Journal of Immunology Research最新文献

The advancement of genetic engineering has revolutionized the field of immunology by allowing the utilization of intrinsic antibody structures. One of the biologics that are being produced by recombinant antibody technology is single-chain fragments variable (scFv). Genes of variable regions, the heavy and light chains that are genetically linked into a single transcript by a short flexible linker peptide, are used to generate this fragment from cellular and synthetic libraries. The specificity and affinity of these molecules are comparable to those of parental antibodies. Fusion with marker proteins and other potent molecules improves their stability, circulation half-life, activity, and efficient purification. Besides, this review comprises construction protocols, therapeutics, and diagnostic applications of scFv, as well as related challenges. Nonetheless, there are still issues with efficacy, stability, safety, intracellular administration, and production costs that need to be addressed.

Macrophage alternative activation is involved in kidney fibrosis. Previous researches have documented that the transcriptional regulators Yes-associated protein (Yap)/transcriptional coactivator with PDZ-binding motif (Taz) are linked to organ fibrosis. However, limited knowledge exists regarding the function and mechanisms of their downstream molecules in regulating macrophage activation and kidney fibrosis. In this paper, we observed that the Hippo pathway was suppressed in macrophages derived from fibrotic kidneys in mice. Knockout of Taz or Tead1 in macrophages inhibited the alternative activation of macrophages and reduced kidney fibrosis. Additionally, by using bone marrow-derived macrophages (BMDMs), we investigated that knockout of Taz or Tead1 in macrophages impeded both cell proliferation and migration. Moreover, deletion of Tead1 reduces p-Smad3 and Smad3 abundance in macrophages. And chromatin immunoprecipitation (ChIP) assays showed that Tead1 could directly bind to the promoter region of Smad3. Collectively, these results indicate that Tead1 knockout in macrophages could reduce TGFβ1-induced phosphorylation Smad3 via transcriptional downregulation of Smad3, thus suppressing macrophage alternative activation and IRI-induced kidney fibrosis.

In recent years, as the aging population continues to grow, osteoarthritis (OA) has emerged as a leading cause of disability, with its incidence rising annually. Current treatments of OA include exercise and medications in the early stages and total joint replacement in the late stages. These approaches only relieve pain and reduce inflammation; however, they have significant side effects and high costs. Therefore, there is an urgent need to identify effective treatment methods that can delay the pathological progression of this condition. The changes in the articular cartilage microenvironment, which are complex and diverse, can aggravate the pathological progression into a vicious cycle, inhibiting the repair and regeneration of articular cartilage. Understanding these intricate changes in the microenvironment is crucial for devising effective treatment modalities. By searching relevant research articles and clinical trials in PubMed according to the keywords of articular cartilage, microenvironment, OA, mechanical force, hypoxia, cytokine, and cell senescence. This study first summarizes the factors affecting articular cartilage regeneration, then proposes corresponding treatment strategies, and finally points out the future research direction. We find that regulating the opening of mechanosensitive ion channels, regulating the expression of HIF-1, delivering growth factors, and clearing senescent cells can promote the formation of articular cartilage regeneration microenvironment. This study provides a new idea for the treatment of OA in the future, which can promote the regeneration of articular cartilage through the regulation of the microenvironment so as to achieve the purpose of treating OA.

Exosome-derived microRNAs (miRNAs) are emerging as pivotal players in the pathophysiology of sepsis, representing a new frontier in both the diagnosis and treatment of this complex condition. Sepsis, a severe systemic response to infection, involves intricate immune and nonimmune mechanisms, where exosome-mediated communication can significantly influence disease progression and outcomes. During the progress of sepsis, the miRNA profile of exosomes undergoes notable alterations, is reflecting, and may affect the progression of the disease. This review comprehensively explores the biology of exosome-derived miRNAs, which originate from both immune cells (such as macrophages and dendritic cells) and nonimmune cells (such as endothelial and epithelial cells) and play a dynamic role in modulating pathways that affect the course of sepsis, including those related to inflammation, immune response, cell survival, and apoptosis. Taking into account these dynamic changes, we further discuss the potential of exosome-derived miRNAs as biomarkers for the early detection and prognosis of sepsis and advantages over traditional biomarkers due to their stability and specificity. Furthermore, this review evaluates exosome-based therapeutic miRNA delivery systems in sepsis, which may pave the way for targeted modulation of the septic response and personalized treatment options.

