bluuebunny/crossref_metadata_2025_split huggingface dataset:
PspA-based sublingual vaccine provides IgA dependent protective immunity to nasopharyngeal carriage by Streptococcus pneumoniae
Authors: Nagano Hiromi , SUGITA Gen , SUGITA rinya , Ikeda Yorihiko , Fujihashi Keiko , Tsuruhara Akitoshi , Kurono Yuichi , Fujihashi Kohtaro 
Published: January 2023

Abstract
Pneumococcal infection caused by Streptococcus pneumoniae is a major upper respiratory tract disease which causes severe illness and mortality. It is important to develop safe and effective vaccines to prevent pneumococcal infections. Sublingual (SL) antigen (Ag) delivery is a non-invasive route which avoids possible entry into the olfactory region and the central nervous system. We examined the potential of Poly (I:C) as a SL adjuvant for the induction of specific immune responses against S. pneumoniae infection. C57BL/6 and IgA−/− mice were SL immunized with 1 μg of pneumococcal surface protein A (PspA) and 10 μg of Poly (I:C) four times at weekly intervals. One week after the final immunization, nasal washes (NWs), saliva and plasma samples were collected and subjected to a PspA-specific ELISA. Further, mice were challenged with S. pneumoniae strain EF3030, and the numbers of CFUs in NWs and nasal passages (NPs) were determined. Significantly increased levels of PspA-specific secretory IgA (SIgA) antibody (Ab) responses were seen in NWs of mice given SL PspA plus Poly (I:C) when compared with controls. Further, higher levels of PspA-specific IgG and IgA Abs were noted in plasma of vaccinated mice. Importantly, mice given SL PspA plus Poly (I:C) showed significantly lower numbers of bacteria in the NPs and NWs when compared with controls. Although IgA−/− mice given SL PspA-vaccine had significantly high levels of PspA-specific IgG Abs, high numbers of CFUs were detected in NWs and NP. These results show that SL immunization is effective mucosal immunization strategy for induction of protective pneumococcal-specific Ab responses and specific SIgA Abs play a necessary role in the blockade of S. pneumoniae colonization of the nasal cavity.
E3 ligase FBXW7 is critical for RIG-I stabilization during antiviral responses
Authors: Wang Qingqing , Song Yinjing , Xue Yue , Yu Hai 
Published: January 2023

Abstract
Viruses can escape from the host recognition by degradation of RIG-I or interference of the RIG-I signaling to establish persistent infections. However, the mechanisms how host cells stabilize RIG-I protein for avoiding its degradation are largely unknown. We report here that, upon virus infection, the E3 ubiquitin ligase FBXW7 translocates from the nucleus into the cytoplasm and stabilizes RIG-I. FBXW7 interacts with SHP2 and mediates the degradation and ubiquitination of SHP2, thus disrupting the SHP2/c-Cbl complex which mediates RIG-I degradation. When infected with VSV or influenza A virus, FBXW7 conditional knockout mice (Lysm+FBXW7f/f) show impaired antiviral immunity. FBXW7 deficient macrophages have decreased RIG-I protein levels and type I interferon signaling. Furthermore, PBMCs from RSV infected children have reduced FBXW7 mRNA levels. Our results identify FBXW7 as an important interacting partner for RIG-I. These findings provide insights into the function of FBXW7 in antiviral immunity and its related clinical significance.
Cytokines and miRNAs levels in nasal lavage correlate with symptoms in patients infected with respiratory viruses
Authors: Rosas-Taraco Adrian Geovanni , Arredondo-Loza Erick , Martinez-Castilla Azalia , Mata-Tijerina Viviana , Salinas-Carmona Mario C 
Published: January 2023

