bluuebunny/crossref_metadata_2025_split huggingface dataset:
89
Authors: Velu Vijayakumar , Govindaraj Sakthivel , Babu Hemalatha , Ali Syed , Rahman Sheikh , Ribeiro Susan , Tomalka Jeff , Sharma Ashish , Sekaly Rafick , Amara Rama , Villinger Francois , Velu Vijayakumar 
Published: November 2024

Abstract
Immunotherapeutic cytokines such as IL-15 enhance follicular CD8 and IL-15 + IL-12 enhances follicular NK cells during chronic SIV infection. Here we tested the therapeutic effects of IL-15 and IL-12 administered alone or in combination during chronic SIV in rhesus macaques (RMs).
Twenty-two RMs infected with SIVmac251 were initiated on antiretroviral therapy (ART) at 8 weeks post-SIV for 9 months. Three groups of RMs received cytokine therapy - IL-15/IL-15Ra (n=6), IL-12 (n=5), IL-15/IL-15Ra+IL-12 (n=6) - in 2 phases (5 doses once a week). The 1st phase was administered at 6 weeks post-SIV (2 weeks before ART) and the 2nd phase was during ART at 12 weeks pre-ATI. ART alone (n=5) group served as the control.
IL-15/IL-15Ra and IL-15/IL-15R+IL-12 therapies induced significant expansion of Ki-67+ (proliferative), CXCR5 (follicular homing) SIV-specific CD8 T and CD16+ NK cells in blood and LN. Importantly, IL-15/IL-15Ra therapy resulted in the expansion of CD107a+CD8 T cells pre-ATI (P=0.03). Further, the blood transcriptomic profile displayed induction of cytolytic molecules (granzyme-B, perforin), Jak/Stat signaling pathway. Post-ATI, the IL-15/IL-15Ra treated animals showed 3-log lower viremia compared to other groups (p=0.004) with 83% of RMs &lt;500 copies/ml at 20 weeks. SIV-specific CXCR5+, CD28+ CD8 T , CD16+ NK in blood, LN were associated with enhanced viral control. These studies define IL-15/IL-15Ra as a potentially effective immune therapy for HIV cure strategy.
SARS-CoV-2 adaptive responses in Confirmed Positive (CP) and non-infected household contacts (HC)
Authors: Lee Yeji , Goodwin Benjamin , Tarke Alison , Frazier April , Grifoni Alba , Dan Jennifer , Sette Alessandro , da Silva Antunes Ricardo 
Published: November 2024

Abstract
Objective: Many studies have explored the protective mechanism from infection of SARS-CoV-2. However, studies of couples living together in which one individual experienced symptomatic Confirmed Positive (CP) while the other consistently tested negative for infection (Household contact; HC) are scarce. Herein, we investigated humoral and T-cell responses in pre- and post-infection samples from CP and HC.
Methods: 52 CP and 44 HC individuals were recruited. Humoral responses were measured from plasma. Antigen-specific T cells against spike, non-spike, and common cold coronaviruses (CCC) were measured using an AIM+ICS from PBMCs.
Results: Humoral and T responses were similar between CP and HC before infection. In longitudinal analyses, except for the spike T responses, those responses were significantly increased after infection in CP but not in HC. One-third of the HC pairs were also associated with increased non-spike reactivity besides displaying increased spike reactivity in post-infection. 41.7% of HC pairs showed high pre-existing or CCC-specific T cells in pre-infection. No obvious pattern was found in the remaining HC pairs.
Conclusions: Measurement of antibody and T cell responses before infection does not predict protective mechanisms in household discordant pairs. Despite testing negative for COVID-19, some HC might have experienced asymptomatic/abortive infections and the other HC might have been protected due to the pre-existing or cross-reactive T cells.
The gastrointestinal tract-restricted helminth H. polygyrus bakeri protects against SARS-CoV-2-induced lung disease in mice
Authors: Karl Courtney , Desai Pritesh , Liu Meizi , Mackin Samantha , Chong Zhenlu , Yu Jinsheng , Thackray Larissa , Diamond Michael 
Published: November 2024

