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关键词： Alzheimer's disease   gut microbiome   microglia   amyloid pathology   and Il-17a  

摘要： Gut bacteria regulate brain pathology of Alzheimer's disease (AD) patients and animal models;however, the underlying mechanism remains unclear. In this study, 3-month-old APP-transgenic female mice with and without knock-out of Il-17a gene were treated with antibiotics-supplemented or normal drinking water for 2 months. The antibiotic treatment eradicated almost all intestinal bacteria, which led to a reduction in Il-17a-expressing CD4-positive T lymphocytes in the spleen and gut, and to a decrease in bacterial DNA in brain tissue. Depletion of gut bacteria inhibited inflammatory activation in both brain tissue and microglia, lowered cerebral A beta levels, and promoted transcription of Arc gene in the brain of APP-transgenic mice, all of which effects were abolished by deficiency of Il-17a. As possible mechanisms regulating A beta pathology, depletion of gut bacteria inhibited beta-secretase activity and increased the expression of Abcb1 and Lrp1 in the brain or at the blood-brain barrier, which were also reversed by the absence of Il-17a. Interestingly, a crossbreeding experiment between APP-transgenic mice and Il-17a knockout mice further showed that deficiency of Il-17a had already increased Abcb1 and Lrp1 expression at the blood-brain barrier. Thus, depletion of gut bacteria attenuates inflammatory activation and amyloid pathology in APP-transgenic mice via Il-17a-involved signaling pathways. Our study contributes to a better understanding of the gut-brain axis in AD pathophysiology and highlights the therapeutic potential of Il-17a inhibition or specific depletion of gut bacteria that stimulate the development of Il-17a-expressing T cells.

关键词： Interleukin-1   genetic variations   polymorphism   hematologic malignancies   meta-analysis  

摘要： The relationship between the IL1B-511C>T (rs16944) polymorphism and the risk of developing hematologic malignancies remains controversial. Thus, we performed a meta-analysis to evaluate the association between IL1B-511C>T polymorphism and the risk of developing hematologic malignancies. A comprehensive search was conducted to identify all eligible studies on IL1B-511C>T polymorphism and hematologic malignancies. Twelve case-control studies, with 2,896 cases and 3,716 controls, were selected for the analysis. The overall data failed to indicate a significant association between IL1B-511C>T polymorphism and the risk of hematologic malignancies (OR:1.06, 95% Confidence Interval [CI]: 0.93-1.22). Moreover, non-significant associations were observed in a stratified analysis according to neoplasm type (multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma), ethnicity (European and Asian), and Hardy-Weinberg equilibrium. In summary, our results suggest that there is no association between the IL1B-511C>T polymorphism and the risk of hematologic malignancies. As such, further large-scale studies are needed to confirm our findings.

关键词： autism spectrum disorder   gut microbiome   metabolomics   metagenomics  

摘要： BACKGROUND:Autism spectrum disorder (ASD) is a persistent neurodevelopmental disorder affecting brains of children. Mounting evidences support the associations between gut microbial dysbiosis and ASD, whereas detailed mechanisms are still obscure. METHODS:Here we probed the potential roles of gut microbiome in ASD using fecal metagenomics and metabolomics. RESULTS:Children with ASD were found to be associated with augmented serum cytokines milieu, especially TNFα. Metagenomic analysis generated 29 differential species and 18 dysregulated functional pathways such as Bifidobacterium bifidum, Segatella copri, and upregulated 'Sphingolipid metabolism' in children with ASD. Metabolomics revealed steroid hormone dysgenesis in children with ASD with lower abundances of metabolites such as estriol, estradiol and deoxycorticosterone. A three-way association analysis showed positive correlations between TNFα and microbial function potentials such as 'Bacterial toxins' and 'Lysosome', indicating the contribution of microbial dysbiosis to neuroinflammation. TNFα also correlated positively with 'Sphingolipid metabolism', which further showed negative correlations with metabolites estriol and deoxycorticosterone. Such results, in consistent with current findings, revealed the contribution of increased TNFα to upregulated sphingolipid metabolism, which further impaired steroid hormone biosynthesis. CONCLUSION:Our study proposed the gut microbial 'TNFα-sphingolipids-steroid hormones' axis in children with ASD, which may provide new perspectives for developing gut microbiome-based treatments in the future.