Abstract
Respiratory viruses are responsible of acute respiratory infections that affect worldwide population causing morbi-mortality. Cytokines and microRNAs can modulate the immune response but little is known in nasal mucosa and less if these would correlate with symptoms severity. We included hundred patients diagnosed with possible viral acute respiratory infections. Patients were sequentially enrolled previous written informed consent was obtained. Virus was detected in pharyngeal exudate by Luminex xTAG RVP kit and qRT-PCR. Nasal lavage were performed in each patients to evaluate microRNAs and cytokines by RT-qPCR, multiplex immunoassay and ELISA, respectively. The symptoms severity was daily monitored throughout seven days by surveys. The respiratory viruses found in these patients were influenza A and B, human rhinovirus, respiratory syncytial virus, human metapneumovirus, parainfluenza, and coronavirus. Viral loads showed no difference between mono-infected patients compared to co-infected; however nasal cytokines and microRNAs profiles differ between these two groups in some cases. Regardless of the viral agent, several nasal microRNAs correlated with symptoms severity. On the other hand, pro-inflammatory and Th2 cytokines correlated positively and negatively with respiratory infection symptoms, respectively. Moreover, correlation between miRNAs and cytokine were found in these patients. Our findings suggest that microRNAs and cytokines in nasal lavage may regulate local immune response against respiratory virus and specific profile may be possible candidates for severity biomarkers.
Three distinct pneumotypes characterize the microbiome of the lung in BALB/cJ mice.
Authors: Scheiermann Julia , Klinman Dennis M 
Published: January 2023

Abstract
Bacteria can rarely be isolated from normal healthy lungs using conventional culture techniques, supporting the traditional belief that the lungs are sterile. Yet recent studies using next generation sequencing report that bacterial DNA commonly found in the upper respiratory tract (URT) is present at lower levels in the lungs. Interpretation of that finding is complicated by the technical limitations and potential for contamination introduced when dealing with low biomass samples. The current work sought to overcome those limitations to clarify the number, type and source of bacteria present in the lungs of normal mice. Results showed that the oral microbiome is large, less diverse and highly conserved whereas murine lung samples fall into three distinct patterns. Most pulmonary samples were sterile, as they lacked culturable bacteria and their bacterial DNA content did not differ from background. 11% of samples contained comparatively higher amounts of bacterial DNA whose composition mimicked that detected in the URT, consistent with (micro)aspiration. A final group (26%) contained smaller amounts of microbial DNA whose composition was similar to that of rodent chow, perhaps acquired by inspiration of food fragments. This work eliminated the bias introduced by aspiration-contaminated samples to establish that three distinct microbiome pneumotypes are present in normal murine lungs of BALB/cJ mice. The presented findings contribute to the knowledge in the growing field of microbiome research in the respiratory tract and are of relevance to researchers evaluating respiratory diseases in murine models.
NLRP3 Inflammasome controls adipose tissue macrophage activation during aging
Authors: Camell Christina , Sander Jil , Spadaro Olga , Lee Aileen , Nguyen Kim Y. , Wing Allison , Goldberg Emily L. , Youm Yun-Hee , Rodeheffer Matthew S. , Schultze Joachim L. , Dixit Vishwa Deep 
Published: January 2023

Abstract
Aging is associated with chronic inflammation and increased risk for degenerative disorders and diseases. In the elderly there is a development of insulin resistance, increased visceral adiposity and dysfunctional adipose tissue (AT) homeostasis; however the mechanisms of age-induced immune defects in AT is unclear. AT contains numerous immune populations, which play well-known roles in regulating both inflammatory responses and metabolic homeostasis. Our prior studies have identified that the canonical inflammasome, NLRP3, is required for diet-induced AT inflammation and age-related inflammation in multiple organs. We hypothesized that NLRP3 is required for age-induced changes in AT immune cells and that deficiency in Nlrp3 will improve AT function during aging. Here we show that unlike obesity, aging is associated with reduction in specific AT macrophages subsets. Whole transcriptome sequencing of AT macrophages from aged mice revealed increased caspase-1 activation and distinct signatures that were regulated in part by Nlrp3. Linear support vector regression and bioinformatics analyses revealed that AT macrophages do not display classical M1–M2 like transcriptome and display AT-specific signatures that are distinct from other tissue macrophages in gut, brain, liver and spleen. We identified that as compared to 24-month old WT, the aged Nlrp3−/− animals were protected from alterations in AT macrophage activation. Furthermore, Nlrp3-mediated reduction in AT inflammation and macrophage activation led to protection from age-related defects in AT function. Overall our findings suggest that NLRP3-dependent immune-metabolic interactions within AT contribute to age-related inflammation and metabolic dysfunction.
Nanoparticle based enrichment and expansion of self and neo-epitope specific CD8+ T cells in murine melanoma.
Authors: Bessell Catherine Ami , Bieler Joan G , Oelke Mathias , Schneck Jonathan P 
Published: January 2023

