Immunoglobulin GM (γ marker) and KM (κ marker) allotypes-encoded by immunoglobulin heavy chain G (IGHG) and immunoglobulin κ constant (IGKC) genes-have been shown to be associated with immune responsiveness to a variety of self and nonself antigens. The aim of the present investigation was to determine whether allelic variation at the GM and KM loci was associated with antibody responsiveness to poly-N-acetyl-D-glucosamine (PNAG), a broadly-conserved surface polysaccharide expressed by many microbial pathogens. In addition, we wished to determine whether Fcγ receptor 2 A (FCGR2A) genotypes, which have been shown to be risk factors for some pathogens, also influenced antibody responses to PNAG. DNA from 257 patients with various pulmonary diseases (PD) was genotyped for several GM, KM, and FCGR2A alleles, and plasma were characterized for anti-PNAG IgG antibodies. The levels of IgG4 antibodies to PNAG were associated with FCGR2A genotypes (p = 0.01). Also, KM and FCGR2A alleles epistatically contributed to anti-PNAG IgG3 antibody responses: subjects with KM 1/1 or KM 1/3 and homozygous for the R allele of FCGR2A had the highest levels of anti-PNAG IgG3 antibodies compared to all other genotype combinations. If confirmed by larger studies, these results are potentially relevant to immunotherapy against many PNAG-expressing infectious pathogens.

Recent studies have highlighted the critical role of lipid metabolism in macrophages concerning lung inflammation. However, it remains unclear whether lipid metabolism is involved in macrophage extracellular traps (METs). We analyzed the GSE40885 dataset from the GEO database using weighted correlation network analysis (WGCNA) and further selection using the least absolute shrinkage and selection operator (LASSO) regression. We identified ABCA1, SLC44A2, and C3 as key genes jointly involved in lipid metabolism and METs. Additionally, immune infiltration analysis was performed using the Xcell and CIBERSORT algorithms, while single-cell transcriptome analysis was utilized using data from the Tabula Muris database. The expression of key genes was validated in external datasets (GSE42606, GSE27066, GSE137268, and GSE256534). Notably, our results indicated that ABCA1 expression was elevated in patients experiencing acute asthma exacerbations, which aligned with its expression trend in lipopolysaccharide (LPS)-induced macrophages. However, ABCA1 expression was reduced in cases of chronic and severe asthma. Results from immunofluorescence (IF), SYTOX Green staining, and Western blot analyses suggested that ABCA1 may play a role in the formation of METs both in vivo and in vitro. In conclusion, this study indicates that ABCA1 may be involved in METs. ABCA1 may represent a promising therapeutic target for asthma.

Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an exceptionally rare inflammatory disorder affecting choroid and retinal pigment epithelial (RPE) cells. Although recent studies suggest an immune-driven nature, the underlying etiology of APMPPE remains elusive. In this study, we conducted a comprehensive investigation on the peripheral blood mononuclear cells (PBMCs) profile of an APMPPE patient using single-cell RNA sequencing. Our analysis revealed striking transcriptional alterations in monocytes within the PBMCs, identifying five distinct subpopulations: S100A12, CD16, pro-inflammatory, megakaryocyte-like, and NK-like monocyte subsets. Employing pseudotime inference, we observed a shift in APMPPE monocytes towards differentiation into inflammation-associated pro-inflammatory monocytes and a CD16 monocyte trajectory. Furthermore, we identified IFITM3 as a key player in the immune response driving the pathogenesis of APMPPE. Notably, two disease-relevant subgroups of monocytes, pro-inflammatory and CD16 monocytes, were implicated in APMPPE. CD16 monocytes, in particular, were involved in melanogenesis, suggesting that the abnormal expression of melanin in monocytes might result from autoimmune responses against pigment-enriched RPE cells. This study provided a comprehensive view of immune landscape in APMPPE, shedding light on the previously unrecognized contributions of pro-inflammatory and CD16 monocytes to this autoimmune condition.

