Immunology最新文献

{"title":"Blocking Deoxycytidine Kinase in Activated Lymphocytes Depletes Deoxycytidine Triphosphate Pools and Alters Cell Cycle Kinetics to Yield Less Disease in a Mouse Multiple Sclerosis Model","authors":"Jessica R. Salas,&nbsp;K. M. Ryan,&nbsp;Alyssa O. Trias,&nbsp;Bao Ying Chen,&nbsp;Miriam Guemes,&nbsp;Zoran Galic,&nbsp;Kenneth A. Schultz,&nbsp;Peter M. Clark","doi":"10.1111/imm.13885","DOIUrl":"10.1111/imm.13885","url":null,"abstract":"<div>\u0000 \u0000 <p>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.</p>\u0000 </div>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"174 2","pages":"247-263"},"PeriodicalIF":4.9,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nucleases: From Primitive Immune Defenders to Modern Biotechnology Tools","authors":"Frank J. Hernandez","doi":"10.1111/imm.13884","DOIUrl":"10.1111/imm.13884","url":null,"abstract":"<p>The story of nucleases begins on the ancient battlefields of early Earth, where simple bacteria fought to survive against viral invaders. Nucleases are enzymes that degrade nucleic acids, with restriction endonucleases emerging as some of the earliest defenders, cutting foreign DNA to protect their bacteria hosts. However, bacteria sought more than just defence. They evolved the CRISPR-Cas system, an adaptive immune mechanism capable of remembering past invaders. The now-famous Cas9 nuclease, a key player in this system, has been harnessed for genome editing, revolutionising biotechnology. Over time, nucleases evolved from basic viral defence tools into complex regulators of immune function in higher organisms. In humans, DNases and RNases maintain immune balance by clearing cellular debris, preventing autoimmunity, and defending against pathogens. These enzymes have transformed from simple bacterial defenders to critical players in both human immunity and biotechnology. This review explores the evolutionary history of nucleases and their vital roles as protectors in the story of life's defence mechanisms.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"174 3","pages":"279-286"},"PeriodicalIF":4.9,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13884","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142835262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Wnt5a in Inflammatory Diseases","authors":"Xin-hua Yu,&nbsp;Xin-ning Guo,&nbsp;Kui Li,&nbsp;Jia-wei Li,&nbsp;Kaijin Wang,&nbsp;Dan Wang,&nbsp;Bi-cui Liu","doi":"10.1111/imm.13882","DOIUrl":"10.1111/imm.13882","url":null,"abstract":"<p>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.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"174 2","pages":"203-212"},"PeriodicalIF":4.9,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13882","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transient Anti-TCRβ mAb Treatment Induces CD4\u0000 + T Cell Exhaustion and Prolongs Survival in a Mouse Model of Systemic Lupus Erythematosus","authors":"Nancy Mize Gonzalez,&nbsp;Dawei Zou,&nbsp;Zihua Zeng,&nbsp;Frances Xiuyan Feng,&nbsp;Xiaolong Zhang,&nbsp;Caitlin Sannes,&nbsp;Andy Gu,&nbsp;Youli Zu,&nbsp;Wenhao Chen","doi":"10.1111/imm.13881","DOIUrl":"10.1111/imm.13881","url":null,"abstract":"<div>\u0000 \u0000 <p>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/<i>lpr</i> 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/<i>lpr</i> mice. Accordingly, MRL/<i>lpr</i> 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/<i>lpr</i> mice. Inducing autoreactive T-cell exhaustion holds promise as an attractive therapeutic approach for SLE.</p>\u0000 </div>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"174 2","pages":"239-246"},"PeriodicalIF":4.9,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RETRACTION: 5-lipoxygenase Knockout Mice Exhibit a Resistance to Acute Pancreatitis Induced by Cerulein","authors":"","doi":"10.1111/imm.13876","DOIUrl":"10.1111/imm.13876","url":null,"abstract":"<p>\u0000 \u0000 <b>RETRACTION</b>: <span>S. Cuzzocrea</span>, <span>A. Rossi</span>, <span>I. Serraino</span>, <span>R. Di Paola</span>, <span>L. Dugo</span>, <span>T. Genovese</span>, <span>D. Britti</span>, <span>G. Sciarra</span>, <span>A. De Sarro</span>, <span>A. P. Caputi</span>, and <span>L. Sautebin</span>, “ <span>5-lipoxygenase Knockout Mice Exhibit a Resistance to Acute Pancreatitis Induced by Cerulein</span>,” <i>Immunology</i> <span>110</span>, no. <span>1</span> (<span>2003</span>): <span>120</span>–<span>130</span>, https://doi.org/10.1046/j.1365-2567.2003.01715.x.\u0000 </p><p>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 &amp; 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.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"174 2","pages":"278"},"PeriodicalIF":4.9,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13876","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RETRACTION: Peroxynitrite-mediated DNA Strand Breakage Activates Poly (ADP-ribose) Synthetase and Causes Cellular Energy Depletion in Carrageenan-induced Pleurisy","authors":"","doi":"10.1111/imm.13877","DOIUrl":"10.1111/imm.13877","url":null,"abstract":"<p><b>RETRACTION</b>: <span>S. Cuzzocrea</span>, <span>A. P. Caputi</span>, and <span>B. Zingarelli</span>, “ <span>Peroxynitrite-mediated DNA Strand Breakage Activates Poly (ADP-ribose) Synthetase and Causes Cellular Energy Depletion in Carrageenan-induced Pleurisy</span>,” <i>Immunology</i> <span>93</span>, no. <span>1</span> (<span>1998</span>): <span>96</span>–<span>101</span>, https://doi.org/10.1046/j.1365-2567.1998.00409.x.