Abstract
Helminth-virus coinfection models can provide valuable insights into the regulation and modulation of host antiviral immunity. Epidemiological evidence suggests that pre-existing helminth infection is associated with reduced risk of severe SARS-CoV-2 infection. Several prior studies have reported that Heligmosomoides polygyrus bakeri (Hpb), an enteral murine helminth, protects against infection by respiratory viruses. Here, we developed an Hpb-SARS-CoV-2 coinfection model and show that coinfection with Hpb protects against mouse-adapted SARS-CoV-2 (MA10) induced weight loss and mortality. Compared to mice infected with MA10 alone, coinfected mice have a small reduction in peak lung viral load, increased eosinophil infiltrates in the lung and bronchoalveolar lavage fluid, and better lung function and blood oxygen levels. Using a series of knockout mice, we found that Hpb protects against SARS-CoV-2 independently of several canonical type 2 immunity pathways including STAT6, tuft cells, and IL-33 signaling as well as adaptive immunity. Coinfected mice that are depleted of eosinophils have a partial loss of protection. Together, these findings suggest that enhanced eosinophil production induced by Hpb infection protects mice from MA10-induced inflammation in a STAT6-independent manner.
PPAR delta promotes tumor-infiltrating Treg plasticity
Authors: Bunk Paul , Maher Timothy , Beyaz Semir 
Published: November 2024

Abstract
Regulatory T-cells (Tregs) accumulate within the tumor microenvironment and are exploited to suppress anti-tumor immune responses. Lipid metabolism has been implicated as a regulator of Treg function. Unexpextedly, we found the master regulator of fatty acid catabolism PPARd as a Treg-intrinsic switch that restricts tumor growth by inducing Treg plasticity. Activation of PPARd in Tregs specifically leads to inflammatory reprograming of the tumor immune microenvironment without adverse effects in the periphery. We identified PPARd-induced transcriptional, epigenetic and metabolic alterations in Tregs that drive this plasticity response. Finally, using an inducible model of PPARd gain-of-function in Tregs, we demonstrate therapeutic potential of targeting this transcription factor to enhance immunotherapy against cancer. Collectively, these results indicate that inducing Treg plasticity in tumors can be harnessed to promote anti-tumor immunity.
Time-resolved analysis of CAR-T Cell induced apoptosis of low frequency target cells using an Image-enhanced flow cytometer was enabled by fluorescent protein compensation with BrightComp eBeads.
Authors: Narayanan Jayanth , Taylor Erin 
Published: November 2024

Abstract
Optimization of CAR-T therapies requires an understanding the dynamic interactions between the CAR-T and target cells. Flow cytometry analysis of CAR-T cell interaction with dimly expressed fluorescent protein in target cells presents a major challenge for compensation especially in the presence of high numbers of non-target cells. Also, short, transient interaction between CAR-T and target cells makes it challenging to observe and characterize CAR-T cell candidate interactions. Here we demonstrate the use of the Attune CytPix imaging cytometer and BrighComp eBead in CFP and mCherry to analyze CAR-T target cell interactions and compensate for dim fluorescent proteins expression. We also leverage the the Caspase 3/7 to report on apoptosis over the entire course CAR-T mediated cell killing. Attune Cytpix image-enhanced flow cytometer enabled the simultaneous characterization of various cellular parameters, including cell morphology, fluorescent protein expression and apoptosis progression. Although apoptosis increased overtime, the frequency of true CAR-T and Target cell interaction did not change with time, however, these interactions were greatly altered by altering the CAR-T cell:Target cell ratios. This comprehensive methodology employed in our study and findings will contribute to the optimization and development of Car-T cell therapy approaches for improved treatment outcomes.
Langerhans cell histiocytosis (LCH) preceding ulcerative proctitis: Immunological insights
Authors: Jafri Ali , Gerardot Shori , Shaya Justin 
Published: November 2024

Abstract
Langerhans cell histiocytosis (LCH) is a disorder of abnormal myeloid dendritic cell proliferation; this process is thought to be linked to mitogen-activated protein kinase (MAPK) pathway mutations. This case report will examine the unusual sequence where LCH preceded the diagnosis of ulcerative proctitis. Interestingly, interleukin-23 (IL-23) is a shared mediator in both processes.
A 25 year-old white male presented with worsening right flank pain and eczematous rash. Skin biopsy revealed numerous Langerhans cells with surrounding inflammatory cells; Immunohistochemical staining was positive for CD1a, s100, and cyclin D1. PET-CT scans revealed pulmonary and bony involvement. Multi-system LCH was diagnosed and complete metabolic response was achieved with cytarabine therapy. Social history included marijuana usage.
Curiously, the patient developed frequent non-bloody diarrhea, and crampy abdominal pain a year later. Colonoscopy and biopsy revealed chronic active proctitis with ulcerative proctitis being the primary differential diagnosis. Mesalamine was started and remission was achieved.
The unusual history of both LCH and ulcerative proctitis raises the possibility of a shared immunological pathway; specifically, if IL-23 is a common mediator. This warrants further research. Additionally, cigarette smoking is a known risk factor for LCH while potentially decreasing risk of ulcerative colitis. As marijuana is increasingly legalized, its profile is also worth exploring.
The production of CXCL13 in CD4+ T cells is influenced by adjacent Tregs in the tertiary lymphoid structures of chronic pemphigus blisters
Authors: Lee A Yeong , Han Dawoon , Kim Taehee , Min SeoYeon , Kim DongJun , Jung Ju Hyun , Kim Changhyeon , Park Kyemyung , Kim Do-Young , Kim Soo-Chan , Kim Jong Hoon 
Published: November 2024

