bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intestinal helminth infection impairs vaccine-induced T cell responses and protection against a SARS-CoV-2 Omicron variant in mice
Authors: Desai Pritesh , Karl Courtney , Ying Baoling , Liang Chieh-Yu , Garcia-Salum Tamara , Santana Ana Carolina , Urban Jr Joseph , Elbashir Sayda , Edwards Darin , Thackray Larissa , Sekaly Rafick , Diamond Michael 
Published: November 2024

Abstract
Although vaccines have reduced the global COVID-19 disease burden, the impact of gastrointestinal helminth infection on their efficacy in endemic regions of the world remains uncertain. Here, using Heligmosomoides polygyrus bakeri (Hpb), a model, non-invasive murine intestinal hookworm, we evaluated whether Hpb infection affects the efficacy of mRNA S6P, a preclinical vaccine encoding a hexaproline stabilized spike of the Wuhan-1 strain of SARS-CoV-2. In the setting of Hpb infection, immunization of mRNA S6P generated equivalent serum antibody and antigen-specific B cell responses. However, antigen-specific CD4+ and CD8+ T cell responses were reduced compared to mice immunized without Hpb infection. Helminth infection did not skew vaccine-induced T cell responses but rather inhibited their capacity to produce polyfunctional cytokines. Hpb infection caused similar T cell defects in mice immunized with an approved adenoviral vectored SARS-CoV-2 vaccine (Ad26.COV2.S). Challenge experiments showed that although Hpb-infected mice vaccinated with mRNA S6P were fully protected against the ancestral SARS-CoV-2 strain WA1/2020, there was a loss of vaccine-mediated protection against Omicron variant BA5.5 compared to animals immunized in the absence of Hpb infection. These results in mice suggest that intestinal helminth infection can compromise T cell responses and protective efficacy of vaccines against SARS-CoV-2 variants that escape neutralizing antibody responses.
Exploring engineered HLA-I chaperones for enhancing the immunogenicity of cold tumors.
Authors: Hwang Daniel , Sun Shirley , Sgourakis Nikolaos 
Published: November 2024

Abstract
Immune surveillance relies upon efficient production of peptide loaded HLA class I molecules (pHLA-I), a process mediated by the antigen processing and presentation (APP) pathway. Accordingly, dysregulation of the APP pathway is a common immune evasion mechanism in cancers. This is especially true for “cold tumors”, a class of cancers with low immunogenicity, typically caused by global downregulation of pHLA-I and/or low mutational burden, resulting in immune escape and overall worse prognosis. We aimed to develop a method for restoring immunological recognition of this class of tumors by leveraging endogenous mediators of the APP pathway. We modified two important HLA-I chaperones, tapasin and TAPBPR, which have essential functions in stabilizing HLA-I molecules and in refining the repertoire of presented antigens. We have engineered variants of these chaperones, including HLA allotype-agnostic variants, which travel along the secretory pathway together with HLA molecules, enabling them to exert their chaperoning function in non-native subcellular compartments, including at the cell surface. We show that these Chaperone Fusion Proteins (CFPs) can increase HLA-A2 expression in multiple cell lines, including in a bona fide cold tumor cell line. Moreover, CFP expression resulted in enhanced T cell recognition and killing of target tumor cells. These data suggest that CFPs may be developed into a platform for enhancing the immunogenicity of cold tumors.
Modulation of antigen presentation by first-in-class ERAP1 and ERAP2 inhibitors for the treatment of cancer and autoimmunity
Authors: Clark Kristopher , Anderton Kate , Paes Wayne , Green Daniel , Khan Faraz , Ternette Nicola , Lam Tsang Wai , Wat Jesse , Bras Maaike , Trelber Tobias , Pfeiffer Anamarija , Redfern Dan , Rozo Annaig , Sabouni Joud , Garside Samantha , Kay Steven , Shiers Jason 
Published: November 2024