关键词： Antigen presentation   HLA class II   neoantigen   tertiary lymphoid structures   Th1 cells  

摘要： Neoantigen-reactive CD4(+) T cells play a key role in the anti-tumor immune response. However, the majority of epithelial tumors are negative for HLA class II (HLA-II) surface expression, and less is known about the processing of HLA-II antigens. Here, we directly identified naturally presented HLA-II neoantigens in HLA-II negative colorectal cancer (CRC) tissue using a proteogenomic approach. The neoantigens were immunogenic and induced patient CD4(+) T cells with a Th1-like memory phenotype that produced IFN-gamma, IL2 and TNF-alpha. Multiplex immunohistochemistry (IHC) demonstrated an interaction between Th cells and HLA-II-positive antigen-presenting cells (APCs) at the invasive margin and within the tertiary lymphoid structures (TLS). In our CRC cohort, the density of stromal APCs was associated with HLA-II antigen presentation in the tumor microenvironment (TME), and the number of TLS was positively correlated with the number of somatic mutations in the tumors. These results demonstrate the presence of neoantigen-specific CD4(+) surveillance in HLA-II-negative CRC and suggest a potential role for macrophages and dendritic cells (DCs) at the invasive margin and in TLS for antigen presentation. Stromal APCs in the TME can potentially be used as a source for HLA-II neoantigen identification.

关键词： Diabetes   Innate immunity   Legionella pneumophila   Pneumonia   Streptococcus pneumoniae  

摘要： Diabetes mellitus is associated with an increased risk of pneumonia, often caused by so-called typical and atypical pathogens including Streptoccocus pneumoniae and Legionella pneumophila, respectively. Here, we employed a variety of mouse models to investigate how diabetes influences pulmonary antibacterial immunity. Following intranasal infection with S. pneumoniae or L. pneumophila, type 2 diabetic and prediabetic mice exhibited higher bacterial loads in their lungs compared to control animals. Single cell RNA sequencing, flow cytometry, and functional analyses revealed a compromised IFNγ production by natural killer cells in diabetic and prediabetic mice, which was associated with reduced IL-12 production by CD103 dendritic cells. Blocking IFNγ enhanced susceptibility of non-diabetic mice to L. pneumophila, while IFNγ treatment restored defense against this intracellular pathogen in diabetic animals. In contrast, IFNγ treatment did not increase resistance of diabetic mice to S. pneumoniae, suggesting that impaired IFNγ production is not the sole mechanism underlying the heightened susceptibility of these animals to pneumococcal infection. Thus, our findings uncover a mechanism that could help to explain how type 2 diabetes predisposes to pneumonia. We establish proof of concept for host-directed treatment strategies to reinforce compromised IFNγ-mediated antibacterial defense against atypical lung pathogens.

关键词： ANV419   cancer immunotherapy   effector T cells   IL-2R beta gamma agonist   immunocytokine   immunotherapy   interleukin-2   natural killer cells   regulatory T cells  

摘要： Novel engineered IL-2 agonists strive to increase the therapeutic window of aldesleukin (human IL-2) by increasing selectivity toward effector over regulatory T cells and reducing dose-limiting toxicities. Here we describe ANV419, an IL-2/anti-IL2 antibody fusion protein designed for selective IL-2 receptor beta gamma (IL-2 R beta gamma) activation by sterically hindering IL-2 from binding to IL-2 R alpha. The fusion protein has an IL-2 connected to the light chain complementarity-determining region (CDR) domain of a humanized antibody that binds to IL-2 at the same epitope as IL-2 R alpha. Optimization of the selectivity and pharmacological properties led to the selection of ANV419. ANV419 preferentially expands CD8+ T cells and natural killer (NK) cells over Tregs and can be safely administered at doses that elicit strong pharmacodynamic effects and efficacy in mouse tumor models. Its anti-tumor efficacy was enhanced when combined with programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors. ANV419 also enhances the NK cell killing capacity and increases tumor growth inhibition when used alongside trastuzumab in a Her-2+ xenograft mouse model. In cynomolgus monkeys, the estimated half-life of ANV419 is 24 h, and doses that induced sustained expansion of effector cells were well tolerated without the severe toxicities typically observed with high-dose IL-2. These data support the clinical development of ANV419 in solid tumors and hematological malignancies as monotherapy and in combination with checkpoint inhibitors or agents that induce antibody-dependent cellular cytotoxicity. ANV419 is currently in Phase 1/2 clinical development and may provide cancer patients with a wider therapeutic window than aldesleukin.

