Immunology最新文献

Retraction: S. Cuzzocrea, A. Rossi, I. Serraino, R. Di Paola, L. Dugo, T. Genovese, D. Britti, G. Sciarra, A. De Sarro, A. P. Caputi, and L. Sautebin, "5-lipoxygenase Knockout Mice Exhibit a Resistance to Acute Pancreatitis Induced by Cerulein," Immunology 110, no. 1 (2003): 120-130, https://doi.org/10.1046/j.1365-2567.2003.01715.x. The above article, published online on 22 August 2003 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Greg Delgoffe; and John Wiley & Sons Ltd. The retraction has been agreed due to concerns raised by third parties on the data presented in the article. Specifically, two panels of Figure 9 were found to have been previously published in articles with at least one common author and presented in a different scientific context. The article is retracted as the editors have lost trust in the accuracy and integrity of the overall body of data presented in the article and consider its conclusions invalid. No confirmation of the decision of retraction could be obtained by the authors.

This study attempted to identify the relevant pathways involved in autophagy activation of pancreatic cancer and explore the mechanisms underlying immune evasion. Western blot (WB) was used to detect the expression of ITGB4, BNIP3, autophagy-related proteins and MHC-I. Co-immunoprecipitation (Co-IP) was used to verify the binding mode of ITGB4 and BNIP3. Flow cytometry was used to detect the expression of MHC-I on the cell membrane. Transmission electron microscope (TEM) was used to observe cell autophagy. Confocal microscopy was used to observe the co-localisation relationship between MHC-I and autophagosomes in cells. ELISA was used to detect the level of lactate dehydrogenase and granzyme B in a tumour cell-CD8⁺ T-cell co-culture system. Mouse syngeneic transplant tumour model and orthotopic tumour model were constructed and treated with PD-1 monoclonal antibody to observe tumour growth. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of ITGB4 and BNIP3 in tumour tissues. WB was used to determine the expression of autophagy-related proteins. Flow cytometry was used to detect the expression of MHC-I on cell membranes and the proportion of CD3⁺ and CD8⁺ cells. The results of Co-IP experiments showed that ITGB4 could bind to BNIP3. It was observed under confocal microscopy that activating ITGB4/BNIP3 could promote the phagocytosis of MHC-I by autophagosomes. Finally, the subcutaneous tumour transplantation and orthotopic tumour experiments in mice demonstrated the downregulation of ITGB4 significantly improved the therapeutic effect of PD-1 antibodies on pancreatic cancer. In pancreatic cancer cells, autophagy is positively correlated with the ITGB4-BNIP3 complex protein expression level. Autophagy diminishes the protein expression of MHC-I, thereby promoting immune escape in pancreatic cancer cells.

Itaconic acid and its metabolites have demonstrated significant therapeutic potential in various immune diseases. Originating from the tricarboxylic acid cycle in immune cells, itaconic acid can modulate immune responses, diminish inflammation, and combat oxidative stress. Recent research has uncovered multiple mechanisms through which itaconic acid exerts its effects, including the inhibition of inflammatory cytokine production, activation of anti-inflammatory pathways, and modulation of immune cell function by regulating cellular metabolism. Cellular actions are influenced by the modulation of metabolic pathways, such as inhibiting succinate dehydrogenase (SDH) activity or glycolysis, activation of nuclear-factor-E2-related factor 2 (Nrf2), boosting cellular defences against oxidative stress, and suppression of immune cell inflammation through the NF-κB pathway. This comprehensive review discusses the initiation, progression, and mechanisms of action of itaconic acid and its metabolites, highlighting their modulatory effects on various immune cell types. Additionally, it examines their involvement in immune disease like rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, and autoimmune hepatitis, offering greater understanding for creating new therapies for these ailments.

