indicated that the HcESPs played important suppressive regulatory roles on PBMCs and provided highlights to the understanding of the host-parasite interactions.

Inflammation and the gut-brain axis have been implicated in the pathogenesis of autism spectrum disorders (ASDs). To further understand the relationship between aberrant immune responses and dysbiotic features of the gut microbiome in ASD, we enrolled 45 ASD individuals and 41 healthy control subjects with ages ranging from 2 to 19 years. We found that ASD group subjects have significantly higher plasma levels of IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α, TNF-β, and IFN-γ when compared to healthy controls (FDR-adjusted p < 0.05). The plasma levels of pro-inflammatory cytokines IFN-γ and IL-6 are found to be further associated with several largely pathogenic gut microbiota uniquely detected in subjects with ASD. Furthermore, the ASD gut microbiome is characterized by reduced levels of several beneficial microbiota, including Bacteroides (FDR-adjusted p < 0.01) and Lachnospiraceae (FDR-adjusted p < 0.001). Analysis of Lachnospiraceae family and genus level taxa suggested that relative abundances of such taxa are negatively correlated with pro-inflammatory signaling cytokines IFN-γ and IL-6, particularly in subjects with severe ASD as defined by CARS (p < 0.05). Several largely pathogenic genera are determined to be associated with the pro-inflammatory cytokines IFN-γ and IL-6 (FDR-adjusted p < 0.1). Additionally, IL-4 is significantly negatively correlated with CARS total score (p < 0.05). Based on such results, we propose that the association between the disturbances of specific cytokines and alterations in gut microbiota abundance observed in children and adolescents with ASD provides additional evidence on the induction of aberrant pro-inflammatory mechanisms in ASD and its early diagnosis.

Type I natural killer T (NKT) cells, or iNKT cells, express a semi-invariant T cell receptor characterized by its unique V α 14-Jα 18 usage (iV α 14TCR). Upon interaction with glycolipid/CD1d complexes, the iV α 14TCRs transduce signals that are essential for iNKT selection and maturation. However, it remains unclear how these signals are regulated and how important such regulations are during iNKT development. Diacylglycerol (DAG) is an essential second messenger downstream of the TCR that activates the PKCθ-IKKα/β-NFκB pathway, known to be crucial for iNKT development, as well as the RasGRP1-Ras-Erk1/2 pathway in T cells. DAG kinases (DGKs) play an important role in controlling intracellular DAG concentration and thereby negatively regulate DAG signaling. Here we report that simultaneous absence of DAG kinase α and ζ causes severe defects in iNKT development, coincident with enhanced IKK-NFκB and Ras-Erk1/2 activation. Moreover, constitutive IKKβ and Ras activities also result in iNKT developmental defects. Thus, DAG-mediated signaling is not only essential but also needs to be tightly regulated for proper iNKT cell development.

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