关键词： Organic dust   therapy   immunology   inflammation   lung disease  

摘要： Efficacious therapeutic options capable of resolving inflammatory lung disease associated with environmental and occupational exposures are lacking. This study sought to determine the preclinical therapeutic potential of lung-delivered recombinant interleukin (IL)-10 therapy following acute organic dust exposure in mice. Here, C57BL/6J mice were intratracheally instilled with swine confinement organic dust extract (ODE) (12.5%, 25%, 50% concentrations) with IL-10 (1 mu g) treatment or vehicle control intratracheally-administered three times: 5 hr post-exposure and then daily for 2 days. The results showed that IL-10 treatment reduced ODE (25%)-induced weight loss by 66% and 46% at Day 1 and Day 2 post-exposure, respectively. IL-10 treatment reduced ODE (25%, 50%)-induced lung levels of TNF alpha (-76%, -83% [reduction], respectively), neutrophil chemoattractant CXCL1 (-51%, -60%), and lavage fluid IL-6 (-84%, -89%). IL-10 treatment reduced ODE (25%, 50%)-induced lung neutrophils (-49%, -70%) and recruited CD11cintCD11b+ monocyte-macrophages (-49%, -70%). IL-10 therapy reduced ODE-associated expression of antigen presentation (MHC Class II, CD80, CD86) and inflammatory (Ly6C) markers and increased anti-inflammatory CD206 expression on CD11cintCD11b+ cells. ODE (12.5%, 25%)-induced lung pathology was also reduced with IL-10 therapy. In conclusion, the studies here showed that short-term, lung-delivered IL-10 treatment induced a beneficial response in reducing inflammatory consequences (that were also associated with striking reduction in recruited monocyte-macrophages) following acute complex organic dust exposure.

关键词： Axial spondyloarthritis   bimekizumab   secukinumab   ixekizumab   cost-effectiveness   Scotland NHS   treatment-pathway   I10   I1   I   I19  

摘要： ObjectiveTo estimate the cost-effectiveness of a treatment-pathway initiated with bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F and IL-17A, in patients with axial spondyloarthritis (axSpA) compared with IL-17Ai's, ixekizumab, and secukinumab, from the NHS Scotland *** axSpA treatment-pathway was modeled using a decision tree followed by a lifetime Markov model. The pathway included first- and second-line biologic disease-modifying antirheumatic drugs (bDMARD), followed by best supportive care (bDMARD, nonbiologic). Bimekizumab followed by any bDMARD ("BKZ") was compared with IL-17Ai's: secukinumab 150 mg followed by a blend ("SEC") of dose up-titration to secukinumab 300 mg and any bDMARD, or ixekizumab followed by any bDMARD ("IXE"). Transition to the next therapy was triggered by Bath Ankylosing Spondylitis Disease Activity Index-50% (BASDAI50) non-response or any-cause discontinuation. A published network meta-analysis provided efficacy data. EuroQoL-5-dimensions utilities were derived by mapping from Ankylosing Spondylitis Disease Activity Score. Costs included disease management (linked to functional limitations), biologics acquisition (list prices), administration and monitoring (NHS 2021/22). Discounting was 3.5%/year. Probabilistic results from patients with non-radiographic axSpA and ankylosing spondylitis were averaged to reflect the axSpA disease spectrum. Scenario and sensitivity analyses were *** incremental cost-effectiveness ratio (ICER) of BKZ was 24,801 pound/quality-adjusted life-year (QALY) vs. SEC (95% credible interval 24,163- pound 25,895) pound. BKZ had similar costs (Delta -385 pound [-15,239- pound 14,468]) pound and QALYs (Delta 0.039 [-0.748-0.825]) to IXE, with 1,523 pound (862- pound 2,222) pound net monetary benefit. Conclusions remained unchanged in most scenarios. Results' drivers included BASDAI50 response rate and disease management ***

