bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maternal Protection from Bacterial Translocation in a Murine Model of Late-Onset Neonatal Sepsis (LOS)
Authors: Tamar Christian , Greenfield Kara , Dziekan Evelyn , Cassidy Mercedes , Knoop Kathryn 
Published: November 2024

Abstract
Late-onset neonatal sepsis (LOS), resulting from a bloodstream infection at least 72 hours after birth, is a major contributor to neonatal mortality. In a substantial portion of LOS cases, the causative pathogen is present as a member of the intestinal microbial community before dissemination, implicating intestinal translocation as a source of bloodstream infections. One potential pathway of bacterial translocation is through goblet cell-associated antigen passages, or GAPs, in colonic goblet cells. The presence of luminal EGF, obtained from breastmilk, and subsequent EGF receptor (EGFR) signaling in the intestine inhibits the formation of GAPs. We have established that disruption of EGFR signaling in pups leads to dissemination of the enteric pathogen Escherichia coli to the mesenteric lymph node (MLN). As pathogen dissemination was quickly followed by mortality, we use this as a preclinical model of LOS. Further work with this model focuses on the role of milk-derived immunoglobulins in reducing pathogen colonization and protecting from disease resulting from intestinal translocation. Through cross-fostering litters between dams immunized against E. coli and unimmunized dams, along with a comparison in disease between litters from immunized wild-type mice and IgA-/- mice, we aim to describe the protective role of mammary IgA. These experiments will also provide further implications for the role of human milk and human milk factors in protection from LOS.
The Immunomodulatory Effects and Mechanism of Wogonin for the Treatment of Multiple Sclerosis in a Murine Experimental Autoimmune Encephalomyelitis Model
Authors: Song Ying-Chyi , Yen Hung-Rong 
Published: November 2024

Abstract
Multiple sclerosis (MS) stands out as the most prevalent inflammatory autoimmune disease affecting the central nervous system (CNS). The primary driver of MS involves myelin-specific autoreactive T cells that infiltrate the CNS, initiating attacks on myelinated axons and triggering neuroinflammatory responses. Wogonin, a flavonoid, exhibits pharmacologic properties, including neuroprotective, anticancer, antiviral, anti-inflammatory, and anti-oxyradical effects. Our study demonstrates that wogonin significantly suppresses TLR-dependent DC activation, migration, and the expression of adhesion molecules in LPS-stimulated bone marrow-derived dendritic cells (BMDCs). In the experimental autoimmune encephalomyelitis (EAE) model, preventive treatment with wogonin led to reduced lymphocyte infiltration, prevented demyelination in the CNS, and consequently mitigated disease symptoms. Moreover, wogonin suppressed the release of neuroinflammatory cytokines by activated microglial cells, Th1 cells, Th2 cells, and Th17 cells in vitro and exerted therapeutic effects on attenuating the disease severity in the early disease onset stage and late disease progression stage. Our study suggests that wogonin treatment may not only prevent the onset of MS by inhibiting DC activation and migration but also potentially ameliorate the progression of MS by reducing neuroinflammation. This opens avenues for the development of new approaches in the therapy of autoimmune diseases.
Rapamycin ameliorates renal pathology in anti-Fx1A induced passive Heymann nephritis
Authors: Chunhui He 
Published: November 2024

Abstract
Our study focused on understanding the pathogenesis and treatment of membranous nephropathy (MN), a common cause of nephrotic syndrome (NS) characterized by glomerular basement membrane (GBM) thickening and immune complex deposition.
Through an Fx1A antibody-induced passive Heymann nephritis rat model, we observed a significant increase in kidney size, weight, and kidney-to-body weight ratio in diseased rats. However, oral administration of rapamycin mitigated renal pathology. Rats treated with rapamycin displayed kidney weights comparable to healthy rats, along with improvements in renal health indicators like proteinuria, blood urea nitrogen (BUN), and creatinine levels.
Furthermore, rapamycin-treated rats exhibited reduced inflammatory cytokine expressions (IL1b, IL6, IL10, IFNgama) comparable to healthy rats, in contrast to elevated expression levels in diseased rats. Histopathological analysis revealed diminished complement C3 and C5b-9 deposits, decreased renal tubular dilatation, and mitigated glomerular collapse upon rapamycin treatment.
Our findings indicate that rapamycin effectively improved renal pathology in anti-FX1A-induced passive Heymann nephritis, potentially suggesting a role for autophagy in modulating this condition.
Role of Immuno-Responsive Gene-1 (IRG1) in regulating Efferocytosis in Mouse Model of EAE
Authors: Nematullah Mohammad , FATMA MENA , RASHID FARAZ , Ayasolla Kameshwar , Ahmed MOHAMMAD EJAZ , WATER JEFFERY , MIR SAJAD , ZAHOOR INSHA , RATTAN RAMANDEEP , GIRI SHAILENDRA 
Published: November 2024

