BMC Immunology最新文献

Background: Interleukin-6 (IL-6) plays a central role in sepsis-induced cytokine storm involving immune hyperactivation and early neutrophil activation. Programmed death protein-1 (PD-1) is associated with sepsis-induced immunosuppression and lymphocyte apoptosis. However, the effects of simultaneous blockade of IL-6 and PD-1 in a murine sepsis model are not well understood.

Results: In this study, sepsis was induced in male C57BL/6 mice through cecal ligation and puncture (CLP). IL-6 blockade, PD-1 blockade, or combination of both was administered 24 h after CLP. Peripheral blood count, cytokine level, lymphocyte apoptosis in the spleen, neutrophil infiltration in the lungs and liver, and survival rate were measured. The mortality rate of the IL-6/PD-1 group was lower, though not statistically significant (p = 0.164), than that of CLP mice (75.0% vs. 91.7%). The IL-6/PD-1 group had lower neutrophil percentage and platelet count compared with the CLP group; no significant difference was observed in other cytokine levels. The IL-6/PD-1 group also showed reduced T lymphocyte apoptosis in the spleen and decreased neutrophil infiltration in the liver and lungs.

Conclusions: IL-6/PD-1 dual blockade reduces neutrophil infiltration, lymphocyte apoptosis, and bacterial burden while preserving tissue integrity in sepsis. Although the improvement in survival was not statistically significant, these findings highlight its potential as a therapeutic approach in sepsis.

Background: B lymphocytes, essential in cellular immunity as antigen-presenting cells and in humoral immunity as major effector cells, play a crucial role in the antitumor response. Our previous work has shown β-glucan enhanced immunoglobulins (Ig) secretion. But the specific mechanisms of B-cell activation with β-glucan are poorly understood. Here, we took advantage of β-glucan to improve the antitumor immune response of B cells.

Results: In vitro experiments demonstrate that β-glucan enhance the differentiation of B220^lo CD138⁺ B cells, up-regulate co-stimulatory molecules, and increase the production of cytokines and Ig in response to various antigens. Using the Dectin-1 knockout mice, we revealed that β-glucan modulate B cell immune responses dependent on Dectin-1 receptor. In mouse models of Lewis lung cancer (LLC) tumors, combining β-glucan with programmed death-1(PD-1) blocking antibodies led to increase recruitment of CD19⁺ B cells in the tumor microenvironment (TME), higher numbers of germinal centers B cells (GC B) in the spleen and draining lymph node (DLN), elevate Ig production, and delay tumor progression.

Conclusions: These findings reveal that β-glucan can serve as a potent adjuvant to modulate B cell immune responses in a Dectin-1 dependent manner and improve immune checkpoint blockade (ICB) therapy in antitumor.

Clinical trial number: Not applicable.

Introduction: We have reanalyzed the genomic data from the International Collaboration for the Genomics of HIV (ICGH), focusing on HIV-1 Elite Controllers (EC).

Methods: A genome-wide association study (GWAS) was performed, comparing 543 HIV-1 EC individuals with 3,272 uninfected controls (CTR) of European ancestry. 8 million single nucleotide polymorphisms (SNPs) and HLA class I and class II gene alleles were imputed to compare EC and CTR.

Results: Two thousand six hundred twenty-six SNPs were associated with EC (p<5.10-8), all located within the Major Histocompatibility Complex (MHC) region. Stepwise regression analysis narrowed this list to 17 SNPs. In parallel, 22 HLA class I and II alleles were associated with EC. Through meticulous mapping of the LD between all identified signals and employing reciprocal covariate analyses, we delineated a final set of 6 independent SNPs and 3 HLA class I gene alleles that accounted for most of the associations observed with EC. Our study revealed the presence of cumulative haploblock effects (SNP rs9264942 contributing to the HLA-B*57:01 effect) and that several HLA allele associations were in fact caused by SNPs in linkage disequilibrium (LD). Upon investigating SNPs in LD with the selected 6 SNPs and 3 HLA class I alleles for their impact on protein function (either damaging or differential expression), we identified several compelling mechanisms potentially explaining EC among which: a multi-action mechanism of HLA-B*57:01 involving MICA mutations and MICB differential expression overcoming the HIV-1 blockade of NK cell response, and overexpression of ZBTB12 with a possible anti-HIV-1 effect through HERV-K interference; a deleterious mutation in PPP1R18 favoring viral budding associated with rs1233396.

