Journal of immunology最新文献

{"title":"B cells and aging: a historical perspective.","authors":"Michael P Cancro","doi":"10.1093/jimmun/vkaf025","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf025","url":null,"abstract":"","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663675","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":"Cathelicidin-related antimicrobial peptide (CRAMP) is toxic during neonatal murine influenza virus infection.","authors":"Abhishek S Rao, Nneka Ugwu, Abigail P Onufer, Ogan Kumova, Alison J Carey","doi":"10.1093/jimmun/vkae053","DOIUrl":"https://doi.org/10.1093/jimmun/vkae053","url":null,"abstract":"<p><p>Respiratory viral infections are a major contributor to mortality in children under 5 years of age, and disproportionately affect preterm neonates. Previously, using our established 3-day-old neonatal murine model of influenza virus infection, we demonstrated that treatment of neonatal mice with intranasal Lactobacillus rhamnosus GG (LGG) prior to influenza viral infection improved survival. Transcriptional analysis revealed expression of the mouse cathelicidin-related antimicrobial peptide (CRAMP, encoded by CRAMP) was downregulated in LGG-treated neonates. Mouse CRAMP is a key effector protein secreted by infected epithelial cells and resident and infiltrating immune cells, but the role of CRAMP in neonatal defense to respiratory viruses is unknown. Neonatal mice with a deleted CRAMP gene (CRAMP-/-) were intranasally infected with influenza virus. CRAMP-/- neonates had improved survival over C57BL/6 neonates after influenza viral infection (75% vs. 14%, p < 0.05). Next, immune cell recruitment to the lung of infected neonates was determined. Surprisingly, at 3-days postinfection, there was increased recruitment of neutrophils, inflammatory monocytes, and alveolar macrophages, coupled with increased proinflammatory cytokine and chemokine production in CRAMP-/- compared to C57BL/6 neonates. However, this changed over the first week of infection. C57BL/6 neonatal mice increased CRAMP production significantly, in direct contrast to their adult counterparts. Inflammatory cytokine production increased that indicated CRAMP amplified the innate immune response later in the infection. Furthermore, we identified pulmonary nonimmune cells as an important source of increased CRAMP levels as the infection progressed and CRAMP production drove mortality. These insights emphasize the age-specific role of CRAMP in influenza viral pathogenesis.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657277","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":"Cellular immune changes during severe antisense oligonucleotide-associated thrombocytopenia in a nonhuman primate model.","authors":"Sheena Gupta, Lijiang Shen, Scott P Henry, Nima Aghaeepour, Padmakumar Narayanan, Holden T Maecker","doi":"10.1093/jimmun/vkae055","DOIUrl":"https://doi.org/10.1093/jimmun/vkae055","url":null,"abstract":"<p><p>Antisense oligonucleotides (ASOs) are a new class of single-stranded DNA-based drugs that hold great therapeutic potential. A low incidence of severe, dose-dependent, and reversible thrombocytopenia (TCP) (platelets < 50 K/μl) has been reported in nonhuman primate (NHP) populations, following treatment of monkeys with 2'-O-methoxy ethyl ASOs (2% to 4% at doses > 8 to 10 mg/kg/week). The potential mechanisms for this effect were studied using the Mauritian-sourced NHPs, which were shown to be more susceptible to ASO-induced TCP than Asian-sourced animals. In this pilot study, we used a mass cytometry-based intracellular cytokine staining assay, to evaluate the immune-phenotypic and functional changes in cryopreserved PBMCs, collected over 8 time points of ASO therapy (ISIS 405879) from 12 Cambodian and 12 Mauritian monkeys (9 treated and 3 controls). Unsupervised clustering was performed across markers used for cell type identification in the pooled dataset, followed by unsupervised comparison at each time point and then longitudinal analysis. Major immune cell types showed differential abundance between the 2 groups prior to start of ASO therapy. These included IFNg- and TNF-producing polyfunctional effector T cells (CD4+ and CD8+), which were lower, and MIP1b-producing monocytes and DCs, which were higher, in the Mauritian monkeys. Immune populations also changed over the course of this treatment, wherein IL-17- and GM-CSF-producing T cells and IgM-producing B cells increased markedly in Mauritians. Identification of these differentially abundant immune cell subsets in treatment sensitive NHPs could help decipher potential immune mechanisms contributing to severe TCP observed during administration of specific ASO sequences in humans.