Abstract
The aminopeptidases ERAP1 and ERAP2 play a central role in the processing of antigens for loading onto MHC-I complexes with links to both autoimmunity and cancer. On one hand, genetic variants of each enzyme are associated with the development of several autoimmune disorders with the formation of autoantigens by ERAP1 and ERAP2 as a leading hypothesis for the mechanism behind this association. On the other hand, it is well established that patients with tumors characterized by high antigen diversity have increased response rates to immune checkpoint inhibitors. It follows that modulation of the cancer immunopeptidome offers a new therapeutic strategy to generate de novo anti-tumor T-cell responses and overcome current challenges of existing immuno-oncology (IO) therapeutics. Collectively, this knowledge implies that ERAP1 and ERAP2 represent a novel category of therapeutic targets for autoimmunity and immuno-oncology that can be manipulated to drive changes in antigen repertoire and thereby modulate the detection of cancer cells and self. Here, we present the characterization of our potent and selective First-in-Class ERAP1 and ERAP2 inhibitors both in vitro and in vivo. Importantly, we apply a state-of-the-art immunopeptidomics pipeline to define the qualitative and quantitative effects of these inhibitors. Our data demonstrate that ERAP1 and ERAP2 have overlapping and distinct effects on the antigen repertoire, consistent with their respective substrate specificities.
Modulation of IL-13 signal in allergic asthma.
Authors: Shankar Archana , McAlees Jaclyn , Hargis Julie , Lewkowich Ian 
Published: November 2024

Abstract
Allergic asthma, a chronic airway inflammatory disease affecting over 300 million people worldwide, is primarily driven by Th2 cytokines such as interleukin-13 (IL-13). Although IL-13 signals through a Jak1/Tyk2/STAT6-driven pathway, activation of other pathways has been reported (e.g., STAT3, SRC). To better understand the totality of signaling intermediates activated by IL-13, we employed an unbiased, phospho-proteomics approach. To this end A549 cells, a human airway epithelial cell line, were stimulated with IL-13 for 15 minutes, and peptides containing a phosphorylated Serine, or Threonine reside were identified by mass spectrometry. &gt;1,200 individual phospho-peptides were identified, and 108 residues were found to be differentially phosphorylated. Based on string DB results, SRC (a non-receptor tyrosine kinase) was identified as a potentially novel IL-13-induced signaling intermediate activated in response to IL-13. Kinetic assessment of SRC activation suggested that it is activated within seconds of IL-13 stimulation, and that its activation preceded activation of canonical signaling intermediates like STAT6. Functionally, SRC antagonists reduced expression of multiple IL-13-induced gene in IL-13-treated A549 cells. Collectively, these data suggest that SRC may represent a novel signaling intermediate activated in response to IL-13, and that SRC antagonism may have therapeutic benefit in the treatment of asthma.
Caveolin-1 restrains pathogenic T follicular helper cell response in primary Sjögren’s syndrome
Authors: Lin Xiang 
Published: November 2024

Abstract
T follicular helper (Tfh) cells play a central role in humoral autoimmunity, including primary Sjögren’s syndrome (pSS). However, targeting Tfh cells is challenging in clinical management. Previous studies suggested that inducible T­cell co­stimulator (ICOS) directed Tfh cell motility in engaging bystander B cells, which promoted plasma cell differentiation and antibodies production. Here, we identified a novel function of caveolin-1 (Cav-1) in restraining ICOS expression in Tfh cells and pSS pathogenesis. Cav-1 deficiency significantly promoted human and murine Tfh cell responses, while Cav-1-/- mice exhibited exacerbated disease pathology of experimental SS (ESS). Peroxisome proliferator-activated receptor alpha (PPARa), a downstream transcription factor of Cav-1, rapidly repressed Icos transcription upon Tfh polarization, interestingly, independence of lipid metabolism. Phenotypic analyses suggested that Cav-1 and PPARa expressions were decreased in CD4+ T cells from pSS patients and ESS mice. Notably, pharmaceutical activation of PPARa with fenofibrate could suppress human and murine Tfh cells both in vitro and in vivo, while oral administration of fenofibrate effectively ameliorated ESS pathology in mice with acute or chronic inflammation. These results revealed an unrecognized role of Cav-1/PPARa axis in Tfh cell tolerance and pSS pathogenesis, suggesting PPARa as a promising target in the treatment of humoral autoimmunity.
Immunization with Sez6L2 protein mimics the human condition of late-onset cerebellar ataxia with associated Sez6L2 autoantibodies in mice
Authors: Reyes-Sepulveda Carlos , Randolph John , Hobbins Alison , Granato Julia , Ryan Allison , Silver Nina , Stout Angela , Hammond Jennetta 
Published: November 2024