</p><p>The above article, published online on 25 December 2001 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Greg Delgoffe; and John Wiley &amp; Sons Ltd. The retraction has been agreed due to concerns raised by third parties on the data presented in the article. Specifically, the Western Blot experiment in Figure 2 was found to have been presented in multiple publications with at least one common author and 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.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"174 3","pages":"374"},"PeriodicalIF":4.9,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13877","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IRF5 Controls Plasma Cell Generation and Antibody Production via Distinct Mechanisms Depending on the Antigenic Trigger","authors":"Bharati Matta,&nbsp;Jenna Battaglia,&nbsp;Margaret Lapan,&nbsp;Vinay Sharma,&nbsp;Betsy J. Barnes","doi":"10.1111/imm.13879","DOIUrl":"10.1111/imm.13879","url":null,"abstract":"<div>\u0000 \u0000 <p>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 (<i>IRF5</i>) has been identified as an autoimmune susceptibility gene and polymorphisms in <i>IRF5</i> 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 <i>Irf5</i>\u0000 ^−/− Balb/c mice in response to immunisation. WT and <i>Irf5</i>\u0000 ^−/− 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 <i>Irf5</i>\u0000 ^−/− 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 <i>Irf5</i>\u0000 ^−/− 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 <i>Irf5</i>\u0000 ^−/− mice. Moreover, T follicular helper cells from <i>Irf5</i>\u0000 ^−/− mice were functionally defective. Even though the downstream phenotype of reduced antibody production in <i>Irf5</i>\u0000 ^−/− mice was conserved between T cell-dependent and TLR9-dependent immunisation, the mechanisms leading to this phenotype were antigen- and cell type-specific.</p>\u0000 </div>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"174 2","pages":"226-238"},"PeriodicalIF":4.9,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Featured Cover","authors":"","doi":"10.1111/imm.13872","DOIUrl":"https://doi.org/10.1111/imm.13872","url":null,"abstract":"<p>Cover illustration: The cover image is based on the article <i>Advancement in the development of mRNA-based vaccines for respiratory viruses</i> by Tays Troncoso-Bravo et al., https://doi.org/10.1111/imm.13844.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 3","pages":"i"},"PeriodicalIF":4.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13872","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LGR4 Deficiency Aggravates Skin Inflammation and Epidermal Hyperplasia in Imiquimod-Induced Psoriasis","authors":"Mengfei Xue,&nbsp;Ruijie Yang,&nbsp;Guihong Li,&nbsp;Zhizhan Ni,&nbsp;Yuqing Chao,&nbsp;Kairui Shen,&nbsp;Hua Ren,&nbsp;Bing Du,&nbsp;Juliang Qin,&nbsp;Zhenliang Sun","doi":"10.1111/imm.13873","DOIUrl":"10.1111/imm.13873","url":null,"abstract":"<div>\u0000 \u0000 <p>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 <i>Lgr4</i>-knockout mouse model further confirmed that LGR4 plays a positive role in psoriasis progression. Specifically, <i>Lgr4</i> 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.</p>\u0000 </div>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"174 2","pages":"213-225"},"PeriodicalIF":4.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SNX17 Regulates Antigen Internalisation and Phagosomal Maturation by Dendritic Cells","authors":"Sofía Dinamarca,&nbsp;Cristina Croce,&nbsp;Anna Salvioni,&nbsp;Facundo Garrido,&nbsp;Sandra Estrada Fidalgo,&nbsp;Gonzalo Bigliani,&nbsp;Luis S. Mayorga,&nbsp;Nicolas Blanchard,&nbsp;Ignacio Cebrian","doi":"10.1111/imm.13878","DOIUrl":"10.1111/imm.13878","url":null,"abstract":"<div>\u0000 \u0000 <p>Antigen cross-presentation is the process whereby small peptides derived from exogenous antigens are attached to MHC-I molecules triggering CD8+ T lymphocyte activation. The endocytic route of dendritic cells (DCs) is highly specialised for cross-presentation to initiate cytotoxic immune responses against numerous intracellular pathogens and tumours. In this study, we identify the endosomal protein sorting nexin (SNX) 17 as a key regulator of antigen internalisation and cross-presentation by DCs. SNX17 expression in DCs guarantees optimal cross-presentation of soluble, particulate, and <i>Toxoplasma gondii</i>-associated antigens. The silencing of SNX17 expression in DCs significantly affected the internalisation of exogenous antigens by fluid-phase endocytosis, phagocytosis, and more strikingly, <i>T</i>. <i>gondii</i> invasion. We show that SNX17 controls proper integrin recycling, actin cytoskeleton organisation, and phagosomal maturation. Altogether, our findings provide compelling evidence that SNX17 plays a central role in the modulation of the DC endocytic network, which is essential for competent antigen cross-presentation.</p>\u0000 </div>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"174 1","pages":"167-185"},"PeriodicalIF":4.9,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}