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摘要： Background The persistence of a replication-competent latent viral reservoir (RC-LVR) during antiretroviral therapy (ART) is a barrier to the development of a cure for HIV-1, but the role of viral genes in influencing RC-LVR size is unclear. We aimed to assess whether the magnitude by which the HIV-1 accessory protein Nef evades the adaptive immune response by downregulating MHC-I or CD4, or both, from the surface of infected cells is associated with the rate at which the RC-LVR in people with HIV-1 changes during long-term ART (>1 year). Methods We conducted an exploratory cohort study in which nef genes were sequenced from outgrowth viruses derived from the quantitative viral outgrowth assay (QVOA) for a group of people with ART-suppressed HIV-1 in Uganda between 2015 and 2020. Study participants were selected from the Rakai Health Sciences Program (RHSP) LVR cohort, a cohort of 90 adults (aged >= 18 years) who were HIV-1 positive, receiving ART, and had maintained viral suppression for at least 1 year at the time of study enrolment. For this study, participants were required to have available p24+ QVOA wells that contained a single viral outgrowth isolate, as assessed by next-generation sequencing. In cases where further sequencing identified wells containing multiple viral clones, all sequenced nef variants were included for functional analysis. The unique isolated nef variants were used to generate pseudoviruses, which were employed to measure cell surface CD4 and MHC-I downregulation in infected CD4+ Sup-T1 cells via flow cytometry. The size and rate of change of the RC-LVR in participants was estimated using previous QVOA results and a Bayesian model. We then assessed whether a correlation existed between the extent to which the Nef proteins downregulated cell surface MHC-I and CD4 and the calculated RC-LVR rate of change during the study period. Findings 14 (15%) of 90 participants from the RHSP cohort met the inclusion criteria and were enrolled in this stu

关键词： B cells   Pyoderma gangrenosum   Spatial transcriptomics   Tertiary lymphoid structures   Ustekinumab   PG   pyoderma gangrenosum  

关键词： PFOA   Anti-TNF   IBD   MASLD  

摘要： Perfluorooctanoic acid (PFOA) is a prevalent and chemically stable environmental contaminant. Our preliminary data suggest that chronic exposure to PFOA induces colonic damage in mice that resembles inflammatory bowel disease (IBD). Anti-TNF therapies are commonly used in the clinical management of IBD. Building upon our previous findings, we administered anti-TNF treatment to mice exposed to PFOA. Our results show that anti-TNF therapy significantly reduces the colonic inflammatory response, activation of the NLR family pyrin domain containing 3 (NLRP) inflammasome, and apoptosis induced by PFOA. Additionally, anti-TNF treatment restores intestinal barrier integrity, which is disrupted by PFOA exposure, and enhances the regenerative capacity of the colon by promoting intestinal stem cell function. Furthermore, anti-TNF therapy effectively mitigates hepatic inflammation, liver dysfunction, lipid metabolism disturbances, NLRP3 inflammasome activation, and apoptosis in the liver triggered by PFOA. In conclusion, our study provides compelling evidence that anti-TNF therapy can alleviate both colonic and hepatic injuries induced by PFOA exposure. This research expands our understanding of environmental toxin-induced diseases and offers potential therapeutic strategies for managing PFOA-related disorders in the future.

关键词： allergic asthma   interleukin-33   interleukin-9   macrophage polarization   macrophage subset  

摘要： BackgroundMacrophages, one of the most abundant immune cells in the lung, have drawn great attention in allergic asthma. Currently, most studies emphasize alternative activated (M2) polarization bias. However, macrophage function in allergic asthma is still controversial. Interleukin (IL)-9 contributes to the development and pathogenesis of allergic airway inflammation. We sought to investigate the IL-9-producing macrophage and its role in allergic *** model of ovalbumin (OVA)-induced allergic airway inflammation was employed to evaluate IL-9 production in macrophages of lung tissues. We used 22 cytokines or stimuli to screen for IL-9-producing mouse macrophage subset in vitro. Real-time PCR, flow cytometry, ELISA, and RNA-seq to explore the subset. Conditional IL-33 receptor knockout (Lyz-ST2KO) mice and cellular adoptive transfer experiment were used to characterize the potential roles of M(IL-33 + IL-2) in allergic *** identified a unique pathogenic IL-9-producing macrophage in OVA-induced allergic airway inflammation. We found that only IL-33 significantly induced IL-9 production in mouse macrophages, and IL-2 collaborated with IL-33 to promote IL-9 production, referred to as M(IL-33 + IL-2). Importantly, human monocyte-derived macrophages produced IL-9 after IL-33 and IL-2 stimulation. Using Lyz-ST2KO mice and adoptive transfer of M(IL-33 + IL-2), we found that M(IL-33 + IL-2) significantly promoted pathogenesis in OVA-induced allergic airway inflammation. M(IL-33 + IL-2) has a distinctive gene expression profile with high expression of IL-9, IL-5, and IL-13 and its polarization is dependent on JAK2-STAT3-IRF1 *** identification of M(IL-33 + IL-2) subset extends the diversity and heterogeneity of macrophage subsets and may offer novel therapeutic strategies for the treatment of allergic inflammation.