Abstract
Neo-antigen T cell responses against tumors has created a new avenue to target and kill patients’ tumors while possibly decreasing autoimmune side effects. CD8+ Neo-antigen T cells have the potential benefit to be a source of T cells that are not limited by peripheral tolerance or deleted from the T cell repertoire by central tolerance. To understand the differences between self and neo-antigens T cell responses, the two types of T cell populations must be compared side-by-side by anti-tumor responses and phenotypic differences. Following another group (Castle; 2012) that identified mutated proteins from long sequences in murine melanoma our current work has identified the short peptide epitopes that can stimulate neo-antigen T cell responses. The candidate neo-epitopes were validated by peptide stabilization assays and in vitro T cell stimulations with nanoparticle artificial antigen presenting cells. 11 naïve neo-antigen T cells responses were identified out of a total of 19 possible candidate neo-antigens. Artificial antigen presenting cells were used to assess neo and self-antigen tumor specific responses in the naïve T cell repertoire and after tumor exposure to B16 murine melanoma. After exposure to tumor, neo-epitope T cell responses showed larger fold expansion as compared to a self-antigens expressed by the tumor cells. From this work, we deliver a proof of concept of a streamlined way to screen candidate neo-epitopes and identify rare endogenous T cell populations; and evaluate the benefit of T cell directed immunotherapies on different T cell populations.
Plasmid electrotransfer activates DNA pattern recognition receptors and induces production of proinflammatory molecules in both B16.F10 and TS/A cells in vitro
Authors: Semenova Nina P. , Znidar Katarina , Bosnjak Masa , Cemazar Maja , Heller Loree 
Published: January 2023

Abstract
Electroporation or electrotransfer effectively delivers plasmid DNA (pDNA) into cells and tissues. pDNA primarily enters the cell via endocytosis, although some pDNA may reach the cytosol to be detected by endosomal, cytosolic, and nuclear DNA-specific pattern recognition receptors (PRRs) which have been described in many cell types. Activated PRRs induce the production of proinflammatory molecules and programmed cell death.
Our previous studies on B16.F10 mouse melanomas showed that electrotransfer of backbone pDNA induced the production of several proinflammatory molecules including IFNβ, implicating PRR binding and activation. Histologically, caspase-3 independent tumor necrosis was observed. In B16. F10 cells, IFNβ mRNA and protein levels were also significantly upregulated. The mRNAs for several PRRs were present in these cells and DAI, DDX60, and p204 mRNAs were significantly upregulated after pDNA electrotransfer. DDX60 protein levels were coordinately upregulated. The goal of our study was to find out whether the effects observed in B16.F10 cells are widespread among tumor types.
The electrotransfer of empty backbone pDNA into TS/A murine mammary adenocarcinoma cells induced the production IFNβ and TNFα mRNA and protein. The mRNA levels for several PRRs (including DAI, DDX60, DDX36, p202 and p204) were significantly upregulated with DAI level upregulation being the most prominent. This upregulation in DAI mRNA translated to the protein level, which was confirmed with Western blotting analysis. This increased IFNβ and DNA sensor expression indicate that pDNA electrotransfer activates intracellular PRRs in multiple tumor cell types, producing in vitro effects similar to what was observed in B16.F10 cells.
Ensemble computational analysis and systems immune monitoring reveal a double negative T cell subset enriched in melanoma tumors following dabrafenib and trametinib
Authors: Greenplate Allison , Oberholtzer Brian K. , Doxie Deon B. , Roe Caroline , Kelley Mark C. , Sosman Jeffrey A , Johnson Douglas B , Irish Jonathan Michael 
Published: January 2023

Abstract
Advances in single cell biology have made it possible to measure &gt; 40 features on millions of cells within clinical samples, but data analysis quickly becomes logistically complex and time-consuming for immune monitoring studies collecting many samples per patient. Here we created an ensemble analysis strategy for longitudinal immune monitoring using single cell platforms like mass cytometry. Multiple tools were employed to give key immunology information in an automated “first pass” analysis and highlight cell subsets for in-depth review. Cells identified by immunologists or computational tools were assessed for four complementary types of cellular information: 1) relative abundance, 2) phenotypic plasticity, 3) novelty of phenotype, and 4) signature features. To challenge this analysis approach, we selected three systems immune monitoring studies focusing on blood from melanoma patients, blood and bone marrow from acute myeloid leukemia (AML) patients, and new mass cytometry data characterizing tumor infiltrating immune cells from melanoma patients. Phenotypic plasticity was revealed in T cells within tumors over the course of MEK/BRAF inhibitor therapy. Changes in the overall T cell landscape were driven by expansion of double negative (DN) T cells (12.38% ± 23.52% pre-therapy; 37.67% ± 17.97% post-therapy, p&lt;0.01). Unlike healthy DN T cells, intratumoral DN T cells were CD45RO+. The ensemble analysis strategy tracked the immune systems of patients over time and quantified key differences in the system as well as cell subsets. The features revealed by this method can now be tested as markers for cell isolation, targets for drug development, receptors for immune engineering, and potential mechanisms of treatment response.
Non-pathogenic CD8+ T cells in lupus-prone mice regulate neurological and peripheral disease.
Authors: Morawski Peter A , Qi Chen-Feng , Bolland Silvia 
Published: January 2023