Conclusion: Our results show that MHC influence on EC likely extends beyond traditional HLA class I or class II allele associations, encompassing other MHC SNPs with various biological impacts. They point to the key role of NK cells in preventing HIV-1 infection. Our analysis shows that HLA-B*57:01 is indeed associated with partially functional MICA/MICB proteins which could also explain this marker's involvement in other diseases such as psoriasis. More broadly, our findings suggest that within any HLA class I and II association in diseases, there may exist distinct causal SNPs within this crucial, gene-rich, and LD-rich MHC region.

Background: Frailty is an emerging global burden of disease, characterized as an age-related clinical syndrome. Recent studies have suggested a potential link of circulating protein levels with the onset of frailty. This study aims to analyze the potential causal relationships of plasma proteins with frailty using a Mendelian Randomization (MR) study design.

Methods: Associations of plasma proteins with frailty were assessed using inverse variance weighted (IVW), MR-Egger regression, weighted median, maximum-likelihood method, and MR-PRESSO test. Protein-protein interaction network construction and gene ontology functional enrichment analysis were conducted based on MR-identified target proteins.

Results: After false discovery rate (FDR) correction, MR analysis identified five plasma proteins, including BIRC2 [OR = 0.978, 95%CI (0.967-0.990)] and PSME1 [OR = 0.936, 95%CI (0.909-0.965)], as protective factors against frailty, and 49 proteins, including APOB [OR = 1.053, 95%CI (1.037-1.069)] and CYP3A4 [OR = 1.098, 95%CI (1.068-1.128)], as risk factors. Network analysis suggested BIRC2, PSME1, APOE, and CTNNB1 as key intervention targets.

Conclusion: This study employed MR design to investigate the association of circulating plasma proteins with frailty, identified five proteins negatively associated with frailty risk and 49 proteins positively associated with frailty.

Epithelial cells (ECs) provide the first line of defense against microbial threats and environmental challenges. They participate in the host's immune responses via the expression and secretion of various immune-related molecules such as cytokines and chemokines, as well as interaction with immune cells. A growing body of evidence suggests that the dysregulated function of ECs can be involved in the pathophysiology of a broad range of infectious, autoimmune, and inflammatory diseases, including inflammatory bowel disease (IBD), asthma, multiple sclerosis, and rheumatoid arthritis. To maintain a substantial immunoregulatory function of ECs, precise expression of different molecules and their regulatory effects are indispensable. MicroRNAs (miRNAs, miRs) are small non-coding RNAs that regulate gene expression commonly at post-transcriptional level through degradation of target messenger RNAs (mRNAs) or suppression of protein translation. MiRNAs implicate as critical regulators in many cellular processes, including apoptosis, growth, differentiation, and immune response. Due to the crucial roles of miRNAs in such a vast range of biological processes, they have become the spotlight of biological research for more than two decades, but we are still at the beginning stages of the use of miRNA-based therapies in the improvement of human health. Hence, in the present paper, attempts are made to provide a comprehensive overview with regard to the roles of miRNAs in the immunoregulatory functions of ECs. A better understanding of the molecular mechanisms through which immunoregulatory properties of ECs are manifested, could aid the development of efficient strategies to prevent and treat multiple human diseases.

Aim: IBD is a condition that may result from the presence of oxidative stress. The objective of this research is to evaluate and compare the potency of probiotics and paraprobiotics to modulate oxidative stress and inflammation.

Methods and results: In the initial phase, the antioxidant capabilities of 88 strains from Lactobacillus and Bifidobacterium were evaluated. In the subsequent phase, during the in-vivo stage, four experimental groups were established, consisting of a high-fat diet (HFD) + PBS, HFD + DSS, HFD + DSS + 10^⁹ cfu/ml of 6 selected native probiotic, and HFD + DSS + 10^⁹ cfu/ml of paraprobiotic (from 6 selected strains), with male wild-type C57BL/6 mice being assigned to these groups. The phenotypical indices and pathological scores along with the evaluation of the expression of genes associated with the NF-kB and Nrf2 signaling pathways, as well as enzymes linked to oxidant/anti-oxidant activities, and proinflammatory/inflammatory cytokines were performed. A significant difference was noted among the groups exposed to DSS and groups that given our native agents. The mice receiving a blend of probiotics and paraprobiotics alongside DSS demonstrated a mitigation of the harmful impacts caused by DSS, both regarding phenotypic traits, including pathological scores and also the level of cytokines and antioxidant markers and also molecular indicators like the Nrf2 and NF-kB associated genes. Also, there was no notable difference between our native probiotic and paraprobiotic.