Abstract
Multiple sclerosis (MS) is a condition characterized by inflammation and demyelination, primarily affecting individuals in their youth. Numerous studies have documented the buildup of dying cells and myelin debris in the CNS, leading to inflammation and disability. This suggests that enhancing the removal of cellular debris could be a promising approach to address disability and promote the restoration of myelin. Efferocytosis is a process in which phagocytes take in apoptotic cells and help maintain tissue balance by releasing anti-inflammatory cytokines. However, the relationship between efferocytosis and EAE pathogenesis is not well understood. Loss of Irg1 is expected to interfere with the efferocytosis process, causing a strong inflammatory environment in the CNS, which in turn impairs disease resolution. We observed that Irg1 knockout displayed more severe experimental autoimmune encephalomyelitis (EAE) disease compared to wild type. Further, macrophages lacking Irg1 showed upregulation in the levels of NLRP3, GSDMD,and IL1β, along with a decrease in the phagocytic activity. Also, it showed reduced expression of key efferocytosis genes such MerTk, CD206, and arginase 1, suggesting that a lack of Irg1 leads to a highly inflammatory environment, resulting in impaired efferocytosis. Our results indicate that directing interventions towards the Irg1 gene could surpass the constraints of existing drugs and open possibilities for novel techniques in the treatment of MS.
Non redundant roles of group 2 innate lymphoid cells and T-helper 2 cells on anti-helminth immunity
Authors: Femoe Ulrich , Musaigwa Fungai , Li-Yin Hung , Inclan-Rico Juan Manuel , Nicolis Imani , Herbert De'Broski 
Published: November 2024

Abstract
The lung microenvironment is a critical target organ for trapping and killing migratory larvae of the murine hookworm Nippostrongylus brasiliensis during memory type 2 immunity. However, the relative contribution(s) of group 2 innate lymphoid (ILC2s) vs. T-helper 2 (TH2) populations in host protection and subsequent tissue repair are currently unknown. Data show that mice lacking locus control region 1 (LCR1-/-) have a selective defect in ILC2s resulting in impaired larval killing, pulmonary hemorrhage, and increased numbers of IL-17-expressing gdT cells. Adoptive transfer of excess numbers of CD4+ T cells into LCR1-/- mice restored larval killing during the secondary challenge but did not promote lung repair or suppress gdT cell-driven neutrophilic inflammation. Moreover, CD4 T cell depletion experiments demonstrate that while CD4 cells were necessary for the initial priming of ILC2s, CD4 cells were not essential for host-protective Type 2 immunity or tissue repair upon secondary challenge. This work suggests a division of labor between TH2 cells and ILC2 during primary and secondary responses, but that ILC2s serve a non-redundant role in limiting tissue injury through suppression of gd T cell dominant inflammation. Ongoing studies are designed to uncover the immunoregulatory/ tissue reparative molecules used by ILC2 during memory type 2 immunity against helminths.
Enteric pathogen targeting of the inflammasome pathway
Authors: Ricci de Azevedo Rafael , Kailasan Vanaja Sivapriya 
Published: November 2024