关键词： EHF   Liver cancer   IL-6   Tumor associated macrophags  

摘要： Background: Macrophages are key immune cell types in liver, which are thought to be involved in tumor development. Recent studies indicated that TAMs exhibit M2 phenotypes. However, the mechanism of macrophages related to tumor progression in liver cancer is largely unknown. We aim to investigate the mechanism of EHF in TAMs associated with liver cancer progression. Methods: The differently expressed genes of M0, M1, and M2 macrophages were analyzed by RNA sequencing. Cytokine array was used to detect the differently expressed cytokines in M2 macrophages. We performed CUT- Tag analysis for the identification of promoter regions that interacting with EHF protein. ChIP and luciferase analysis were used to verify the interaction between EHF and KDM2B. Results: EHF was overexpressed in M2 macrophages. Knockdown of EHF in M2 macrophages could inhibit migration and invasion of MHCC97-L cells co-cultured with M2 macrophages in vitro and in vivo. The level of IL- 6 was decreased in M2 macrophages with lower expression of EHF. EHF could bind the promoter region of KDM2B. The transcription level of KDM2B was down-regulated by knockdown of EHF in M2 macrophages. The results of this study indicated that EHF could promote liver cancer cell metastasis by IL-6 through regulating the transcription level of KDM2B in M2 macrophages. Conclusion: Our study revealed a novel aspect of macrophages in liver cancer and showed EHF could be a promising therapeutic target of liver cancer.

关键词： NitraTh   MHC-II-restricted neoantigens   Cancer vaccine   Antitumor immunity  

摘要： Tumor neoantigens, defined as tumor-specific antigens arising from somatic mutations, have shown great potential as targets for cancer vaccines in clinical studies. However, the number of neoantigens capable of effectively activating immune responses is quite limited. Over the past few decades, tumor neoantigen vaccines based on MHC-I epitopes that activate CD8+ T cells have been extensively studied. However, growing evidence suggests that CD4+ T cells are important in cancer immunotherapy. In contrast to CD8+ T cells, the receptors on CD4+ T cells exhibit a wider range of antigen peptide-MHC recognition, which can detect more tumor mutation antigens. In our earlier studies, a nitrated CD4+ T-cell epitope (NitraTh) was constructed as a novel CD4+ T-cell epitope that can enhance the immunogenicity of multiple tumor antigens. Therefore, we designed vaccines targeting MHC-II neoantigen epitopes using the nitrated T-cell epitope containing immunogenic amino acids. We found that vaccines conjugated with NitraTh exhibited enhanced immunogenicity. Crucially, the NitraTh-modified MHC-II tumor neoantigen vaccines increased the proportion of CD4+ T cells that infiltrate tumors and the spleen, elevated the expression of several cytokines with antitumor effects and facilitated the transformation of CD4+ T cells into Th1 cells, thereby reducing tumor growth. Additionally, the nitrated epitope has been shown to transform na & iuml;ve CD4+ T cells into effector memory cells, thus facilitating enduring antitumor actions. The strategy of combining nitrated epitopes with MHC-II neoantigen epitopes confirms the significance of CD4+ T-cell immunity in cancer and may provide a novel approach for cancer vaccine design. Significance Statement: This study presents a novel design paradigm for tumor vaccinesdcombining MHC-II epitopes with nitrated CD4+ T-cell epitopes. This approach promotes the differentiation of CD4+ T cells toward a Th1 phenotype and generates long-lasting effector memory

关键词： colony-stimulating factor 1   interleukin 34   therapy resistance   tumor microenvironment   tumor-associated macrophages  

摘要： Interleukin (IL)-34 is a relatively recently discovered cytokine which binds to colony-stimulating factor-1 receptor (CSF-1R). So far, there has been no clear explanation as to why CSF-1R requires two ligands. While CSF-1 is ubiquitously expressed, the expression of IL-34 is relatively restricted. However, it has been revealed that IL-34 expression increases in various diseases and is associated with their pathology. Naturally, both IL-34 and CSF-1 stimulate CSF-1R, thereby contributing to the differentiation of monocytes into macrophages. In many cases, the induced macrophages significantly influence the disease pathology. In particular, we have demonstrated that IL-34 expression in cancer is deeply involved in tumor progression and therapeutic resistance. We have shown that the blockade of IL-34 significantly improved therapeutic efficacy such as chemotherapy, radiotherapy, and immune checkpoint blockade against IL-34-expressing cancers. Recently, since macrophages induced by IL-34 exhibit immunosuppressive properties, whereas IL-34 can enhance inflammation, there is growing interest in actively regulating inflammation utilizing IL-34. In this review article, we provide an overview of the characteristics and roles of IL-34 and discuss how it could be applied to future diagnostics and therapeutics.

关键词： commensal bacteria   ILC2  

摘要： Intestinal bacteria play a critical role in the regulation of the host immune system and an imbalance in the intestinal bacterial composition induces various host diseases. Therefore, maintaining a balance in the intestinal bacterial composition is crucial for health. Immunoglobulin A (IgA), produced through T cell-dependent and T cell-independent (TI) pathways, is essential for host defense against pathogen invasion and maintaining the balance of intestinal symbiotic bacteria. Interleukin (IL)-5 is constitutively produced by Group 2 innate lymphoid cells (ILC2s) and plays a critical role in the survival and proliferation of B cells and eosinophils. Here, we show the role of IL-5-producing ILC2s in intestinal TI IgA production at steady state using T cell receptor alpha deficient mice. In this mouse model, ILC2s increased fecal TI IgA levels in a non-inflammatory state in an IL-5-dependent manner. The administration of recombinant IL-33 (rIL-33) increased the amount of TI IgA production, accompanied by an increase in the number of IL-5-producing ILC2s in the large intestine. In addition, rIL-33 treatment increased IL-5-dependent IgA+ cells in isolated lymphoid follicles, the site of TI IgA production. Furthermore, eosinophils recruited by ILC2s were required for the maximal production of IgA in the TI pathway. Moreover, IL-5 increased the frequency of TI IgA-binding intestinal bacteria and was involved in the maintenance of intestinal bacterial composition. These findings indicate that IL-5-producing ILC2s together with eosinophils contribute to TI IgA production. In addition to their role in TI IgA production, IL-5-producing ILC2s may contribute to the homeostasis of intestinal commensal bacteria.