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657331","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":"A genetically modulated Toll-like receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome.","authors":"Rehan Khan, Weizhen Ji, Jeisac Guzman Rivera, Abhilasha Madhvi, Tracy Andrews, Benjamin Richlin, Christian Suarez, Sunanda Gaur, Uzma N Hasan, William Cuddy, Aalok R Singh, Hulya Bukulmez, David Kaelber, Yukiko Kimura, Usha Ganapathi, Ioannis E Michailidis, Rahul Ukey, Sandra Moroso-Fela, John K Kuster, Myriam Casseus, Jason Roy, Jane C Burns, Lawrence C Kleinman, Daniel B Horton, Saquib A Lakhani, Maria Laura Gennaro","doi":"10.1093/jimmun/vkaf006","DOIUrl":"10.1093/jimmun/vkaf006","url":null,"abstract":"<p><p>Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To investigate innate immune functions, we stimulated ex vivo peripheral blood cells from MIS-C patients with agonists of Toll-like receptors (TLR), key innate immune response initiators. We found severely dampened cytokine responses and elevated gene expression of negative regulators of TLR signaling. Increased plasma levels of zonulin, a gut leakage marker, were also detected. These effects were also observed in fully convalescent children months after MIS-C recovery. When we investigated the genetic background of patients in relation to TLR responsiveness, we found that cells from MIS-C children carrying rare heterozygous variants of lysosomal trafficking regulator (LYST) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Moreover, these rare LYST variant heterozygous carriers tended to exhibit unfavorable clinical laboratory indicators of inflammation, including more profound lymphopenia. The results of our observational study have several implications. First, TLR hyporesponsiveness may be associated with hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands. Second, TLR hyporesponsiveness during MIS-C may be protective, since LYST variant heterozygous carriers exhibited reduced TLR hyporesponsiveness and unfavorable clinical laboratory indicators of inflammation. Thus, links may exist between genetic background, ability to establish a refractory immune state, and MIS-C clinical spectrum. Third, the possibility exists that prolonged TLR hyporesponsiveness is one of the mechanisms driving long coronavirus disease (COVID), which highlights the need to monitor long-term consequences of MIS-C.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657275","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":"CD209d/e are required for macrophage-mediated phagocytosis and activation during methicillin-resistant Staphylococcus aureus pulmonary host defense.","authors":"Flavia Rago, Mohamed Y Ahmed, Michael A Marinelli, Leigh M Miller, Alexis M Duray, Brooke P Dresden, Nicholas J Constantinesco, Peyton K F Sims, Lacee J Richwalls, Saran Kupul, Jay K Kolls, Radha Gopal, John F Alcorn","doi":"10.1093/jimmun/vkae061","DOIUrl":"https://doi.org/10.1093/jimmun/vkae061","url":null,"abstract":"<p><p>Staphylococcus aureus is a commensal and opportunist pathogen of the upper respiratory tract. The recognition of pathogen-associated molecular patterns through pattern-recognition receptors is crucial for eliminating microorganisms such as S. aureus. DC-SIGN (CD209) is a pattern-recognition receptor that binds to a broad range of pathogens, promoting phagocytosis. Here we aimed to study the role of mouse homologues of DC-SIGN, CD209d/e, in a methicillin-resistant S. aureus (MRSA) pulmonary infection model. CD209d/e-/- and wild-type C57BL/6 mice were infected with MRSA and inflammatory parameters were evaluated. CD209d/e-/- mice had delayed bacterial burden and mortality together with increased frequency of neutrophils and decreased dendritic cells in the lung compared with control mice. iNOS+ macrophages, and regulatory T cell frequency were decreased in the lungs of CD209d/e-/- mice. CD209d/e-/- mice had increased levels of inflammatory cytokines in the lungs, but levels of IL-12p40 were decreased. MRSA reduced expression of interferon-γ and pattern-recognition receptors in CD209d/e-/- mice. MRSA uptake by phagocytes was decreased in the lungs of CD209d/e-/- versus control mice. CD209d/e-/- bone marrow derived macrophages showed impaired MRSA uptake and killing. These data suggest that CD209d/e are essential receptors to control inflammation by activating macrophages leading to MRSA uptake and killing.