关键词： Psoriasis   anti-interleukin-23 antibody   neutropenia   pharmacoepidemiology   real-world evidence  

摘要： Background: To evaluate the risk of neutropenia during treatment with anti-IL-23 antibodies in patients with psoriasis. Method: We conducted an observational study with cohort design using MID-NET (R) in Japan. We identified patients with psoriasis who were newly prescribed anti-IL-23 antibodies, anti-IL-17-antibodies, adalimumab, or apremilast between January 1, 2009, and March 31, 2021. We estimated the adjusted hazard ratio (aHR) of anti-IL-23 antibodies compared to that of anti-IL-17 antibodies, adalimumab, or apremilast, for the risk of grade 2 (neutrophil count < 1,500/mu L) or grade 3 (neutrophil count < 1,000/mu L) neutropenia. Results: Overall, 287 patients on anti-IL-23 antibodies, 189 patients on anti-IL-17 antibodies, 293 patients on adalimumab, and 540 patients on apremilast were included. Compared with anti-IL-17 antibodies, the aHR (95% confidence interval (CI)) of anti-IL-23 antibodies was 0.83 (0.27-2.51) for grade 2 and 0.40 (0.02-7.60) for grade 3 neutropenia;that when compared with adalimumab was 0.76 (0.28-2.06) for grade 2 but was not calculated for grade 3 as no cases were found;and that compared with apremilast was 3.88 (0.62-24.48) for grade 2 and 0.43 (0.02-11.63) for grade 3 neutropenia. Conclusion: No clear increase in the risk of neutropenia with anti-IL-23 antibodies was observed.

关键词： Endometriosis   ectopic endometrial stromal cells   NK-92 cells   IL-2   MEK/ERK signalling pathway  

摘要： BackgroundInterleukin (IL)-2 is a key cytokine capable of modulating the immune response by activating natural killer (NK) cells. This study was recruited to explore the therapeutic potential of IL-2-activated NK-92 cells in endometriosis in *** endometrial stromal cells (EESCs) were isolated and co-cultured with IL-2-activated NK-92 cells at varying effector-to-target (E:T) ratios (1:0 [Control], 1:1, 1:3, and 1:9). The viability, cytotoxicity, and cell surface antigen expression of IL-2-activated NK-92 cells were assessed. The viability, apoptosis, invasion, and migration ability of EESCs co-cultured with NK-92 cells at different ratios were evaluated. The apoptosis-related proteins, invasion and migration-related proteins as well as MEK/ERK pathway were examined via western blot. Each experiment was repeated three ***-2 activation enhanced NK-92 cytotoxicity in a concentration-dependent manner. Co-culturing EESCs with IL-2-activated NK-92 cells at E:T ratios of 1:1, 1:3, and 1:9 reduced EESC viability by 20%, 45%, and 70%, respectively, compared to the control group. Apoptosis rates in EESCs increased in correlation with the NK-92 cell proportion, with the highest rate observed at a 1:9 ratio. Moreover, EESC invasion and migration were significantly inhibited by IL-2-activated NK-92 cells, with a 60% reduction in invasion and a 50% decrease in migration at the 1:9 ratio. Besides, the MEK/ERK signalling pathway was down-regulated in EESCs by IL-2-activated NK-92 ***-2-activated NK-92 cells exhibit potent cytotoxic effects against EESCs. They promote EESC apoptosis and inhibit viability, invasion, and migration through modulating the MEK/ERK signalling pathway. Endometriosis is a common chronic systemic disease affecting approximately 190 million women worldwide. However, clinical treatments for endometriosis remain challenging due to the scarcity of high-quality scientific evidence and conflicting available guidelines. T