Abstract
Pemphigus is a rare and life-threatening autoimmune blistering disease mediated by autoreactive B cells targeting desmogleins (DSGs) in keratinocytes. Anti-DSG autoantibodies disrupt cell-cell adhesion, leading to suprabasal acantholytic blisters. Our investigation reveals the presence of tertiary lymphoid structures (TLSs) harboring DSG-specific B cells and plasma cells in chronic skin blisters of pemphigus. TLSs, resembling B-cell follicles of secondary lymphoid organs, are detected in various inflammatory diseases. CXCL13 is an important chemokine for recruiting CXCR5-expressing naïve B and T follicular helper cells. Through immunofluorescence studies, we found that CXCL13+ cells were mainly produced by CD4+ T cells. Single-cell RNA sequencing revealed clonally expanded CXCL13+CD4+ T cells containing DSG3-specific memory T cells with activated cytotoxic features. Paradoxically, these cells exhibit an attenuation of T-cell receptor (TCR) signaling when expressing high levels of CXCL13. Spatial proteomics reveals that Tregs are spatially adjacent to CXCL13+CD4+ T cells within the skin TLSs. In vitro depletion of Tregs leads to decreased CXCL13 production by CD4+ T cells. These data suggest that adjacent Tregs play a role in regulating CXCL13+CD4+ T cells. In conclusion, skin TLSs are associated with the maintenance of chronic blisters, and the microenvironmental network involving CXCL13+CD4+ T cells and Tregs plays a crucial role in CXCL13 production.
Dissecting signaling parameters in autoreactive B cells
Authors: Pozovskiy Rita , Atisha - Fregoso Yemil 
Published: November 2024

Abstract
In systemic lupus erythematosus (SLE), IgG antibodies (Abs) directed against nuclear antigens (ANA) are pathogenic. Healthy individuals (HC) harbor a similar frequency of ANA+ mature B cells without producing pathogenic IgG Abs. Differences in behavior between ANA+/- B cells in SLE patients and HC have not been explored. The aim of this study was to measure the response to BCR activation in the ANA+/- B cell subpopulations in SLE patients and HC. B cells from 7 SLE patients and 5 HC were isolated and activated with F(ab)'2 fragments of anti-IgG Abs. Calcium flux was measured using indo-1 AM. The response was quantified by area under the curve (AUC), using the bound/unbound ratio of the marker for 5 minutes after activation. Values were compared using Wilcoxon rank sum test. In SLE patients, ANA+ IgG memory cells have a stronger calcium influx than ANA- (AUC for ANA + vs -: 89.46±18.51 vs 76.17±12.65; p=0.05). This difference is not present in HC (AUC for ANA + vs -: 88.02±16.51 vs 89.52±14.49; p=ns). In both HC and SLE patients, ANA+ naïve B cells are less responsive to BCR activation, suggesting anergy. IgM+ B cells overall, irrespective of ANA status, seem to be less responsive in patients with SLE. These results show that ANA+ IgG memory B cells are hyperreactive in SLE patients. The data also suggests a mechanism for the breach in tolerance that is observed in SLE. Further studies are warranted to explore the mechanism and effects on autoantibody generation in SLE.
CCR2, CCR4 and CCR9 expression on T cells is required for homing to colon cancer as demonstrated by Zr-89 T cell labeling
Authors: Sato Noriko , Olkowski Colleen , Minor Hannah , Lin Qiaoya , Choyke Peter 
Published: November 2024