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657281","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":"Exploring the genetic mechanisms driving KIR diversification.","authors":"Marit K H van der Wiel, Ngoc Giang Le, Nanine de Groot, Natasja G de Groot, Ronald E Bontrop, Jesse Bruijnesteijn","doi":"10.1093/jimmun/vkae047","DOIUrl":"https://doi.org/10.1093/jimmun/vkae047","url":null,"abstract":"<p><p>Killer cell immunoglobulin-like receptors (KIRs) are key modulators of natural killer cell activity, displaying either activating or inhibitory potential upon recognition of major histocompatibility complex (MHC) class I molecules. The genomic organization of KIR genes is complex, involving copy number variation and allelic polymorphism, which is probably due to their coevolution with highly polymorphic MHC ligands. The KIR diversity is reflected by more than 70 similar region configurations encountered in humans, generated through meiotic recombination events. Rhesus macaques happen to display even more diversity, and over 100 distinct configurations were identified in a relatively small cohort of animals. More than half of these region configurations feature hybrid KIR genes, suggesting a more pronounced mode of diversification in macaques. The molecular mechanism facilitating meiotic rearrangements in the KIR region is poorly understood. Examination of 21 rhesus macaque and 14 human KIR region configurations revealed the presence of long terminal repeats and PRDM9 binding motifs associated with recombination hotspots. The variable DNA recognition patterns of PRDM9 could potentially contribute to the differing recombination activities documented for the KIR region in humans and macaques. The diversification process of the KIR repertoire in natural killer cells is fundamentally distinct from the mechanisms generating T and B cell receptor diversity or MHC polymorphisms. This sophisticated recombination machinery preserves the functional integrity by the frequent generation of in-frame KIR genes. A diverse KIR repertoire contributes to the protection of individuals and populations against pathogen evasion and subversion.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649130","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":"High fat diet feeding impairs neutrophil phagocytosis, bacterial killing, and neutrophil-induced hematopoietic regeneration.","authors":"Emily Bowers, Gabrielle P Entrup, Mohammed Islam, Ramkumar Mohan, Arianna Lerner, Peter Mancuso, Bethany B Moore, Kanakadurga Singer","doi":"10.1093/jimmun/vkaf024","DOIUrl":"10.1093/jimmun/vkaf024","url":null,"abstract":"<p><p>The prevalence of obesity and metabolic diseases have risen significantly over the past decades. Chronic inflammation in obesity is a link between obesity and secondary disease. While macrophages and monocytes are known to contribute to metabolic disease risk during diet exposure, little is known about the contribution of neutrophils. We assessed the impact of obesity on neutrophils using a 16-week model of diet-induced obesity. Bone marrow (BM) neutrophils significantly expanded with chronic high-fat diet (HFD), significantly decreased TNFɑ protein release, and impaired neutrophil regenerative function compared to normal diet (ND) neutrophils. scRNAseq and flow cytometry demonstrated HFD neutrophil heterogeneity and validated that these cells do not have elevated expression of proinflammatory genes without secondary stimulation. HFD neutrophils showed elevated expression of genes associated with lipid metabolism-acyl-CoA thioesterase 1 (Acot1), carnitine palmitoyltransferase 1a (Cpt1a), and perilipin 2 (Plin2). Consistent with the importance of lipid metabolism in driving dysfunction, neutrophils from HFD-fed animals and neutrophils treated with palmitate had impaired bacterial phagocytosis and killing responses. These data shed light on the complex regulation of intracellular lipids and the role of metabolism on neutrophil function during homeostasis and disease.