Ischemic stroke (IS) significantly impacts patients' health and quality of life, with the roles of autophagy and autophagy-related genes in IS still not fully understood. In this study, IS datasets were retrieved from the GEO database. Autophagy-related genes(ARGs) were identified and screened for differential expression. A prediction model was constructed using machine learning algorithm. WGCNA was employed to analyze differential regulation modules among different clusters of stroke patients. The analysis results were validated using single-cell sequencing data. Finally, autophagy hub genes were validated in an external cohort and an IS mouse model. We observed suppressed autophagy states in IS patients. A diagnostic model with good clinical efficacy for stroke diagnosis was constructed based on the selected key genes (AUC = 0.87). Consensus clustering identified two IS subtypes with distinct gene expression patterns and immune cell infiltration. scRNA-seq data analysis confirmed downregulation of pexophagy in IS. CellChat analysis identified key signaling pathways and intercellular interactions related to pexophagy. Validation in an external cohort and IS mouse model confirmed differential gene expression, supporting the involvement of pexophagy in IS pathogenesis. The identified key genes, molecular subtypes, and cellular interactions provide a foundation for further research into targeted therapies and precision medicine approaches for IS patients.

The Cre/loxP system is extensively utilized to pinpoint gene functions in specific cell types or developmental stages, typically without major disturbance to the host's genome. However, we found that the random insertion of the Mrp8-cre transgene significantly promotes the host's innate immune response. This effect is characterized by elevated susceptibility to cartilage antibody-induced arthritis, likely due to interference with genes near the insertion site. These findings underscore the potential biological disturbances caused by random transgene integration, and the necessity for stringent control strategies to avoid biased interpretations when using Cre-conditional strains.

There are studies reporting that glucoside xylosyltransferase 2 (GXYLT2) has a role in promoting tumor progression, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, RT-qPCR and western blotting were employed to detect the expression level of GXYLT2. RNA interference assays were used to knock down GXYLT2. CCK-8, wound healing assays, clone formation assays, and Transwell assays were utilized to investigate the function of GXYLT2. Bioinformatics analysis was used to explore the tumor microenvironment and potential biological mechanisms. We found that the expression level of GXYLT2 in ccRCC was higher than that in adjacent normal renal tissues. Patients with high GXYLT2 expression have worse clinical outcomes. Knockdown of GXYLT2 inhibits the proliferation, invasion, migration, and clone formation ability of ccRCC cells. Enrichment analysis uncovered that GXYLT2 participates in Wnt, cell cycle, and actin cytoskeleton regulation signaling pathways. After receiving anti-PD-1 therapy, patients with high GXYLT2 expression had longer progression-free survival compared with those with low GXYLT2 expression. In conclusion, GXYLT2 is a novel potential therapeutic target for ccRCC. Meanwhile, GXYLT2 can be used as a novel marker for predicting immunotherapeutic response.

Microsatellite instability (MSI) is a phenotype characterized by changes in the sequence length of microsatellites in tumor cells and is closely linked to tumorigenesis and prognosis. Immune checkpoint inhibitors have shown good therapeutic effects in gastric cancer (GC) with MSI-high (MSI-H). However, the role of the novel immune checkpoint fibrinogen-like protein 1 (FGL1) in GC treatment has not been fully investigated. FGL1 expression in GC tissues and the difference in FGL1 immune infiltration between MSI/ microsatellite stability (MSS) patients were analyzed by bioinformatics and were verified in clinical samples. Xenograft models of MSS and MSI GC were constructed in human immune reconstitution mice, and FGL1 expression in tumors was detected. Immunofluorescence and immunohistochemistry were used to assay the infiltration of immune cells in the two types of mice. Cytotoxicity and chemotaxis tests were used to detect the toxicity and chemotaxis of CD8T cells to GC cells, respectively. The cytokine content was detected by enzyme-linked immunosorbent assay. The therapeutic effects of FGL1 antibody on different types of GC were analyzed by xenograft mouse models. FGL1 exhibited significantly higher expression in GC, and its expression and immune cell infiltration levels were significantly higher in MSI GC than in MSS GC. CD8T cells were significantly more effective in killing and chemotaxis of MSI GC cells than MSS GC cells. The FGL1 antibody was more effective in treating MSI GC.The novel immunosuppressor FGL1 antibody exerts a good therapeutic influence on MSI GC. These findings provide a basis for the development of drugs targeting FGL1 for MSI GC treatment.

