• Covington Grimes posted an update 6 months ago

    These findings suggested that apremilast alleviated EAU by regulating Th17 and Treg through the PI3K/AKT/FoxO1 pathway.Sporotrichosis is a subcutaneous mycotic infection, and Sporothrixglobosa is one of the causative agents with a worldwide distribution, notably in Asia. However, the immune profile in human sporotrichosis caused by S. globosa still remains obscure. Here, we demonstrated enhanced Th2 response in circulation with significant increases in Th2 frequency, Th2/Tregs as well as IL-4 seretion in patients. Elevated IL-17A+Th17 percentage was accompanied with reduced IL-17A level in serum, which may imply a dysfunction of this CD4+T subset in S. globosa infection. In addition, Th2 percentage, the ratios of Th2/Tregs and Th17/Tregs were all raised in patients with fixed cutaneous form, while only Th2/Tregs displayed increment in lymphocutaneous form. Meanwhile, the percentage of double negative B cells was significantly increased and positively correlated with Th2 and Tregs in whole patients. Except naïve B cells, all memory B cells together with Th2 cells increased in patients with short duration (less than 6 months), which may suggest a collaboration of T cells with altered B cell profile in human sporotrichosis caused by S. globosa. In consistent with the changes of IFN-γ+Th1, IL-4+Th2 and IL-17A+Th17 in patients with short duration, the percentages of these effector T cells all expanded when cocultured with S. globosa yeast cells in vitro. These data shed light on the potential involvement of peripheral T and B cell immunity against this mycotic infection and indicated that different immune responses existed in different stages of sporotrichosis; meanwhile different immune profile may contribute to different clinical manifestations of this disease.A hallmark of enteroaggregative Escherichia coli (EAEC) infection is the formation of an intestinal biofilm, which comprises a mucus layer with immersed bacteria. Pic is an autotransporter secreted by EAEC, and other E. coli pathotypes, and has been involved in two apparently contradictory phenotypes, as a mucus secretagogue and as a mucinase. Here, we investigated this Pic dual activity, mucus secretagogue capability and mucinolytic activity, in human goblet cells that secrete MUC2 and MUC5AC. Pic induced mucus hypersecretion directly in the goblet cells, without other intestinal cell types involved. At the same time, Pic exhibited strong proteolytic activity on the secreted mucins. These activities were independent since a mutation in the serine protease motif (PicS258I) abolished mucin degradation while maintaining the mucus secretagogue activity intact. Furthermore, deoxycholic acid (DCA)-induced mucins were proteolytically degraded when goblet cells were co-incubated with DCA/Pic, while co-incubation with DCA/PicS258I induced a synergistic effect on mucus hypersecretion. Pic was more efficient degrading MUC5AC than MUC2, but no degradation was detected with Pic inactivated at the active site by mutation or pharmacological inhibition. Remarkably, Pic cleaved MUC2 and MUC5AC in the C-terminal domain, leaving N-terminal subproducts, impacting the feature of gel-forming mucins and allowing mucus layer penetration by EAEC. Astonishingly, Pic stimulated rapid mucin secretion in goblet-like cells by activating the intracellular calcium pathway resulting from the PLC signal transduction pathway, leading to the production of DAG and releasing IP3, a second messenger of calcium signaling. Selleckchem Ferroptosis inhibitor Therefore, the dual activity of Pic, as a mucus secretagogue and a mucinase, is relevant in the context of carbon source generation and mucus layer penetration, allowing EAEC to live within the layer of mucus but also access epithelial cells.Repeated infections by Plasmodium falciparum result in a humoral response that could reduce disease symptoms and prevent the development of clinical malaria. The principal mechanism underlying this humoral response is that immunoglobulin G (IgG) binds directly to the parasites, thus causing their neutralization. However, the action of antibodies alone is not always sufficient to eliminate pathogens from an organism. One key element involved in the recognition of IgG that plays a crucial role in the destruction of the parasites responsible for spreading malaria is the family of Fc gamma receptors. These receptors are expressed on the surface of immune cells. Several polymorphisms have been detected in the genes encoding these receptors, associated with susceptibility or resistance to malaria in different populations. In this review, we describe identified polymorphisms within the family of Fc gamma receptors and the impact of these variations on the response of a host to infection as well as provide new perspectives for the design of an effective vaccine for malaria.Piscirickettsia salmonis, an aggressive intracellular pathogen, is the etiological agent of salmonid rickettsial septicemia (SRS). This is a chronic multisystemic disease that generates high mortalities and large losses in Chilean salmon farming, threatening the sustainability of the salmon industry. Previous reports suggest that P. salmonis is able to survive and replicate in salmonid macrophages, inducing an anti-inflammatory environment and a limited lysosomal response that may be associated with host immune evasion mechanisms favoring bacterial survival. Current control and prophylaxis strategies against P. salmonis (based on the use of antibiotics and vaccines) have not had the expected success against infection. This makes it urgent to unravel the host-pathogen interaction to develop more effective therapeutic strategies. In this study, we evaluated the effect of treatment with IgM-beads on lysosomal activity in Atlantic salmon macrophage-enriched cell cultures infected with P. salmonis by analyzing the new important evidence to understand the bacterial evasion mechanisms established by P. salmonis and contribute to the development of new effective therapeutic strategies against SRS.While chimeric antigen receptor-modified T (CAR-T) cells have shown great success for the treatment of B cell leukemia, their efficacy appears to be compromised in B cell derived lymphoma and solid tumors. Optimization of the CAR design to improve persistence and cytotoxicity is a focus of the current CAR-T study. Herein, we established a novel CAR structure by adding a full length 4-1BB co-stimulatory receptor to a 28Z-based second generation CAR that targets CD20. Our data indicated that this new 2028Z-4-1BB CAR-T cell showed improved proliferation and cytotoxic ability. To further understand the mechanism of action, we found that constitutive 4-1BB sensing significantly reduced the apoptosis of CAR-T cells, enhanced proliferation, and increased NF-κB pathway activation. Consistent with the enhanced proliferation and cytotoxicity in vitro, this new structure of CAR-T cells exhibited robust persistence and anti-tumor activity in a mouse xenograft lymphoma model. This work provides evidence for a new strategy to optimize the function of CAR-T against lymphoma.

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