Abstract
Adoptive T cell therapy relies on trafficking of infused T cells to the tumor. Chemokine gradients and chemokine receptors expressed on T cells mediate this recruitment of T cells. However, due to the high complexity of the tumor microenvironment, regulation of T cell homing to tumors remains poorly understood. We examined how various chemokine receptors expressed on T cells impact their ability to home to cancer using zirconium-89 (89Zr)-oxine cell labeling. Ex vivo activated mouse T cells, wild type (WT) or deficient (KO) for a chemokine receptor, were labeled with 89Zr-oxine and intravenously infused into WT mice bearing subcutaneous syngeneic MC38 colon cancer. Bulk T cells, not tumor antigen specific T cells, were used to determine homing capability of the cells independent of their antigen interaction. Serial PET imaging demonstrated initial lung accumulation of the T cells followed by trafficking to the liver, spleen, and to a much lesser extent other tissues, including the tumor. Ex vivo biodistribution analyses on Day 2 showed CCR2KO, CCR4KO and CCR9KO T cells homed significantly less to the tumor compared to WT T cells, indicating that CCR2, CCR4 and CCR9 expression on T cells is important for homing to colon cancer. Augmenting expression of these chemokine receptors on T cells, or the relevant ligands in the tumor, could enhance T cell homing to colon cancer thereby improving efficacy of T cell therapy.
Correlates of susceptibility in household influenza studies
Authors: St. James Deryn , Souquette Aisha , Mettelman Robert , Van de Velde Lee-Ann , Wilson Taylor , Vegesana Kasi , Allen E Kaitlynn , Petrie Joshua , Gordon Aubree , Martin Emily , Monto Arnold , Thomas Paul 
Published: November 2024

Abstract
Every year there is an estimated one billion cases of seasonal influenza, with varying disease severity. While some have asymptomatic infections, others are hospitalized which can result in fatal disease. It is still unclear why only some will develop symptomatic or severe illness. Household studies allow us to investigate infection status after a known exposure to influenza. The Nicaragua Household study, and the Household Influenza Vaccine Effectiveness (HIVE) study have been formed to further understand of protection and severity. To this end, we characterized distinct cellular profiles in our subjects with diverse infection outcomes. Acute infection sampling in the Nicaragua study identified high frequencies of basophils, gamma delta T cells, and interferon gamma producing natural killer (NK) cells in subjects with mild disease, whereas granzyme B producing NK cell populations were correlated with severe disease. In the HIVE study, pre-infection samples with higher cytotoxic and cytokine producing NK cells as well as high neutrophil cell populations were correlated with protection from influenza infection and severe disease. Further analysis is in progress to train and test models to predict susceptibility to influenza and disease severity. These analyses expand the diversity of subjects analyzed for immune features in influenza disease to identify more universal correlates of susceptibility.
Heme drives proliferation of naïve and memory B cells by enhancing G1/S phase cell cycle progression
Authors: Padilla-Quirarte Herbey , Scharer Christopher , Kania Anna , Janto Nic , Hicks Sakeenah , Maurer Jeffrey , Boss Jeremy 
Published: November 2024

Abstract
Iron is elemental for multiple cellular biochemical processes like DNA synthesis and energy generation and recently the role of it has been reported to be important for B cells to produce antibodies. B cell differentiation to plasma cells is tightly regulated with cell division, where several epigenetic and metabolic changes occur, as cell divides. RNAseq performed on iron/heme treated differentiating naïve B cells (nB) after activation with LPS showed that heme regulated cell cycle, proliferation, and DNA synthesis genes when compared to cells treated with vehicle. Genes like Cdkn1a, Cdkn2a and Cdkn2b, which codify for cyclin-dependent kinase inhibitors that control the retinoblastoma protein activity were DEG with heme treatment, as was as Rb1 gene itself. To understand better how heme regulates cell division, ex vivo cultures of naïve and memory B cells (MBC) were stained with the cell tracing dye CTY and followed activation after T dependent or T independent activating signals. Both nB and MBC showed increased proliferative capacity against two antigens when treated with heme that correlated with higher levels of replicating cells as BrDu stain indicated. Furthermore, the Rb protein levels of total form were decreased on nB treated with heme compared to vehicle control. In summary, this work provides more insight to the mechanism of heme promoting plasma cell differentiation by enhancing the proliferation by enhancing G1/S phase cell cycle progression.
Corneal GR signaling is critical for preventing neovascularization and immune cell infiltration of the cornea
Authors: Diaz-Jimenez David , O'Neill Erin , Aguayo-Abarca Felipe , Kadmiel Mahita , Cidlowski John 
Published: November 2024