Abstract
Sez6L2 autoantibodies have been identified in a subset of human patients with progressive cerebellar ataxia. Sez6L2 is a transmembrane protein expressed by most neurons, including Purkinje cells and granular cells of the cerebellum. Patients with Sez6L2 autoantibodies present with gait ataxia, slurred speech, and ocular motor symptoms. Some patients also develop limb ataxia and cognitive deficits. These case studies have led to the hypothesis that autoimmunity against Sez6L2 can directly cause cerebellar damage leading to ataxia. We tested whether C57BL/6J mice immunized against Sez6L2 protein develop ataxia symptoms. We also investigated the systemic immune response against Sez6L2 and whether there was increased immune cell infiltration into the brain. We found that mice immunized with Sez6L2 generated significant levels of anti-Sez6L2 antibodies, in addition to a significant population of Sez6L2-specific CD4 and CD8 T cells. Furthermore, these mice had increased CD4+ T cell infiltration into the brain. The Sez6L2 immunized mice also exhibited mild mobility impairments in open field and wire grid walk assays. Overall, our results demonstrate that an autoimmune response to Sez6L2 in mice can lead to mobility impairments and pathology consistent with human patients who develop cerebellar ataxia associated with Sez6L2 autoantibodies. This new mouse model should be useful for mechanistic studies on a poorly understood autoimmune disease.
The impact of pediatric obesity on T cell function
Authors: Hay Ceire , Sayed Samir , Knight Montana , Campos Jose , Nelson Molly , Abrams Eric , Gunnala Pooja , Gonzalez Elena , Espinoza Diego , Beers Jarad , Collins Joy , Ruffner Melanie , Henao-Mejia Jorge , Vahedi Golnaz , Dumon Kristoffel , Prout Elizabeth , Henrickson Sarah 
Published: November 2024

Abstract
The increasing prevalence of childhood obesity is an urgent public health crisis. Children with obesity (≥ 95th percentile BMI for age and sex) are at an increased risk for developing asthma as well as cardiometabolic and autoimmune disorders. However, the mechanisms by which excess weight impacts immune function in children is incompletely understood. To address this gap in knowledge, we assessed changes in immune cell function in obese children before and after bariatric surgery, a procedure used to facilitate weight loss in patients with severe obesity. We integrated high dimensional spectral flow cytometry, in vitro functional assays, and single-cell RNA-sequencing of intra-operative visceral adipose tissue and PBMCs to find that CD8+ T cells from obese children, compared to age-matched controls, had increased expression of TOX and inhibitory receptors (PD-1, LAG-3). This dysfunctional phenotype was persistent 6-18 months after surgery, despite significant weight loss (average change in BMI of 17%). Moreover, baseline CD8+ T cells from obese patients exhibit impaired proliferation and altered metabolic profiles following TCR stimulation. Future work will determine functional differences in the peripheral T cells of bariatric surgery patients at baseline compared to 6-18 months post-surgery and assess the local immune landscape within visceral adipose depots from obese compared to non-obese children.
Soluble Plasma Proteins of Tumor Necrosis Factor and Immunoglobulin Superfamilies Reveal New Insights into Immune Regulation in People with HIV and Opioid Use Disorde
Authors: Ghanta Priya , Dang Christine , Nelson Mindy , Feaster Daniel , Forrest David , Pahwa Rajemdra , Tookes Hansel , Pallikkuth Suresh , Pahwa Savita 
Published: November 2024

Abstract
Opioid Use Disorder (OUD) is present in high frequency in people with HIV (PWH). This study investigated proteins of the TNF and Immunoglobulin superfamilies (SF) in relation to Flu vaccine responses in PWH with and without OUD. 210 participants (median age 46 years) were recruited into OUD groups: HIV+OP+ and HIV-OP+, and non-opioid users: HIV+OP- and HIV-OP-. Flu vaccine titers post-vaccination at 21-28 days (T2) and fold change (T2/T0) were higher in people with OUD compared to PWH without Opioid use, while being equivalent to controls (HIV-OP-). 48 soluble molecules of the Tumor necrosing factor (TNF) and Immunoglobulin (Ig) superfamilies (SF) were analyzed in plasma by multiplex Luminex technology. Both OP+ groups (HIV+OP+ and HIV- OP+) had higher co-stimulatory TNF SF molecules including 4-1BB, OX-40, CD40 that were positively correlated with Flu vaccine responses. The HIV+ OP- group displayed a different profile, with high Ig SF molecules including PD-L2, CTLA-4 and Perforin, of which PD-L2 was negatively associated with Flu vaccine titers. The higher Flu vaccine response in the groups with OUD (HIV+OP+ and HIV- OP+) could be attributed to high levels of specific plasma proteins of the TNF superfamily that are known to be important for T cell activation, proliferation, and T-B interactions needed for antibody responses and could have negated the immunosuppressive effects of HIV. These findings could lead to development of new diagnostic and therapeutic tools.
Interferon responses in monocytes at the febrile phase of PFAPA
Authors: Seo Euri , Kim Youngun , Koh June Young , Kang Ji-Man , Shin Eui-cheol 
Published: November 2024

