BMC Immunology最新文献

Moyamoya disease (MMD) is a rare chronic vascular disease leads to cognitive impairment and stroke with its etiology unknown. The relationship between necroptosis or necroinflammation and MMD pathogenesis was poorly understood. Differentially expressed necroinflammation and necroptosis related genes (DE-NiNRGs) were selected based on the public gene expression data from Gene Expression Omnibus (GEO) and validated by our self-test data of MMD patients and control group. Functional enrichment analysis, PPI network and multi-factors regulation network construction of DE-NiNRGs were employed to discover the connections between these genes. DE-NiNRGs and immune cells correlation analysis provided evidence for the relationship between DE-NiNRGs and necroinflammation in MMD patients. We then established an MMD prediction model using support vector machine (SVM) and selected DE-NiNRGs as features. The DE-NiNRGs based MMD prediction model had excellent performance on test set with the area under the curve (AUC) higher than 0.9. Four genes, PTGER3, ANXA1, ID1, and IL1R1, that contributed significantly to the SVM model and passed the test of validation set are key genes in DE-NiNRGs. The upregulation of PTGER3 expression indicated that necroptosis and angiogenesis were promoted in MMD patients, whereas the downregulation of ANXA1 expression indicated that the migration and differentiation of immune cells are closely related to MMD pathogenesis. These findings provided new inspiration for our study of the immune-related pathogenesis and therapeutic targets of MMD.

Background: Pulmonary arterial hypertension (PAH) is a critical cardiopulmonary vascular disorder marked by the progressive elevation of pulmonary artery pressure, increased pulmonary vascular resistance, and eventual right heart failure. Research has shown that various immune cells play a significant role in the pathogenesis of PAH, both in patients diagnosed with the condition and in experimental models of PAH. Cell-cell communication is important for PAH progression and therapies, while the global cell landscape of intercellular signaling has not been elucidated.

Methods: We performed single-cell RNA sequencing on NCBI Gene Expression Omnibus (GEO) databases GSE169471, GSE 210248, GSE228643 and GSE244781, and analyzed lung tissue samples across healthy controls and PAH patients. In total, approximately 124,561 cells were analyzed and a total 34 clusters were identified. We integrated the sequencing results of multiple samples and used an enhanced single-cell sequencing workflow to overcome the limitations of a single study.

Results: In this study, we elucidated the functional characteristics and potential regulatory interactions of several cell subpopulations that have not been previously documented in similar research. We constructed a comprehensive landscape of cell communications at the single-cell resolution, which is expected to significantly advance the development of personalized diagnostic and therapeutic strategies for PAH. We demonstrated the transcriptomic features of different cell types in PAH patients. We presented an in-depth analysis of T cell subsets, myeloid cell heterogeneity and a comprehensive analysis of SMCs and FBs subsets in PAH. T cell heterogeneity and functional dynamics were exhibited in PAH, which suggests that targeting cytotoxic regulation may be a potential therapeutic strategy. Significant changes and potential functions of myeloid cell subsets in PAH patients and we especially focused on GPNMB⁺ macrophages. In addition, CellChat and NicheNet analyses reveal altered intercellular communication and dys-regulated signaling pathways in PAH progression. The enhanced MIF and IL-1 signaling suggests that the induced inflammatory response in PAH is greatly driven.

Conclusions: We systematically explored the immune heterogeneity and population and target cells in PAH, which may be valuable for developing new and precise therapies.

Vanishing bile duct syndrome (VBDS) is a serious drug induced liver injury characterized by chronic cholestasis and loss of intrahepatic bile ducts. VBDS has been reported also following checkpoint inhibitor treatment. We compared CD3 + , CD4 + , CD8 + , CD20 + , CD57 + , PD-1 + and PD-L1 + lymphocyte infiltrates in liver biopsies of patients that encountered VBDS (n = 2) or hepatotoxicity (n = 3) after pembrolizumab (n = 4) or nivolumab (n = 1) treatment with samples from normal liver (n = 10), non-alcohol steatohepatitis (NASH, n = 10), primary biliary cholangitis (PBC, n = 10) or pembrolizumab-treated patients without adverse events (n = 2). Notably, none of the cancer patients had primary nor metastatic liver tumors. We also studied direct growth effects of pembrolizumab on primary human intrahepatic biliary epithelial cells (HIBEpiC) in vitro. Liver sections of all checkpoint inhibitor- treated patients exhibited significantly higher CD3 + infiltration than normal livers, and significantly higher PD-L1 + , CD4 + and CD8 + infiltration, than other groups. PD-1 + infiltration was significantly increased in livers of patients with severe hepatic adverse event. CD57 + infiltration was similar in normal livers, NASH- and PBC groups, but highly increased in the checkpoint inhibitor-treated patients. Immune cell infiltrates were similar between NASH and normal livers. PBC samples had significantly higher CD3 + , CD4 + , CD8 + and CD20 + infiltrates than normal livers. HIBEpiC express PD-L1 but pembrolizumab did not affect their viability in vitro. Our findings suggest that VBDS is not due to direct cytotoxicity of checkpoint inhibitors and that the immunological attack against livers induced by these drugs is different from other cholestatic liver conditions.Biological insight: Checkpoint inhibitors upregulate PD-1 and PD-L1, as well as cytotoxic CD57 + cells in the non-cancerous liver tissues and this may be associated with checkpoint inhibitor-induced hepatotoxicity.

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.