The first few days of life are characterized by rapid external and internal changes that require substantial immune system adaptations. Despite growing evidence of the impact of this period on lifelong immune health, this period remains largely uncharted. To identify factors that may impact the trajectory of immune development, we conducted stringently standardized, high-throughput phenotyping of peripheral white blood cell (WBC) populations from 796 newborns across two distinct cohorts (The Gambia, West Africa; Papua New Guinea, Melanesia) in the framework of a Human Immunology Project Consortium (HIPC) study. Samples were collected twice from each newborn during the first week of life, first at Day of Life 0 (at birth) and then subsequently at Day of Life 1, 3, or 7 depending on the randomization group the newborn belongs to. The subsequent analysis was conducted at an unprecedented level of detail using flow cytometry and an unbiased automated gating algorithm. The results showed that WBC composition in peripheral blood changes along patterns highly conserved across populations and environments. Changes across days of life were most pronounced in the innate myeloid compartment. Breastfeeding, and at a smaller scale neonatal vaccination, were associated with changes in peripheral blood neutrophil and monocyte cell counts. Our results suggest a common trajectory of immune development in newborns and possible association with timing of breastfeeding initiation, which may contribute to immune-mediated protection from infection in early life. These data begin to outline a specific window of opportunity for interventions that could deliberately direct WBC composition, and with that, immune trajectory and thus ontogeny in early life. This trial is registered with NCT03246230.

It has been reported that carbonic anhydrase I (CA1) is a target for the diagnosis and therapy of atherosclerosis (AS) since CA1 can promote AS aortic calcification. We also found that methazolamide (MTZ), a drug for glaucoma treatment and an inhibitor of carbonic anhydrases, can treat AS by inhibiting calcification in aortic tissues. This study focused on the therapeutic mechanism of MTZ and the pathogenic mechanism of AS. In this study, a routine AS animal model was established in ApoE-/- mice, which were treated with MTZ. The aortic tissues were analyzed using single-cell sequencing. MTZ significantly increased the proportions of B-1/MZB B cells with high expressions of Nr4A1 and Ccr7, CD8+CD122+ Treg-like cells with high Nr4A1 expression, and smooth muscle cells with high Tpm2 expression. These cells or their marker genes were reported to exert immunosuppressive, anti-proinflammatory, and atheroprotective effects. MTZ also decreased the proportions of endothelial cells with high expressions of Retn, Apoc1, Lcn2, Mt1, Serpina3, Lpl, and Lgals3; nonclassical CD14+CD16++ monocytes with high expressions of Mt1, Tyrobp, Lgals3, and Cxcl2; and Spp1+ macrophages with high expressions of Mmp-12, Trem2, Mt1, Lgals3, Cxcl2, and Lpl. These cells or their marker genes have been reported to promote inflammation, calcification, tissue remodeling, and atherogenesis. A significant decrease in the proportion of CD8+CD183 (CXCR3)+ T cells, the counterpart of murine CD8+CD122+ T cells, was detected in the peripheral blood of newly diagnosed AS patients rather than in that of patients receiving anti-AS treatments. These results suggest that MTZ can treat AS by increasing immunosuppressive cells and decreasing expressions of genes related to inflammation, calcification, and tissue remodeling.

CD8⁺ T cells are essential for adaptive immunity against infection and tumors. Their ability to proliferate after stimulation is crucial to their functionality. Dendritic cells (DCs) are professional antigen-presenting cells that induce their proliferation. Here, we show that thapsigargin-induced LAD2 mast cell (MC) line-released products can impair the ability of monocyte-derived DCs to induce CD8⁺ T-cell proliferation and the generation of Th1 cytokine-producing T cells. We found that culture medium conditioned with LAD2 MCs previously stimulated with thapsigargin (thapsLAD2) induces maturation of DCs as determined by the maturation markers CD80, CD83, CD86, and HLA-DR. However, thapsLAD2-matured DCs produced no detectable TNFα or IL-12 during the maturation. In addition, although their surface expression of PD-L1 was comparable with the immature or TLR7/8-agonist (R848)-matured DCs, their TIM-3 expression was significantly higher than in immature DCs and even much higher than in R848-matured DCs. In addition, contrary to R848-matured DCs, the thapsLAD2-matured DCs only tended to induce enhanced proliferation of CD4⁺ T cells than immature DCs. For CD8⁺ T cells, this tendency was not even detected because thapsLAD2-matured and immature DCs comparably induced their proliferation, which contrasted with the significantly enhanced proliferation induced by R848-matured DCs. Furthermore, these differences were comparably recapitulated in the ability of the tested DCs to induce IFNγ- and IFNγ/TNFα-producing T cells. These findings show a novel mechanism of MC-mediated regulation of adaptive immune responses.