Conclusion: The study's findings provide evidence that the expression of inflammation can be successfully alleviated by utilizing our native probiotics and paraprobiotics, with a greater emphasis on the latter due to its inherent safety.

Impact statements: This study highlighted the anti-inflammatory and antioxidant properties of probiotic and paraprobiotic that could be useful for patients with inflammatory status.

Purpose: Immunotherapy is a promising treatment for cancers but should be optimized for malignant gliomas. Because of immune privilege feature of the brain, local administration of immunotherapy may be a promising strategy for malignant glioma treatment. Identification of patients who may benefit from local immunotherapy is essential.

Methods: We retrospectively reviewed the clinicopathological characteristics and outcomes of six malignant glioma patients who received local administration of autologous cytokine-induced killer (CIK) cells through Ommaya reservoirs implanted into the tumor resection cavity. Profiles of tumor genome, transcriptome and immune microenvironment were also investigated by genomic target sequencing, RNA sequencing, electrochemiluminescence assay and immunohistochemistry (IHC) staining.

Results: Four patients died from tumor progression and the overall survival ranged from 10.0 to 33.9 months. Remarkably, two patients, including one diagnosed as diffuse hemispheric glioma H3 G34-mutant (G34-DHG, WHO grade 4) and the other diagnosed as astrocytoma (IDH1 mutation, WHO grade 3) survived more than 20 years without evidence of recurrence. The distinctive clinical feature of the two long-term survivors was tumor gross total resection (GTR) before CIK therapy. NTRK1 mutation was uniquely present and 353 genes were differentially expressed in the long-term survivors compared with the short-term survivors. These differential expression genes were highly associated with immune function. Electrochemiluminescence assay and IHC staining revealed higher expressions of cytokines and lower infiltrations of tumor-associated macrophages in the tumors of the long-term survivors.

Conclusion: These findings suggest that certain patients diagnosed as malignant gliomas, including G34-DHG (WHO grade 4), can acquire long-term survival after local immunotherapy. Tumor GTR before local immunotherapy and relatively weaker immunosuppressive tumor microenvironment are the favorable factors for long-term survival. Larger, controlled studies with standardized treatment protocols, including consistent use of GTR, are warranted to further evaluate the potential benefits of locally delivered immunotherapy.

Background: HIV-exposed uninfected (HEU) children are at increased risk of morbidity during the first years of life. Although the immune responses of HEU infants in early-life are relatively well described, studies of natural killer (NK) cells in older HEU children are lacking. NK cell subsets were analysed in HEU children and compared to those in HIV unexposed uninfected (HUU) children aged ~ five years.

Methods: Multi-parametric flow cytometry was used to characterize peripheral blood-derived NK cell CD56, CD16, CD57, NKG2A and KIR3DL1/KIR2DL2/L3 expression, including intracellular perforin and granzyme B. NK cell subsets were compared between HEU children exposed to prenatal antiretroviral therapy (ART) from conception [long-term (HEULT)]; those exposed to ART during pregnancy [medium-term (HEUMT)] with continued exposure throughout the breastfeeding period and HUU peers. Furthermore, clinical data of the children, including sick clinic visits and hospitalizations documented in morbidity diaries from birth to 5 years were compared between HEU and HUU groups. Frequencies of CD56^bright and CD56^dim NK cell were correlated with these clinical parameters.