Abstract
The cornea protects the interior of the eye from external agents such as bacteria, viruses and debris. Synthetic glucocorticoids are widely prescribed in the treatment of ocular infections and disorders. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR); however, the molecular and physiological functions of GR signaling in the cornea are poorly understood. In this study, we show that treatment of mice with glucocorticoid eye drops led to regulation of the corneal transcriptome associated with multiple biological functions including the immune response. To understand the direct role of GR signaling in the cornea, we developed mice with conditional knockout of GR in the corneal epithelium. We discovered that an intact corneal GR signaling pathway is required for ocular development. Mice lacking corneal GR exhibited microphthalmia, loss of pupils, and mislocalization of key structural proteins within the corneal epithelial layers. Global transcriptomic approaches revealed that loss of GR signaling in the cornea also resulted in the dysregulation of a large cohort of genes strongly associated with an enhanced inflammatory response. Finally, corneal GR signaling was required for preventing neovascularization of blood and lymphatic vessels and thereby immune cell infiltration of the cornea. These results reveal that corneal GR signaling plays a critical role in ocular development and in maintaining the homeostasis of the eye.
Understanding immune responses in children who remain aparasitemic despite exposure to Plasmodium falciparum malaria
Authors: Holla Prasida , Bhardwaj Jyoti , Gaskin Erik , Doumbo Safiatou , Ongoiba Aissata , Felgner Philip , Hopp Christine , Xuei Xiaoling , Kayentao Kassoum , Traore Boubacar , Crompton Peter , Tran Tuan 
Published: November 2024

Abstract
Reliable immune correlates of protection against Plasmodium falciparum (Pf) malaria remain elusive, partly because sustained protection from parasitemia through natural exposure is rarely observed. In a prospective cohort study in an area of intense malaria transmission in Mali, we identified a subset of young children who remained aparasitemic during 7 months of active and passive surveillance, despite boosting of Pf-specific IgG. To identify immune responses associated with apparent elite control of infection, we carried out CITE-seq of PBMCs from 7 pairs of age- and sex- matched aparasitemic and parasitemic children. We included Pf antigens MSP1- and AMA1- specific B cell tetramers in the CITE-seq cocktail and sequenced B cell receptors (BCRs) from these cells. To identify epigenetic changes, we performed scATAC-seq on additional samples. Immune cell types from aparasitemic children exhibited markedly different transcriptional states and epigenetic landscapes. Notably, CD14+ monocytes in aparasitemic children showed enrichment of inflammatory signatures including TNFα signaling via NF-κB along with differently accessible chromatin in the target genes of these pathways. We also identified 44 antigen-specific B cells, primarily from aparasitemic children, and cloned their BCRs into expression plasmids to produce Pf-specific monoclonal antibodies in vitro to test their ability to control parasite growth and enhance the opsonophagocytosis capacity of monocytes.
Rapid non-invasive tracking of splenomegaly with hands-free 3D ultrasound for on-demand assessment of immune disorders and cancer
Authors: Houston Zachary , Braza Julie , Tseng Jen-Chieh , Stanley Alexis , McMannus Craig , Czernuszewicz Tomasz , Gessner Ryan , Peterson Jeffrey 
Published: November 2024

Abstract
Splenomegaly is an important measure of cancer progression and immune disorders. Magnetic resonance imaging (MRI) and computed tomography (CT) are the standard in the field but are not optimal for preclinical studies due to their high cost, low throughput and reliance on contrast agents for soft tissue. Here, we report the use of a novel 3D automated ultrasound scanner (Vega, Revvity Inc.) for the rapid assessment of spleen volume in two murine models (cancer and lupus).
Cancer cohort: Tumor-bearing (4T1 breast cancer, right flank) mice were imaged alongside control mice at five timepoints over 25 days. Spleen volume was found to increase 18-fold (30±3 mm3 to 545±105 mm3) after 25 days of tumor growth (938±77 mm3).
Lupus cohort: MRL/lpr mice were allowed to age until they developed lymphoproliferation (12-14 weeks) and then imaged biweekly until 20 weeks of age. A 300-fold increase in calculated spleen volume by 18 weeks of age in MRL/ lpr mice was observed. Kidney volume doubled and a statistical increase (p&lt;0.05) in vascular density was observed (using acoustic angiography), indicating systemic disease progression.
Average acquisition times for both cohorts were 30 seconds per mouse, showing excellent applicability of spleen volume as a measurement of disease progression compared to more laborious techniques (e.g. MRI). Future work in this area will explore the application of machine learning and AI-assisted auto segmentation tools for higher throughput data analysis.