Elevated levels of serum autoantibodies are a hallmark of systemic lupus erythematosus (SLE) and are produced by plasma cells in response to a variety of antigenic triggers. In SLE, the triggers are complex and may include both T cell-dependent/-independent and TLR-dependent/-independent mechanisms of immune activation, which ultimately contributes to the significant immune dysregulation seen in patients at the level of cytokine production and cellular activation (B cells, T cells, dendritic cells, neutrophils and macrophages). Interferon regulatory factor 5 (IRF5) has been identified as an autoimmune susceptibility gene and polymorphisms in IRF5 associate with altered expression and hyper-activation in distinct SLE immune cell subsets. To gain further insight into the mechanisms that drive IRF5-mediated SLE immune activation, we characterised wild-type (WT) and Irf5 ^-/- Balb/c mice in response to immunisation. WT and Irf5 ^-/- Balb/c mice were immunised to activate various signalling pathways in vivo followed by systemic immunophenotyping and detection of antibody production by multi-colour flow cytometry and ELISPOT. We identified two pathways, TLR9-dependent and T cell-dependent that resulted in IRF5 cell type-specific function. Immunisation with either CpG-B + Alum or NP-KLH + Alum but not with R848 + Alum, NP-LPS + Alum or NP-Ficoll+Alum resulted in decreased plasma cell generation and reduced antibody production in Irf5 ^-/- mice. Notably, the mechanism(s) leading to this downstream phenotype was distinct. In CpG-B + Alum immunised mice, we found reduced activation of plasmacytoid dendritic cells, resulting in reduced IFNα and IL6 production in Irf5 ^-/- mice. Conversely, mice immunised with NP-KLH + Alum had reduced numbers of T follicular helper cells and germinal centre B cells with reduced expression of Bcl6 in Irf5 ^-/- mice. Moreover, T follicular helper cells from Irf5 ^-/- mice were functionally defective. Even though the downstream phenotype of reduced antibody production in Irf5 ^-/- mice was conserved between T cell-dependent and TLR9-dependent immunisation, the mechanisms leading to this phenotype were antigen- and cell type-specific.

T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Chronic T cell receptor (TCR) signalling induces T cell exhaustion, characterised by reduced capacity to induce tissue damage. Here, we investigated the therapeutic potential of the anti-TCRβ (H57-597) monoclonal antibody (mAb) in a mouse model of SLE. Four-month-old MRL/lpr mice exhibiting SLE phenotypes received 5 weekly doses of anti-TCRβ mAb or phosphate-buffered saline (PBS) vehicle control. Subsequently, mouse survival was monitored daily. On day 1 post the final dose of treatment, SLE pathogenesis was determined using histological staining and spot urine test. T and B cell states in the brain, kidney, and secondary lymphoid organs were determined by flow cytometry. Transient treatment of anti-TCRβ mAb significantly prolonged the survival of MRL/lpr mice. Accordingly, MRL/lpr mice in the anti-TCRβ mAb group exhibited decreased proteinuria scores and minimal renal pathological damage compared to the PBS control group. Flow cytometric analysis revealed that anti-TCRβ mAb treatment resulted in a reduction in the frequencies of CD4⁺ T cells and CD138⁺B220^lo/- plasma cells, plus an increase in Foxp3⁺ regulatory T cell frequency. Furthermore, CD4⁺ T cells from anti-TCRβ mAb treated mice exhibited elevated expression levels of PD-1 and TIM-3, with reduced IFN-γ production, indicative of an exhaustion-like phenotype. Therefore, transient administration of anti-TCRβ mAb treatment induces an exhaustion-like phenotype in CD4⁺ T cells, resulting in prolonged survival of MRL/lpr mice. Inducing autoreactive T-cell exhaustion holds promise as an attractive therapeutic approach for SLE.

Wnt5a plays an important role in cell development and maturation and is closely associated with various diseases, such as malignant tumours, metabolic disorders, fibrosis, growth and development. Recent studies have shown that Wnt5a expression and signal transduction are strongly involved in the inflammatory response. This study comprehensively reviewed the latest research progress on the association between Wnt5a and several inflammatory diseases, such as sepsis, asthma, chronic obstructive pulmonary disease, tuberculosis, rheumatoid arthritis, atherosclerosis and psoriasis vulgare. We elucidated the mechanism by which the Wnt5a protein is involved in the pathogenesis of these diseases, providing a basis for the prevention and treatment of inflammatory diseases.

Psoriasis is a chronic inflammatory skin disease characterised by inflammatory cell infiltration, keratinocyte hyperproliferation and increased neovascularization. Despite extensive research, the precise mechanisms underlying psoriasis pathology and treatment strategies remain unclear because of a complex aetiology and disease progression. Hence, in this study, we aimed to identify potential therapeutic targets for psoriasis and explore their effects on disease progression. We observed that G protein-coupled receptor LGR4 attenuates psoriasis progression. Bioinformatics analysis of publicly available clinical data revealed lower LGR4 expression in the skin lesions of patients with psoriasis than in their non-lesioned skin. Both in vitro (HaCaT cell) and in vivo (mouse) models confirmed this phenomenon. The Lgr4-knockout mouse model further confirmed that LGR4 plays a positive role in psoriasis progression. Specifically, Lgr4 knockout promoted the secretion of inflammatory factors, accumulation of local immunocyte infiltration in skin lesions, and keratinocyte proliferation. In conclusion, we demonstrated that LGR4 is critical to limiting psoriasis progression, suggesting that it is a viable target for the clinical management of this skin condition.