Preeclampsia is a common multifactorial disease of pregnancy. Dysregulation of complement activation is among emerging candidates responsible for disease pathogenesis. In a targeted exomic sequencing study of 609 women with preeclampsia and 2092 non-preeclamptic controls, we identified 14 variants within nine genes coding for components of the membrane attack complex (MAC, C5b-9) that are associated with preeclampsia. We found two rare missense variants in the C5 gene that predispose to preeclampsia (rs200674959: I1296V, OR (CI95) = 24.13 (1.25-467.43), p value = 0.01 and rs147430470: I330T, OR (CI95) = 22.75 (1.17-440.78), p value = 0.01). In addition, one predisposing rare variant and one protective rare variant were discovered in C6 (rs41271067: D396G, OR (CI95) = 2.93 (1.18-7.10), p value = 0.01 and rs114609505: T190I, 0.02 OR (CI95) = 0.47 (0.22-0.92), p value = 0.02). The results suggest that variants in the terminal complement pathway predispose to preeclampsia.

The hypoxic microenvironment is an essential feature of solid tumors. Autophagy has been controversial in its role in immune regulation. This project aims to elucidate the impact of autophagy in pancreatic cancer (PC) under specific conditions (hypoxia) on CD8 T cells and the regulatory mechanisms behind it.The levels of HIF1α and autophagy were analyzed by western blot (WB) and immunofluorescence (IF). The effects of HIF1α on cell autophagy were assessed in normoxic or hypoxic treatments using KC7F2 (HIF-1 channel inhibitor) or chloroquine (autophagy inhibitor). CD8 T cells were co-cultured with PC cells to assess the cytotoxicity using lactate dehydrogenase (LDH) and Hoechst/PI staining. The content of cytokines and the activation level of CD8 T cells were measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. MHC-I expression in PC cells (membranes) was analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR), WB, IF, and flow cytometry. Humanized immune-reconstituted mice were applied to investigate the impact of HIF1α-induced autophagy on in vivo immunity.When cells were in hypoxia, the levels of HIF1α and autophagy were higher compared to normoxic conditions. Treatment with KC7F2 resulted in similar levels of HIF1α and autophagy as those in normoxic state. Chloroquine treatment reversed the autophagy level to the normoxic state. The autophagy level of PC cells transfected with oe-HIF1α was increased, with reduced MHC-I expression on cells (membranes), which impaired the cytotoxicity of CD8 T cells, and thus decreasing the probability of recognition and attack by CD8 T cells when co-cultured with them. In mice, overexpression of HIF1α hindered the immune suppressive function of CD8 T cells and facilitated the immune escape of PC by reducing antigen presentation of MHC-I.Under hypoxia, HIF1α-induced autophagy reduces the cytotoxicity of CD8 T cells by repressing MHC-I expression.

The development of personalized anticancer vaccines based on neoantigens represents a new direction in cancer immunotherapy. The latest advancement in dendritic cell (DC) tumor vaccine construction involves loading DC with mRNA-encoding neoantigens, which allows for rapid production and is suitable for personalized preparation. Cell-penetrating peptides (CPPs) are emerging as biological delivery systems in which negatively charged nucleic acids can be wound onto the cationic CPP backbone to form nanoscale complexes. This preparation method facilitates standardization. If DC can express and present neoantigen mRNA at high levels, it holds promising application potential. In this study, we developed a neoantigen-mRNA/DC vaccine using candidate neoantigens from mouse colon cancer (MC38) and examined its immune and antitumor effects. The results demonstrated that neoantigen-mRNA/DC vaccines induced strong T cell immune responses and exhibited significant antitumor effects, effectively preventing tumor growth. Our study provides an experimental basis for further optimizing the preparation of DC vaccines and reducing their costs.

Glioblastoma (GBM) is the deadliest malignant brain tumor, with a survival of less than 14 months after diagnosis. The highly invasive nature of GBM makes total surgical resection challenging, leading to tumor recurrence and declined survival. The heterocellular composition of the GBM reprograms its microenvironment, favoring tumor growth, proliferation, and migration. The innate immune cells in the GBM tumor microenvironment, including microglia, astrocytes, and macrophages, express pattern recognition receptors such as NLRs (Nucleotide-binding domain and leucine-rich repeat-containing) that sense pathogen- and damage-associated molecular patterns initiating inflammation. Upon activation, NLRP3 promotes inflammation by NLRP3 inflammasome formation. Auto-proteolytic cleavage and activation of Caspase-1 within the inflammasome leads to caspase-1-mediated cleavage, activation, and conversion of pro-IL-1ß and pro-IL-18 to IL-1ß and IL-18, leading to pyroptosis. In contrast, NLRP12 downregulates inflammatory responses in microglia and macrophages by regulating the NF-κB pathway. NLRP3 and NLRP12 have been implicated in the disease pathophysiology of several cancers with cell-context-dependent, pro- or anti-tumorigenic roles. In this review, we discuss the current literature on the mechanistic roles of NLRP3 and NLRP12 in GBM and the gaps in the scientific literature in the context of GBM pathophysiology with potential for targeted therapeutics.