Abstract
Pattern recognition receptors-based sensing of microbial products and activities to mount an effective antibacterial defense is an evolutionarily conserved immune strategy. Cytosolic LPS sensing by caspase-11 or -4 and the ensuing noncanonical inflammasome-mediated IL-1 and cell death responses play a central role in the clearance of bacterial pathogens. In response to this selection pressure from the host it is natural that pathogens have developed strategies to actively antagonize or evade inflammasome responses. However, the mechanisms by which bacterial pathogens subvert the noncanonical inflammasome pathway is only beginning to be understood. In this context, this study investigates bacterial modulation of noncanonical inflammasome by utilizing Salmonella entericaserovar Typhimurium as a model enteric pathogen. By screening a library of defined single gene mutants of S. Typhimurium, we found that a mutant that lacks a Salmonella Pathogenicity Island 1 (SPI-1) effector triggers a markedly higher cell death and IL-1 responses in epithelial and professional innate immune cells indicating that this effector protein is a suppressor of inflammasome responses. Further characterization indicated that this effector protein-mediated inhibition of inflammasome responses occurs at the level of gasdermin D, the pyroptotic executioner. Together, this study attributes a novel inflammasome inhibitory function to a Salmonella SPI-1 effector.
Comparison of FOXP3 methylation status using three different methods
Authors: Hudzik Collin , Poulin Matthew 
Published: November 2024

Abstract
The FOXP3 gene is an X chromosome encoded transcription factor that is critical for the function of regulatory T (Treg) cells that maintain immunological self-tolerance and homeostasis. FOXP3 expression is primarily controlled by DNA methylation and the necessary development of Treg cells requires the establishment of Treg-specific DNA methylation patterns. FOXP3 and its epigenetic control genes have been associated with several immune-related conditions such as auto-immunity, asthma, food allergies and cancer. Here, we have conducted a study comparing the sensitivity to methylation status within our assays that cover FOXP3 using pyrosequencing, targeted bisulfite NGS (tbNGS), and methylation-sensitive high-resolution melting (MS-HRM) using a variety of different starting materials in both human and mice. As we transition away from pyrosequencing, we ensure that both tbNGS and MS-HRM result in methylation profiles which do not exhibit significant differences in sensitivity and accuracy to pyrosequencing, while also reducing the cost to the end user.
Anti-TIGIT antibody tiragolumab improves PD-L1 blockade via myeloid and Treg cells
Authors: Guan Xiangnan , Hu Ruozhen , Choi Yoonha , Srivats Shyam , Nabet Barzin , Silva John , McGinnis Lisa , Hendricks Robert , Nutsch Katherine , Banta Karl , Duong Ellen , Dunkle Alexis , Chang Patrick , Han Joy , Mittman Stephanie , Molden Nandini , Daggumati Pallavi 
Published: November 2024

Abstract
Tiragolumab, an anti-TIGIT antibody with an active IgG1/kappa Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone. To understand the mechanism(s) of response with this combination, we leveraged tumor pretreatment samples, and peripheral blood mononuclear cells (PBMC) and serum samples (baseline and on-treatment) collected from patients enrolled in the clinical trials, as well as the syngeneic CT26 mouse tumor model by using mouse tiragolumab surrogate antibodies. Bulk RNA-seq, proteomics, scSeq, and flow cytometry were performed. We found that high baseline intratumoral macrophages and Tregs were associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Comparing the on-treatment versus baseline serum samples revealed that macrophage activation was associated with clinical benefit in patients receiving the combination treatment. In mouse tumor models, tiragolumab surrogate antibodies inflamed tumor-associated macrophages, monocytes, and dendritic cells through Fc gamma receptors (FcɣR), in turn driving anti-tumor CD8+ T cells from an exhausted effector-like state to a more memory-like one. These results uncover a mechanism of action by which TIGIT checkpoint inhibitors can remodel immunosuppressive tumor microenvironments, and suggest that FcɣR engagement is an important consideration in anti-TIGIT antibody development.
Unraveling the immune dynamics of lung tissue infected with Francisella tularensis in a spatial context
Authors: Arakkal Leanne , Roberts Lydia , Schwarz Benjamin , Bohrnsen Eric , Wehrly Tara , Germain Ronald , Bosio Catharine , Speranza Emily 
Published: November 2024