Autoreactive, aberrantly activated lymphocytes that target myelin antigens in the central nervous system (CNS) are primary drivers of the autoimmune disease multiple sclerosis (MS). Proliferating cells including activated lymphocytes require deoxyribonucleoside triphosphates (dNTPs) for DNA replication. dNTPs can be synthesised via the de novo pathway from precursors such as glucose and amino acids or the deoxyribonucleoside salvage pathway from extracellular deoxyribonucleosides. Deoxycytidine kinase (dCK) is the rate-limiting enzyme in the salvage pathway. In prior work, we showed that targeting dCK with the small molecule inhibitor TRE-515 limits clinical symptoms in two myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) mouse models of MS and decreases the levels of activated CD4 T and B lymphocytes in vivo. However, whether targeting dCK limits disease in additional EAE models and how targeting dCK directly impacts activated and proliferating CD4 T and B cells has yet to be determined. Here, we show that dCK is activated in the lymph nodes and spleen in an EAE model induced by amino acids 139-151 of the proteolipid protein (PLP_139-151) that is driven by CD4 T and B cells and is characterised by acute disease followed by disease remission. Treating this model with TRE-515 limits clinical symptoms and decreases the levels of activated CD4 T and B cells. In culture, CD4 T and B cells induce deoxyribonucleoside salvage following activation, and TRE-515 directly blocks CD4 T and B cell activation-induced proliferation and activation marker expression. TRE-515 decreases deoxycytidine triphosphate (dCTP) and deoxythymidine triphosphate (dTTP) pools and increases the length of time cells spend in S phase of the cell cycle without inducing a replication stress response in B cells. Our results suggest that dCK activity is required to supply needed dNTPs and to enable rapid cell division following lymphocyte activation against autoantigens in EAE mouse models.

Cancer is one of the leading causes of death worldwide. In recent years, immune checkpoint inhibitor therapies, in addition to standard immuno- or chemotherapy and surgical approaches, have massively improved the outcome for cancer patients. However, these therapies have their limitations and improved strategies, including access to reliable cancer vaccines, are needed. Here, we describe the use of self-assembling artificial cell membrane (ACM) polymersomes to deliver tumour-specific peptides to trigger sustainable and efficient anti-tumour immune responses. We found that ACM polymersomes were highly efficient in targeting and activating mononuclear phagocytes (MNP) including dendritic cells (DC), while providing long-term reservoirs of antigens for continued immune cell priming. Subcutaneous injection of ACM-encapsulated tumour-antigen-peptides into tumour-bearing mice resulted in improved priming of CD8⁺ T cells and increased generation of tumour-antigen-peptide specific CD8⁺ effector T cells. Prophylactic and therapeutic immunisation with ACM-encapsulated peptides resulted in changes to the MNP composition in the tumour microenvironment, tumour regression and improved survival of immunised mice. Combining anti-PD-1 immune checkpoint inhibitor therapy with ACM polymersome peptide delivery further boosted anti-tumour immunity. Our results show that ACM polymersome nanocarriers efficiently instruct anti-tumour immune responses offering a promising new approach for vaccination and cancer immunotherapy. Trial Registration: NCT05385991.

Epstein-Barr virus-induced 3 (EBI3) functions as a component of the heterodimer cytokine IL-27, which regulates innate and acquired immune responses. The expression of EBI3 gene is induced by Toll-like receptors (TLRs). Repeated treatment with imiquimod (IMQ), a TLR7 agonist, induces splenomegaly and cytopaenia due to increased splenic function. Although immune cell activation is speculated to play a role in chronic infection-mediated splenomegaly, the detailed mechanisms remain unknown. This study shows that IMQ treatment induces marked splenomegaly and severe bicytopaenia (anaemia and thrombocytopaenia) in wild-type mice. In IMQ-treated mice, myeloid cell populations in the spleen increased, and extramedullary haematopoiesis was observed. RNA-seq analysis revealed the upregulation of type I interferon (IFN)-related genes in the spleens of IMQ-treated mice. IMQ-induced pathological changes were partially mitigated by EBI3 deficiency. To investigate the mechanism of the improved phenotypes in the Ebi3 KO mice, we examined the involvement of IL-27, a heterodimer of EBI3 and IL-27p28. The expression of Il27a, which encodes IL-27p28, was increased in the spleen and peripheral blood by IMQ treatment. Furthermore, IL-27 stimulation upregulated type I IFN-related genes in bone marrow-derived macrophage cultures without type I IFN. These findings suggest that EBI3 deficiency mitigated IMQ-mediated pathological changes, presumably via a lack of IL-27 formation. Our study thus provides insights into the molecular mechanisms underlying chronic infection-mediated splenomegaly.