Liver regeneration following resection is a complex process relying on coordinated pathways and cell types in the remnant organ. Myeloid-Derived Suppressor Cells (MDSCs) have a role in liver regeneration-related angiogenesis but other roles they may play in this process remain to be elucidated. In this study, we sought to examine the effect of G-MDSCs on hepatocytes proliferation and immune modulation during liver regeneration. Global gene expression profiling of regenerating hepatocytes in mice with CD11bLy6G MDSCs (G-MDSCs) depletion revealed disrupted transcriptional progression from day one to day two after major liver resection. Key genes and pathways related to hepatocyte proliferation and immune response were differentially expressed upon MDSC depletion. Hepatocytes cellularity increased when co-cultured with G-MDSCs, or treated with amphiregulin, which G-MDSCs upregulate during regeneration. Cytometry by time-of-flight (CyTOF) analysis of the intra-liver immune milieu upon MDSC depletion during regeneration demonstrated increased natural killer cell proportions, alongside changes in other immune cell populations. Taken together, these results provide evidence that MDSCs contribute to early liver regeneration by promoting hepatocyte proliferation and modulating the intra-liver immune response, and illuminate the multifaceted role of MDSCs in liver regeneration.

The present study utilized large-scale genome-wide association studies (GWAS) summary data (731 immune cell subtypes and three primary sclerosing cholangitis (PSC) GWAS datasets), meta-analysis, and two PSC transcriptome data to elucidate the pivotal role of Tregs proportion imbalance in the occurrence of PSC. Then, we employed weighted gene co-expression network analysis (WGCNA), differential analysis, and 107 combinations of 12 machine-learning algorithms to construct and validate an artificial intelligence-derived diagnostic model (Tregs classifier) according to the average area under curve (AUC) (0.959) in two cohorts. Quantitative real-time polymerase chain reaction (qRT-PCR) verified that compared to control, Akap10, Basp1, Dennd3, Plxnc1, and Tmco3 were significantly up-regulated in the PSC mice model yet the expression level of Klf13, and Scap was significantly lower. Furthermore, immune cell infiltration and functional enrichment analysis revealed significant associations of the hub Tregs-related gene with M2 macrophage, neutrophils, megakaryocyte-erythroid progenitor (MEP), natural killer T cell (NKT), and enrichment scores of the autophagic cell death, complement and coagulation cascades, metabolic disturbance, Fc gamma R-mediated phagocytosis, mitochondrial dysfunction, potentially mediating PSC onset. XGBoost algorithm and SHapley Additive exPlanations (SHAP) identified AKAP10 and KLF13 as optimal genes, which may be an important target for PSC.

CD8 T cells play a critical role in specific immunity. In recent years, cell therapy has been emerging rapidly. The specific cytotoxic capabilities of these cells enable them to precisely identify and kill cells presenting specific antigens. This has demonstrated promise in the treatment of autoimmune diseases and cancers, with wide-ranging applications and value. However, in some diseases, such as tumors and chronic infections, T cells may adopt an exhausted phenotype, resulting in a loss of cytotoxicity and limiting their further application. Epigenetics plays a significant role in the differentiation and regulation of gene expression in cells. There is extensive evidence indicating that epigenetic remodeling plays an important role in T cell exhaustion. Therefore, further understanding its role in CD8 T cell function can provide insights into the programmatic regulation of CD8 T cells from a genetic perspective and overcome these diseases. We attempted to describe the relationship between the activation, function, and exhaustion mechanisms of CD8 T cells, as well as epigenetics. This understanding makes it possible for us to address the aforementioned issues.