As another receptor for complement activation product C5a, C5aR2 has been paid much attention these years. Although controversial and complex, its specific signals or roles in modulating the classic receptor C5aR1 have been investigated and gradually revealed. The hypothesis of the heterodimer of C5aR1 and C5aR2 has also been suggested and observed under extremely high C5a concentrations. In this article, we tried to investigate whether C5aR2 would affect C5aR1 expression under normal or inflammatory conditions in WT and C5ar2 ^-/- mice of C57BL/6 background. We focused on the innate immune cells-neutrophils and macrophages. The mRNA levels of C5ar1 in normal kidney, liver, and the mRNA or protein levels of naïve-bone marrow and peripheral blood leukocytes and peritoneal Mφs were comparable between WT and C5ar2 ^-/- mice, indicating the technique of C5aR2 knockout did not affect the transcription of its neighboring gene C5aR1. However, the mean fluorescence intensity of surface C5aR1 on naïve circulating C5ar2 ^-/- neutrophils detected by FACS was reduced, which might be due to the reduced internalization of C5aR1 on C5ar2 ^-/- neutrophils. In the peritonitis model induced by i.p. injection of thioglycollate, more neutrophils were raised after 10 hr in C5ar2 ^-/- peritoneal cavity, indicating the antagonism of C5aR2 on C5aR1 signal in neutrophil chemotaxis. After 3 days of thioglycollate injection, the mainly infiltrating macrophages were comparable between WT and C5ar2 ^-/- mice, but the C5ar1 mRNA and surface or total C5aR1 protein expression were both reduced in C5ar2 ^-/- macrophages, combined with our previous study of reduced chemokines and cytokines expression in C5ar2 ^-/- peritoneal macrophages, indicating that C5aR2 in macrophages may cooperate with C5aR1 inflammatory signals. Our article found C5aR2 deficiency lessened C5aR1 distribution and expression in neutrophils and macrophages with different functions, indicating C5aR2 might function differently in different cells.

Materials and methods: We analyzed RNA-seq data from the Cancer Genome Atlas (TCGA-STAD) and Gene Expression Omnibus (GEO) datasets, focusing on five cDC1-related genes. The cDC1-related signature was defined and divided into high and low expression groups. We employed gene set variation analysis (GSVA) for oncogenic signaling pathways and conducted comprehensive statistical analyses, including Kaplan-Meier and Cox proportional hazards models.

Results: The high cDC1-related gene signature group was associated with poorer overall and disease-free survival in the TCGA-STAD cohort. Significant differences in CD8+ T cell infiltration and cytotoxic capabilities were observed between high and low CDC1-related signature groups. The study also revealed a strong correlation between CDC1-related signature and increased expression of immune checkpoint proteins and oncogenic pathways, suggesting a complex immunosuppressive tumor microenvironment.

Conclusions: Our findings indicate the potential of the cDC1-related signature as a prognostic marker in GC, offering insights into the tumor-immune interplay. The study underscores the importance of cDC1s in shaping the tumor microenvironment and their influence on patient prognosis in GC. These results may contribute to the development of novel therapeutic strategies targeting the immune microenvironment in GC.

Background: This work focused on investigating the role of programmed death ligand 2 (PD-L2) in the progression of breast cancer by utilizing breast cancer specimens and cells.

Materials and methods: The serum levels of soluble PD-L2 (sPD-L2) in breast cancer patients and healthy individuals were analyzed by means of the enzyme-linked immunosorbent assay, and the PD-L2 levels within 416 resected breast cancer specimens were assessed through immunohistochemistry. Concurrently, in vitro cell experiments and in vivo animal experiments were carried out to analyze the relationship between PD-L2 and the invasion and migration of breast cancer.

Results: The concentration of sPD-L2 in breast cancer patients significantly increased compared to that in the control groups. Additionally, breast cancer patients with high concentrations of sPD-L2 had higher Ki67 values (≥30%) and tumor grades. PD-L2 was expressed in 79.09% of the cancer samples, which exhibited a positive correlation with the progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2). Furthermore, we discovered that knockdown of PD-L2 inhibited the migratory and invasive abilities of both MCF-7 and MDA-MB231 cells.

Conclusion: Our findings demonstrated that knockdown of PD-L2 suppressed tumor growth, providing novel insights into important biological functions.