Abstract
Francisella tularensis (Ftt) is a highly virulent bacterial pathogen whose vaccine offers only short-lived immunity. While CD4+ T cells are required for protection, the mechanism behind waning immunity remains unclear. One potential reason is that the local environment induced by the bacteria inhibits T cell function. We therefore carried out a multi-omics study of the infection microenvironment following vaccination and secondary challenge in mice. Flow cytometry and single cell sequencing analysis revealed that during Ftt secondary challenge, the CD4+ T cells in vaccinated animals show a delayed proliferative response and produced high levels of IFN-γ which correlated with an up-regulation of indoleamine 2,3-dioxygenase (IDO1) by endothelial cells. Importantly, increased IDO1 expression corresponded with decreased levels of tryptophan in the lung as measured by LC/MS. Given the requirement for tryptophan in optimal T cell proliferation, we investigated if IDO1 expression was spatially associated with sites of bacterial replication. We performed multiplex immunohistochemistry targeting bacterial antigen, immune cells, and nutrient depleting enzymes and quantified the proximity of CD4+ T cells to IDO1-expressing cells which arose just outside the points of bacterial replication. Overall, this research uncovered a potential systems level of regulation that is inhibiting T cell function.
All studies were approved by the IACUC and was supported by the IRP of the NIH/NIAID
IL-18 promotes pro-inflammatory cell death in cytotoxic T-cell responses
Authors: Frank-Kamenetskii Anastasia , Varghese Jemy , Klinghoffer Hannah , Carrafiell Olivia , Morrisseette Jeremy , Canna Scott 
Published: November 2024

Abstract
Hyperinflammation is a life-threatening systemic inflammatory state that complicates 11% of all SIRS cases. Clinical observations have identified several genetic and/or acquired suseptibility factors. Though Perforin-deficiency is the best-studied mechanism of hyperinflammatory susceptibility, several genetic and biomarker discoveries support excess IL-18 is another. However, it remains unclear how IL-18 drives hyperinflammation. We hypothesized that excess IL-18 leads to excess IFN-y that operates, at least in part, at the critical point of T-cell activation known as the immunological synapse (IS).
Methods. We observed the effects of IL-18 and IFN-y on three IS parameters: IS duration, cytokine production, and the mode of target cell death. We measured IS duration by live-cell microscopy, and measured cytokine levels in supernatants. We performed experiments in the presence of several cell death inhibitors. In vitro findings were further analyzed in Il18tg and Prf1-/- mice infected with LCMV.
Results . Prf deficiency has been shown to increase IS duration and IFN-y production, however, excess IL-18 shortened IS duration but increased IFN-y production. Moreover, excess IL-18 or the use of BMDCs that were pre-exposed to high levels of IFN-y induced RIPK-1 dependent cell death. These data suggest that T-cell IFN-y, amplified by IL-18, acts on target BMDC to promote necroptosis. Correspondingly, in vivo Nec-1 (RIPK-1 inhibitor) dampened inflammation during LCMV infection.
Lipid activated T cell Inflammation in Type 2 Diabetes
Authors: Ayala Angulo Julio , Lopez Miranda , Wiggins Kiara 
Published: November 2024

Abstract
Current mouse models of Type 2 Diabetes (T2D) do not recapitulate the complexity of the human disease. Chronic inflammation in T2D patients has been described in the literature extensively. However, there are no clear answers describing what molecules are causing this inflammation and how it contributes to disease progression. Classically, T cells are known to mediate immune responses by recognizing protein that is presented to them. Recently, T cells have been shown to respond to lipids that are presented on a molecule called CD1a. This molecule is expressed by humans and not by mice. Using mice expressing human CD1a with comparable CD1a expression to human cells, we show these humanized mice on a high fat diet have human-like T2D including liver and adipose inflammation as well as higher glucose intolerance without insulin intolerance when compared to wildtype mice. We also see elevated immune infiltration into adipose and liver tissue in high fat CD1a mice. In addition, CD1a are more likely to have smaller islet on a high fat diet relative to wildtype as well as sign of pancreatic atrophy, a hallmark of T2D progression.These data validate T cell responses to lipids via CD1a as a potential contributor to T2D and will establish a more physiologically relevant mouse model of T2D through an immunological mechanism.
A Case for idiopathic CD8 T cell lymphocytopenia as a medical condition
Authors: Sung Alexander , Hudig Dorothy , Cruz-Amaya Judith , Dooley Staci , Hess John 
Published: November 2024