Abstract
Periodic fever, aphthous stomatitis, pharyngitis, and adenitis, generally called PFAPA, is a disease in which symptoms like the name of the disease appear with a regular periodicity. Each fever event can be ended with one dose of steroids. To identify its pathogenesis, which remained unknown, we performed single-cell mRNA sequencing using PBMCs obtained from 4 patients at 4 time points during one event cycle and from 8 healthy children. At the febrile phase, patients exhibited hyper-inflammatory signatures in 3 monocyte clusters, including S100A12-low classical monocyte, non-classical monocyte, and S100A12-high classical monocyte, among total 21 clusters compared to the non-febrile phase of patients and healthy children. These three clusters had upregulation of gene sets associated with interferon (IFN) response. By steroid treatment, IFN response pathway was downregulated in the three monocyte clusters and CD16high NK cell cluster, suggesting that steroid treatment reduces IFN responses. Just before the febrile phase, patients exhibited increased expression of gene sets associated with response to GM-CSF. Taken together, our single-cell transcriptomic study identified that monocytes play a key role in the regularly periodic manifestation of PFAPA and are targets of therapeutic agents.
Single-cell analysis using Imaging Mass Cytometry spatially resolves immune activity in neurodegenerative brain pathology
Authors: Motta Vinicius , Zabinyakov Nick , Raza Qanber , Pfister Thomas D , Howell David , Parsotam Nikesh , Lim Liang , Loh Christina 
Published: November 2024

Abstract
Immune response plays a significant role in the progression of neurodegenerative diseases (NDs) such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and multiple sclerosis (MS). It is paramount to quantify the immune and structural spatial microenvironment of ND brain using research approaches that resolve tissue at a single-cell level. Imaging Mass Cytometry™ (IMC™) is a spatial biology technique that provides quantitative phenotypic evaluation of 40-plus markers.
We report the application of two new IMC imaging modes with 40-marker panels for ND research. Tissue mode (TM) was applied to perform a scan of the entire tissue followed by pixel-based analysis (PBA) to uncover spatial distribution of relevant markers. Preview mode (PM) was applied to sample the tissue at low resolution, improving informed selection of areas for high-resolution cell mode (CM) imaging on the same slide.
Using TM with PBA, we quantified the spatial distribution of immune cells in tissue compartments of ND tissues. PM and CM highlighted MS lesions devoid of myelinization and a network of α-synuclein in PD tissue. Single-cell analysis identified heterogeneity of amyloid precursor protein aggregates in AD that encompassed total and phosphorylated species of tau and phosphorylated α-synuclein. Overall, whole slide imaging techniques using IMC provide quantitative immunological and structural insights into the spatial biology of ND.
For Research Use Only. Not for use in diagnostic procedures.
Metabolism of Inflammatory T helper 17 cells from Type 2 Diabetic Patients
Authors: Ujagar Naveena , Sriram Trupti , Nicholas Dequina 
Published: November 2024

Abstract
Around 90% of the 537 million global diabetic adults suffer from type 2 diabetes (T2D), a metabolic disorder marked by heightened blood glucose due to insulin resistance or inadequate insulin production. T2D onset involves chronic systemic inflammation, predominantly influenced by T-helper 17 (Th17) cells. In T2D patients, defective fatty acid metabolic pathways contribute to Th17-driven inflammation. While lipid metabolism's role is established in in vitro Th17 cells, in vivo differentiated Th17 cells remain underexplored due to their low abundance. We addressed this challenge with a novel Th17 cell enrichment assay, capturing CD4+ T cells and magnetically purifying them based on IL-17A/17F/21 secretion for scRNAseq. From this transcriptomic data we established that the subsets of Th17 cells found in mice - pathogenic and non-pathogenic, are also present in humans, and that in vivo differentiated Th17 cells have a unique lipid metabolic phenotype from in vitro differentiated Th17 cells. We also characterized the metabolic state of these Th17 cells by utilizing the metabolic modeling algorithm Compass. Overlaying scRNAseq data from diabetic and control patients, we identified key lipid pathways driving Th17 inflammation in T2D. This pioneering study on endogenous Th17 cells in healthy and T2D patients, coupled with functional validation, unveils potential targets for developing immunotherapy for T2D.
TL1A drives Innate lymphoid cell-mediated granulopoiesis and colitis associated cancer
Authors: Sarmento Pires Silvia , Yang Wei , Loius Cynthia , Tran Nancy , Hassan-Zahraee Mina , Ye Zhan , Hyde Craig , Hung Kenneth , Ng Charles , Grier Alexander , Paddock Lucy , Cheing Jin , Live cell bank JRI , Targan Stephan , Niec Rachel , Josefowicz Steven , Dow Lukas 
Published: November 2024