Host genetics shape immune responses and influence severity of infectious diseases. The HLA-B -21 M/T dimorphism tunes the functionality of natural killer (NK) cells expressing the inhibitory receptor NKG2A. NKG2A NK cells have been reported to recognize SARS-CoV-2-infected cells, but it remains unclear whether the HLA-B -21 M/T dimorphism associates with COVID-19 severity. Here, we investigated the influence of the HLA-B -21 M/T dimorphism in a cohort of 230 unvaccinated patients hospitalized with COVID-19 and requiring respiratory support. We found that HLA-B -21 M/M genotypes were more prevalent in patients with moderate compared to severe COVID-19 (6.0% vs. 0.9%). Comparison of age- and sex-matched sub-groups revealed that patients with M/M genotypes required mechanical respiratory support less frequently (OR = 0.13, 95% CI = 0.01-0.76, P = 0.013). Furthermore, patients with M/M genotypes showed a coordinately shifted signature of clinical laboratory parameters, coinciding with elevated serum levels of the anti-viral cytokine IFN-γ. These findings demonstrate that HLA-B variants associate with COVID-19 severity and suggest that the robust functionality of NKG2A NK cells in patients carrying the M/M genotype may contribute to protection from severe disease.

The relationships among immune cells, metabolites, and AS events were analyzed via Mendelian randomization (MR), and potential immune cells and metabolites were identified as risk factors for AS. Their relationships were subjected to intermediary MR analysis to identify the final immune cells and metabolites. The vertebral bone marrow blood samples from three patients with and without AS were subjected to 10× single-cell sequencing to further elucidate the role of immune cells in AS. The key genes were screened via expression quantitative trait loci (eQTLs) and MR analyses. The metabolic differences between the two groups were compared through single-cell metabolism analysis. Two subgroups of differentiated (CD)8+ memory T cells and naive B cells were obtained from the combined results of intermediary MR analysis and AS single-cell analysis. After the verification of key genes, inorganic pyrophosphatase 1 (PPA1) was identified as the hub gene, as it is differentially expressed in CD8+ memory T cells and can affect the metabolism of T cells in AS by affecting the expression of ferulic acid (FA)4 sulfate, which participates in the cellular immunity in AS.

Immunotherapy has showcased remarkable progress in the management of gastric cancer (GC), prompting the need to proactively identify and classify patients suitable for immunotherapy. Here, 30 patients were enrolled and stratified into three groups (PR, partial response; SD, stable disease; PD, progressive disease) based on efficacy assessment. 16S rRNA sequencing were performed to analyze the gut microbiome signature of patients at three timepoints. We found that immunotherapy interventions perturbed the gut microbiota of patients. Additionally, although differences at the enterotype level did not distinguish patients' immunotherapy response, we identified 6, 7, and 19 species that were significantly enriched in PR, SD, and PD, respectively. Functional analysis showed that betalain biosynthesis and indole alkaloid biosynthesis were significantly different between the responders and non-responders. Furthermore, machine learning model utilizing only bacterial biomarkers accurately predicted immunotherapy efficacy with an Area Under the Curve (AUC) of 0.941. Notably, Akkermansia muciniphila and Dorea formicigenerans played a significant role in the classification of immunotherapy efficacy. In conclusion, our study reveals that gut microbiome signatures can be utilized as effective biomarkers for predicting the immunotherapy efficacy for GC.

The T cell Ubiquitin Ligand (TULA) protein family contains two members, UBASH3A and UBASH3B, that display similarities in protein sequence and domain structure. Both TULA proteins act to repress T cell activation via a combination of overlapping and nonredundant functions. UBASH3B acts mainly as a phosphatase that suppresses proximal T cell receptor (TCR) signaling. In contrast, UBASH3A acts primarily as an adaptor protein, interacting with other proteins (including UBASH3B) in T cells upon TCR stimulation and resulting in downregulation of TCR signaling and NF-κB signaling. Human genetic and functional studies have revealed another notable distinction between UBASH3A and UBASH3B: numerous genome-wide association studies have identified statistically significant associations between genetic variants in and around the UBASH3A gene and at least seven different autoimmune diseases, suggesting a key role of UBASH3A in autoimmunity. However, the evidence for an independent role of UBASH3B in autoimmune disease is limited. This review summarizes key findings regarding the roles of TULA proteins in T cell biology and autoimmunity, highlights the commonalities and differences between UBASH3A and UBASH3B, and speculates on the individual and joint effects of TULA proteins on T cell signaling.