Abstract
Idiopathic CD4 Lymphocytopenia (ICL) is a clinical condition where patients (pts) have CD4 T cell counts less than 300/ul of blood, detected twice at least 6 weeks apart, are HIV-negative, and lack familial inheritance or therapy-caused lymphodepletion (A. Lisco et al., NEJM 2023). Many of these pts have papillomavirus-related diseases and cryptococcosis. We propose another low T cell condition, “Idiopathic CD8 Lymphocytopenia (IC8L)”, in which pts would have low CD8 T counts (&lt;165 cells/ul blood, tested twice) with CD4 T cells &gt; 300/ul. I C8L exclusion is based on HIV positivity or immunosuppressive therapies. The IC8L concept started with JH’s concern for pts with recurrent infections and notably low absolute lymphocyte counts that decreased after SARS-CoV-2 infection. Five pts were identified with CD8 counts ranging from 104-155/ul and CD4:CD8 T cell ratios as high as 5.3. For one pt, low CD8 T cells were transient. Three pts had stable CD8 T cell counts and another pt awaits retesting. The three pts (of a cohort of ~580 pts also &gt;65 years of age in the practices of JH&SD) who met the proposed criteria had serious and recurrent infections. We conclude: (1) cause-and-effect relationships between SARS-CoV-2 infections, low CD8 T cells, and infectious diseases are impossible to assess for the individual pts and (2) it is essential to examine a large database to determine occurrence rates of “Idiopathic CD8 Lymphocytopenia” and its risks for infectious diseases.
Evidence of immune activation in pathogenesis of the HLA class II associated disease, podoconiosis
Authors: Gemeda Mikias , Newport Melanie , Howe Rawleig , Chanyalew Menberework , Teferi Tigist , Alcantra Diana , Towler Ben , Altmann Danniel , Boyton Rosemary 
Published: November 2024

Abstract
Podoconiosis is a form of lymphedema that causes bilateral swelling of the lower legs, resulting from exposure of bare feet to volcanic clay soils. There is an association between genetic variation in class II human leukocyte antigen genes and development of podoconiosis, raising the hypothesis that it is caused by an inflammatory immune response to an unknown soil component. Therefore, we aimed to characterise the immune profile and differential gene expression of podoconiosis patients relative to healthy controls. Here we report that, peripheral blood immunophenotyping of T cells indicated podoconiosis patients had significantly higher surface expression of HLA-DR molecules on both CD4 and CD8 T lymphocytes compared to healthy controls, while CD62L expression was significantly lower. The levels of the activation markers CD40 and CD86 were significantly higher on monocytes and dendritic cell subsets in patients compared to the controls. RNA sequencing gene expression data indicated higher levels of transcripts for activation markers, scavenger receptors and inflammation while lower levels of histones, T cell receptors, and immunoglobulin chain expression were found in podoconiosis patients. Our finding provides evidence that podoconiosis is associated with high levels of immune activation and inflammation compared to control subjects with over-expression of genes within the pro-inflammatory axis which could play a role in the pathology and lymphedema in the patients.
Metabolic dysfunction is associated with alterations in gut microbiota in obese adolescents
Authors: Xie Quin , Granato Alessandra , Paun Alexandra , Wong Anthony , Yau Christopher , Chu Lisa , Steele Shawna , Hamilton Jill , Danska Jayne 
Published: November 2024

Abstract
The gut microbiota (MB) has been implicated in adult metabolic dysfunction given evidence of dysbiosis in obesity and type 2 diabetes. However, few studies have investigated the relationship between metabolic disease, inflammation and the gut microbiota in children. We characterized the gut MB and immunometabolic profile of a cohort of obese, non-diabetic adolescents (MI4D) using high throughput fecal DNA sequencing with absolute bacterial quantitation. In the absence of antibiotics, we observed multi-log differences in fecal biomass correlated with stool water content and MB composition. Moreover, fecal bacterial biomass was associated with metabolic measures including serum triglycerides and insulin resistance in a sex-dependent manner. Mass cytometry demonstrated no significant associations of major immune cell subsets to fecal biomass or metabolic markers. In contrast, there were male-specific associations between serum markers of systemic inflammation and neutrophil activity with fecal biomass and waist circumference. Given the infiltration of visceral adipose tissue by myeloid cells in metabolic inflammation, our findings suggest that lower fecal biomass is associated with elevated systemic inflammation, especially in obese adolescent males. This study expands the understanding of sex-specific mechanism driving metabolic dysfunction in obese youth and suggests that gut MB alterations contribute to their metabolic and inflammatory dysregulation before diabetes diagnosis.