Abstract
Inflammatory changes play an important role in tumorigenesis, and patients with chronic inflammatory bowel disease (IBD) are at an increased risk of developing colitis-associated cancer (CAC). Variants in TNFSF15, the gene that encodes TL1A, are associated with more aggressive IBD and advanced CRC. Here, we show that TL1A signaling is required for colitis-associated tumorigenesis and sufficient to promote CRC in mouse models. TL1A signaling in group 3 innate lymphoid cells (ILC3) promotes GM-CSF dependent activation of colonic neutrophils and colitis-associated tumors in mouse models. TL1A-mediated ILC3-dependent tumor-associated neutrophil (TAN) signatures were evident in mouse models and reduced in subjects with UC treated with anti-TL1A therapy. Furthermore, TL1A promoted ILC-dependent emergency granulopoiesis, which is similarly evident in IBD subjects with TNFSF15 risk variants. These results reveal a new mechanism by which TL1A signaling in tissue resident ILCs shape TANs and emergency granulopoiesis with the potential to guide emerging anti-TL1A therapies for IBD.
The role of 12/15-Lipoxygenase in myeloid cells during allergic fungal asthma
Authors: Makullah Mgayya , Ellis Diandra , Jones MaryJane , Steele Chad 
Published: November 2024

Abstract
Immunopathogenic mediators derived from the metabolism of arachidonic acid by lipoxygenases are often elevated in severe asthma. Using bone marrow chimeras, we previously reported that 12/15-lipoxygenase (12/15-LOX; Alox15) activity, specifically in hematopoietic cells, negatively contributes to airway hyperreactivity (AHR) during allergic fungal asthma. This warranted investigation into the role of 12/15-LOX in specific hematopoietic cell types during fungal asthma. CD11c is widely expressed on lung dendritic cells and alveolar macrophages. Surprisingly, deletion of 12/15-LOX in these cell types via Cd11c-Cre/Alox15fl/fl mice revealed no changes in AHR. In contrast, deletion of 12/15-LOX in neutrophils via Mrp8-Cre/Alox15fl/fl mice resulted in a small but significant reduction in AHR, suggesting that 12/15-LOX expressed by neutrophils drives immunopathogenesis during allergic fungal asthma. We further show that lungs from allergic Mrp8-Cre/Alox15fl/fl mice have a reduction in the total number of neutrophils, dendritic cells and gamma delta T cells compared to Mrp8-Cre controls. Changes in cellularity did not correlate with lung cell production of type 1, type 2 or type 17 cytokines, although specific growth factors and chemokines were lower in Mrp8-Cre/Alox15fl/fl mice. These results suggest that absence of 12/15-LOX in neutrophils is sufficient for regulating the magnitude of AHR during allergic fungal asthma, which correlated with cellular changes in the lung.
Immunology education in post-pandemic times-Hangover effects!
Authors: House Monique , Graefen Bahar , Raihan MD Obayed , Qasmieh Samah , Faridi Hafeez , Fazal Nadeem 
Published: November 2024

Abstract
Pandemic brought a different perspective to all ways of lives of all the people, and this included “Teachers” and “Learners” in educational world including Immunology education. We were also challenged with keeping the functional operations of our student organization alive during and after pandemic. The mission of our student chapter organization is to enhance Immunology education and encourage students to make an impact and showcase cutting science in our university. Our Facebook page during the pandemic attracted enormous visits not only by our own University students but national and even international visitors. Our Immunology student organization chapter worked in collaboration with the American Society for Microbiology (ASM) chapter during fall and spring semester. We organized tutorials, workshops, and virtual laboratories for the students. This was taken as an experiment and our data suggests that student learning, motivation, interest in immunology and educational outcomes were improved. The assessment results reported by Professor of Immunology suggest that both objective, as well as subjective educational and academic performance increased by 50% as compared to the same course taught last year. According to our data we suggest as Immunology education continues to embrace online pace, it is now more important than ever to engage with students via the social media platforms and it is well-known fact that the newer generation of students consume that the most.