Abstract
Lupus is a systemic autoimmune disorder affecting multiple organ systems including the skin, kidneys, spleen, lungs, and brain. Severe SLE often manifests with multiple psychiatric and neurological sequelae, and may be accompanied by CNS vasculitis. However, the cellular contributors to CNS disease in lupus patients remain poorly defined. We have uncovered a unique bias for CD8+ T cell infiltration in the CNS of mice expressing multiple copies of Toll-like receptor 7 (TLR7[Tg]), which present with a lupus-like disease. These animals exhibit blood brain barrier damage and neuropathology in the presence of infiltrating T cells. However, genetic ablation of CD8+ T cells in lupus-prone mice by removal of the major histocompatibility complex (MHC) adaptor protein b2m results in aggravation of disease, suggesting the removal of a protective population. Relative to the peripheral CD8+ T cells in lupus-prone mice, those in the CNS represent the most activated lymphocytes in the animal, display a tissue resident-memory phenotype, and can home to the brain. We have also identified a population of CD8+ T cells in the cerebrospinal fluid (CSF) of several lupus patients. Similar to our animal model findings the human CD8+ T cells in the CSF have a large increase in antigen experience by surface phenotyping relative to lymphocytes from peripheral blood. Our ongoing studies aim to elucidate specifically how these CD8+ T cells enter the CNS and further clarify their role in neuropathology. Our findings suggest a possible mechanism of CNS pathology regulation that could have applicability to human neuropsychiatric manifestations of SLE.
System control of auto-reactive T cells
Authors: Wong Harikesh S. , Gola Anita , Angermann Bastian , Germain Ronald N. 
Published: January 2023

Abstract
Potentially auto-reactive T cells routinely escape thymic negative selection, but rarely elicit peripheral autoimmunity. We investigated the fate of these cells in murine secondary lymphoid organs using quantitative imaging approaches. During steady state, a small number of seemingly auto-reactive CD4+ T cells were detected along the T cell zone border. These cells displayed clear signs of antigenic stimulation, specifically plasmalemma expression of PD-1, in the absence of foreign bacteria or host commensals. Remarkably, high densities of regulatory T cells routinely converged on the auto-reactive CD4+ T cells, which in turn, exhibited compromised plasma membrane integrity consistent with cell death. Acute depletion of regulatory T cells resulted in uncontrolled expansion of the auto-reactive cells and correlated with reduced death. Collectively, these results suggest that regulatory T cells may not only suppress, but also prune the repertoire of dangerous clones, thereby minimizing the risk of autoimmunity.
Selective PRMT5 inhibition suppresses inflammatory T cell responses and autoimmunity.
Authors: Webb Lindsay M , Savardekar Himanshu , Jablonski Kyle A , Amici Stephanie A , Panfil Amanda , Li Linsen , Green Patrick L , Li Chenglong , Baiocchi Robert A , Guerau-De-Arellano Mireia 
Published: January 2023