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649106","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":"IL-2Rα is dispensable for murine B cell development and humoral response.","authors":"Priyanka Chowdhury, Kalina T Belcheva, Ryan M Smolkin, Montserrat Cols, Jason D Fontenot, William T Yewdell, Jayanta Chaudhuri","doi":"10.1093/jimmun/vkae045","DOIUrl":"https://doi.org/10.1093/jimmun/vkae045","url":null,"abstract":"<p><p>The cytokine IL-2 plays a pivotal role in the immune system, specifically in the proliferation of T, B, and NK cells. The alpha subunit of the IL-2 receptor, IL-2Rα (CD25), is known to regulate the expansion and differentiation of T lymphocytes. CD25 is also expressed in developing B cells; however, its B cell intrinsic role remains undefined. We generated a mouse model with a B cell-specific deletion of CD25 to ascertain its role in B cell development and function. Unexpectedly, we found that the loss of CD25 had no impact on B cell development, homeostasis, or immune response to model antigens. Additionally, while CD25 expression was upregulated in activated splenic B cells, its absence did not affect class switch recombination in vitro or in vivo. We conclude that in contrast to its critical role in T cell differentiation and function, and despite its expression in developing and activated B cells, CD25 does not have any significant role in B cell development and adaptive immune functions.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649137","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":"Correction to: Impact of sleep deprivation on monocyte subclasses and function.","authors":"","doi":"10.1093/jimmun/vkaf044","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf044","url":null,"abstract":"","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649129","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":"Sustained activation induced cytidine deaminase (AID) expression in B cells following Plasmodium falciparum malaria infection in Kenyan children.","authors":"Bonface Ariera, Bernard Guyah, Jeremy Rahkola, Ian Arao, Kevin Waomba, Emmily Koech, Gabriela Samayoa-Reyes, Katherine R Sabourin, Sidney Ogolla, Rosemary Rochford","doi":"10.1093/jimmun/vkaf005","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf005","url":null,"abstract":"<p><p>Burkitt lymphoma (BL) is characterized by elevated levels of the enzyme activation-induced cytidine deaminase (AID), an enzyme critical for MYC translocation that is the hallmark of BL. Both EBV and Plasmodium falciparum malaria are cofactors in the etiology of BL. However, how these 2 pathogens drive BL pathogenesis is not yet understood. In this study, we tested the hypothesis that P. falciparum and EBV synergize to induce dysregulated expression of AID. Using flow cytometry, intracellular AID expression was measured in PBMCs from a cohort of children from Western Kenya with uncomplicated malaria and community controls. Children with uncomplicated malaria had elevated levels of CD19+ AID+ B cells compared to controls. This high level of AID was sustained up to 8 weeks after parasite clearance. Using ImageStream flow cytometry, we found that 52% of AID was localized in the nucleus of CD19+ B cells in children with malaria. To test whether EBV and P. falciparum synergized to drive the expression of AID, we stimulated CD19+ B cells with EBV, CpG (to mimic P. falciparum DNA), or BAFF (induced during P. falciparum infection), or as a combination. Individually, EBV, BAFF and CpG induced AID expression. However, when combined, there was a significant increase of ∼30% in the frequency of CD19+AID+ cells above cells treated with EBV, BAFF, or CpG individually. Collectively, these data suggest that P. falciparum malaria and EBV coinfection result in sustained AID expression, potentially influencing the MYC translocation that is characteristic of BL.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630611","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}