Results: 139 children were enrolled however, 133 comprising 43 HEULT, 38 HEUMT and 52 HUU were included in the main analyses. Total NK cell, CD56^bright nor CD56^dim NK cell proportions differed between HEU and HUU children. However, HEULT children had lower frequencies of CD56^dim NK cells compared to HEUMT children, (p = 0.002) which maintained significance after controlling for preterm birth, p = 0.012. No differences were observed between HEULT and HUU. The expressions of NKG2A, KIR3DL1/KIR2DL2/L3 and CD57 on CD56^bright and CD56^dim NK cells were similar between the three groups. Furthermore, the frequencies of granzyme B and perforin double positive NK cells were similar between the HUU with HEULT and HEUMT children. CD56^dim NK cell counts had a significant moderate negative correlation with recurrent respiratory infections (rho=-0.38; p = 0.010) in HUU children and negatively correlated with total sick clinic visits in HEUMT (rho=-0.40, p = 0.064).

Conclusion: The proportions of total NK cell, CD56^bright and CD56^dim NK cells, NK cells inhibitory and differentiation surface marker expression and cytolytic granule-positive cells were similar between HEU and HUU children. These data suggest that early-life HIV/ART exposure may not result in major changes in NK cell subsets at 5 years of age.

Background: The relationship of serum 25-hydroxyvitamin D concentrations and ANA positivity according to sex stratification is unclear. The propose of this study was to reveal the sex-specific relationship of serum 25-hydroxyvitamin D concentrations and ANA positivity in American people.

Methods: The study was conducted in 2757 subjects from the National Health and Nutrition Examination Survey (NHANES) 2001-2004. The logistic regression models were used to assess the correlation between the risk of ANA positivity and serum 25-hydroxyvitamin D concentrations. Generalized additive models and smooth fitting curves were used to evaluate the non-linear relationship of the risk of ANA positivity and serum 25-hydroxyvitamin D levels.

Results: Following multivariable adjustment, we observed a negative correlation between serum 25-hydroxyvitamin D concentrations and the risk of ANA positivity in male participants, particularly in men non-white individuals and those exposed to second-hand smoke. However, there was no significant relationship observed in the female participants. Additionally, the relationship between serum 25-hydroxyvitamin D concentrations and the risk of ANA positivity followed an L-shaped pattern, with an inflection point at 18 ng/mL. When serum 25-hydroxyvitamin D levels fell below this inflection point, decrease of 1 unit in serum 25-hydroxyvitamin D concentrations was linked to an 8% increase in the adjusted OR of ANA positivity (OR 0.92; 95% CI 0.87, 0.97; p 0.0026).

Conclusions: In American men, nonlinear relationships were observed between serum 25-hydroxyvitamin D concentrations and the risk of ANA positivity.

Purpose: This research probes into genes related to the risk of concurrent kidney injury in septic patients to provide reliable targets for early identification of sepsis-associated kidney injury and prognosis research.

Methods: Peripheral blood samples were isolated from 10 healthy individuals and 22 septic patients for RNA sequencing and differential analyses. Meanwhile, the top 1000 kidney-associated genes were chosen from the GTEx website. Subsequently, DEGs in sepsis were intersected with kidney-specific genes, followed by GO and KEGG analyses on these intersection genes. The predictive ability of hub genes for prognosis was evaluated using survival analysis. A meta-analysis was carried out to determine the differential expression profiles of hub genes between the sepsis surviving and dead groups. ROC curves were plotted to screen hub genes and clarify their diagnostic value. Cell line localization of hub genes was further clarified through single-cell RNA sequencing.

Results: There were 40 targets in the intersection between 1328 DEGs in sepsis and 1000 kidney-associated genes. These intersection genes were mainly engaged in functions and signaling pathways .Survival curves linked the higher levels of CD74 and IL32 to raised survival rates of patients, indicating positive correlations of CD74 and IL32 with patient prognosis. Meta-analysis revealed that CD74 and IL32 were highly expressed in the sepsis surviving group but poorly expressed in the sepsis dead group, showing statistically significant differences between these two groups. In the ROC analysis of hub genes, AUC values of CD74 (0.983) and IL32 (0.980) suggested their high diagnostic value. Lastly, CD74 was principally expressed in macrophages, while IL32 was mainly presented in T cells.

Conclusion: CD74 and IL32, as biomarkers for early diagnosis and prognostic evaluation of sepsis complicated with kidney injury, are highly expressed in macrophages and T cells, respectively, providing new diagnostic and prognostic targets for sepsis complicated with acute kidney injury.