Abstract
In the autoimmune disease Multiple Sclerosis (MS), pro-inflammatory, pathogenic T helper (Th) 1 and Th17 responses promote demyelination and disability. MS treatments that preferentially target inflammatory T cell responses may be beneficial to the field. Epigenetic modifications regulate cellular functions and phenotype and inhibition of all methylation reactions suppresses T cell proliferation and experimental autoimmune encephalomyelitis (EAE). However, the specific enzyme(s) responsible for these effects remain to be determined. Protein arginine methyltransferase 5 (PRMT5), the major Type II methyltransferase enzyme, mediates symmetric dimethylation of arginine residues of histones. Although PRMT5 is known to be up-regulated in many lymphoid malignancies, currently there is no known role for PRMT5 in T cells. In this study, we use memory Th cells and animal models to study the role of PRMT5 in T cell responses and autoimmunity. PRMT5 was up-regulated in memory Th cells upon activation in a process. We found that PRMT5 drove T cell proliferation, and pathogenic Th1 cells were more susceptible to PRMT5-selective inhibitor treatment than benign Th2 cells. PRMT5-selective inhibitors ameliorated disease severity in EAE, the mouse model of MS. This disease suppression correlated with suppression of myelin-specific T cell proliferation as well as IFNg and IL-17 cytokine production. Additionally, PRMT5 inhibitors suppressed pathogenic Th17 cell populations ex vivo. These results indicate that PRMT5 may be a promising therapeutic target in T cell-mediated autoimmune diseases such as Multiple Sclerosis.
Inhibition of Th17 by targeted degradation of HIF1-α
Authors: Lai Ming-Zong , Chou Ting-Fang , Chuang Ya-Ting , Hsieh Wan-Chen , Chang Pei-Yun , Hsu Tzu-Sheng , Miaw Shi-Chuen , Chen Ruey-Hwa , Kimchi Adi 
Published: January 2023

Abstract
Death-associated protein kinase (DAPK) is a tumor suppressor, while hypoxia-inducible factor 1α (HIF-1α) promotes tumorigenesis in various type of cancers. Here we report a targeted degradation of HIF-1α mediated by DAPK in T helper 17 (Th17) cells. HIF-1α is a transcription factor critical for Th17 development. We found that DAPK inhibits Th17 differentiation and prevents Th17-mediated autoimmune diseases. DAPK suppresses the expression of RORγt and IL-17, which could be attributed to a specific suppression of HIF-1α. In contrast, Th1 cell differentiation and T-bet expression is not affected by DAPK. We demonstrate that DAPK specifically downregulates HIF-1α in a unique process. While HIF-1α is predominant nuclear localized in many cancer cells, HIF-1α is located in both cytosol and nucleus in T cells. This leads to an interaction between HIF-1α and DAPK in T cell cytoplasm. The simultaneous binding of DAPK to prolyl hydroxylase domain protein 2 (PHD2) increases the association between HIF-1α and PHD2. Consequently, DAPK enhances the proline hydroxylation and proteasome degradation of HIF-1α in Th17 cells. DAPK-deficiency thus results in excess HIF-1α accumulation, enhanced Th17 generation, and exacerbated experimental autoimmune encephalomyelitis (EAE). Transgenic DAPK expression, in contrast, suppresses Th17 differentiation and prevents EAE generation. The overproduction of Th17 cells and exacerbated EAE development in Dapk−/− mice is fully reversed by knockout of HIF-1α. Our results demonstrate a new process involving DAPK-mediated degradation of cytoplasmic HIF-1α, and suggest that a potential therapy for Th17-associated inflammatory diseases by targeted elevation of DAPK.
Micromanaging lupus nephritis: miR17-92 modulates TFH development and regulatory T cell activity
Authors: Yang Huang-Yu , Wu Chao-Yi , Pan Fan , Pardoll Drew , Yang Chih-Wei 
Published: January 2023

Abstract
T follicular helper (TFH) cell provide crucial growth signals to germinal center (GC) B cells supporting antibody production. Tight control of TFH numbers maintains self-tolerance. Regulatory T (Treg) cells play a critical role in maintaining self-tolerance and controlling the magnitude of physiologic immune response. The Treg transcription factor forkhead box P3 (Foxp3) works in concert with other co-regulator molecules to determine suppressive phenotype of Treg. Compiling evidence show that aberrant TFH, GC responses and deficiencies of Treg are associated with systemic lupus erythematous and autoantibody production. We induce pristane nephropathy on T cell specific miR-17–92 knockout (miR-17–92−/−) mice. Mir17-92 T cell specific deficiency mitigates pristane induced-lupus nephropathy in mice. The mice showed less TFH cells, less GC B cells and lower autoantibody formation. Consistent with the reduction in autoantibody production, histological analysis revealed a lower mean renal histopathology score and less compliment deposition. We demonstrate that the miR17-92 cluster regulates TFH development by targeting Akt pathway. Moreover, miR17-92 mitigate the suppression function of Tregs by targeting Foxp3 co-regulators. Ectopic expression of miR17-92 downmodulates the suppression functions of Tregs and provides Tregs with partial effector activity via de-repression of cytokine genes. Our studies suggest that miR17-92 modulates lupus activity through critical regulation in TFH and Treg, unveiling the future therapeutic potential of microRNA manipulation in lupus nephritis.