bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative immunology protein panel built on the SomaScan assay platform
Authors: Katilius Evaldas , Keeney Tracy , Tabacman Eduardo , Liu Rong , Yearwood Graham , Schafer Peter 
Published: November 2024

Abstract
The SomaScan™ assay is a highly multiplexed proteomic assay that uses SOMAmer™ reagents to detect proteins in various biological samples. The latest version of the SomaScan assay allows researchers to measure over 11,000 proteins in human blood. The SomaScan assay is designed to provide protein epitope abundance measurements by reporting relative SOMAmer reagent abundance quantified using DNA microarrays. This is common for highly multiplexed proteomic assays but different from clinical protein assays, which report protein concentrations. We set out to develop a Quantitative Immunology Protein Panel (QuIPP) built on the SomaScan 7K assay, focused on a set of 58 immunologically-relevant cytokines, chemokines, and growth factors. Panel qualification was performed by developing calibration curves and demonstrating reproducibility for the biomarker measurements in serum samples with defined LLOQ and ULOQ acceptance criteria. Intra-run and inter-run CVs were calculated for high, medium, and low QC samples. 54 analytes met the standard curve, QC sample reproducibility, and plate edge effect acceptance criteria, with 34 analytes meeting strict parallelism acceptance criteria.
We have demonstrated the process for developing the QuIPP using SomaScan assay as a core technology. The ability to generate quantitative results will allow SomaScan users to compare protein concentrations across datasets and further validate biomarker discoveries on the SomaScan platform.
Purine catabolism regulates the production of IL-1beta in macrophages
Authors: Archambault Anne-Sophie , de Brito Monteiro Lauar , Starchuck Lucas , Oh Juhee , Perraso Emilia , Patterson Annette , Verchere C Bruce , Klein Geltink Ramon 
Published: November 2024

Abstract
Activation of pro-inflammatory (M1-like) macrophages leads to the production of pro-inflammatory cytokines, such as IL-1b, TNFa and IL-6. Those cytokines are important in the control of infections, but overproduction can lead to chronic inflammation. M1-like macrophages undergo metabolic remodeling, including the upregulation of purine metabolism. Using inhibitors of purine breakdown or purine synthesis, we aimed to identify the role of purine metabolism in M1-like macrophage function.
Blocking purine synthesis or purine breakdown did not affect the frequency of CD80+CD86+iNOS+macrophages, nor the accumulation of the M1-like macrophages hallmark metabolites itaconate and succinate, critical for immune function. However, inhibition of purine synthesis significantly reduced IL-1bsecretion. Mature IL-1b release is dependent on both transcriptional activation of the pro-IL1 gene and NLRP3-inflammasome. Blockade of purine synthesis sustained pro-IL1 transcription, an accumulation of pro-IL1b and significantly reduced caspase-1 activity. When purine degradation was inhibited, we observed no change in IL-1b production, but a reduced TNFa and IL-6.
In summary, purine metabolism is dispensable for the immunophenotype of M1-like macrophages, but it regulates macrophage cytokine production. Targeting specific nodes in purine metabolism in macrophages provides opportunities for immunomodulation in inflammatory diseases affected by pro-inflammatory macrophage-linked cytokines.
Tertiary Lymphoid Organs promote allograft rejection
Authors: Feizi Neda , Feizi Neda , Zhang Gang , Halesha Latha , Abou Daya Khodor , H. Oberbarnscheidt Martin 
Published: November 2024

Abstract
Tertiary lymphoid organs (TLOs) are ectopic lymphoid structures that arise in non-lymphoid tissues and are frequently observed in tissue affected by non-resolving chronic inflammation. If TLOs are beneficial or detrimental in transplantation is controversial. We investigate the role of TLO and LTbR in transplantation by manipulating the LTa-LTbR pathway.
Using a mouse allo kidney transplantation model, we found that preformed intragraft TLO are sufficient to precipitate rejection in recipients lacking all secondary lymphoid organs (SLO)(LTbRko). In WT recipients with a complete set of SLO, intragraft TLO accelerated rejection (MST=63 vs. 225 d). Donor grafts that cannot form TLO (LTbRko) prolonged allograft survival (MST 24 vs 11 d) in an acute kidney rejection model. Intravital imaging confirmed that T and B cell activation takes place in renal TLO upon migration of naïve T and B cells and prolonged interactions with dendritic cells. T cells produced IFNg and Confetti+/+ B cells clonally expanded within TLO.
In summary, intragraft TLO are sufficient for and accelerate allograft rejection. Local immune responses are initiated and maintained in intragraft TLO, while disruption of TLO formation in the allograft leads to prolonged allograft survival. TLO support T and B cell activation as well as local DSA formation. These findings highlight the importance of TLO in local immune responses with implications for cancer, autoimmunity and transplantation.
The role of virtual memory CD8+ T cells in pulmonary viral and bacterial infection
Authors: Li Dong-Lin , Lin Jr-Shiuan , Tai Chi , Xie Jia-Xun , Wang Ching-Chun , Lai Meng-Chih 
Published: November 2024

Abstract
Virtual memory CD8+ T (TVM) cells, also known as antigen-inexperienced T cells with memory phenotypes, have been reported to mediate bystander protection against primary infection. It is known that the expansion of TVM cells depends largely on IL-4; thus, we used α-galactosylceramide (α-GalCer), which activates invariant natural killer T (iNKT) cells to trigger a strong IL-4 response to expand TVM cells in mice. Whether expanded TVM cells could grant protection against influenza A virus (IAV) and Streptococcus pneumoniae (SPN) infections and the functions of TVM cells in the lungs in these settings remain unknown. Here, we revealed that TVM cells significantly increased in the respiratory tract after α-GalCer treatment and maintained for at least 14 days. In contrast, the percentage of iNKT cells has returned to basal levels at this time. Furthermore, α-GalCer treatment generated more effector functional CD8+ cells and the proportion of TVM cells in the cytokine-producing CD8+ cell population significantly increased in the lungs and mediastinal lymph nodes. Notably, α-GalCer treatment decreased the viral titer after mice were challenged with a high dose of IAV as well as significantly improved the survival of SPN-infected mice. These results suggested that the protection may be attributed to TVM cells. Therefore, we further established a reliable intranasal transfer model to investigate the direct role of TVM cells in pulmonary viral and bacterial infections.
Loss of TET2 increases cell number and reduces immunoglobulin CDR3 diversity in B-1 cells
Authors: Dennis Emily , Murach Maria , Blackburn Cassidy , Marshall Melissa , Root Katherine , Pattarabanjird Tanyaporn , Erickson Loren , Binder Christoph , Bekiranov Stefan , McNamara Coleen 
Published: November 2024

Abstract
Ten-Eleven Translocation-2 (TET2) is an epigenetic modifier and potent regulator of immune cells, yet its role in B-1 cell biology is largely unknown. B-1 cells protect against infection and clear apoptotic cells via the production of natural IgM. Our study analyzed B-1 cell subsets from mice with global knockout of TET2 compared to WT controls using flow cytometry to determine the frequency and number of B cell subsets, RNAseq to determine differences in global gene expression as well as BCR repertoire analysis, and ELISA to evaluate plasma IgM levels. Results revealed that mice with TET2-KO had elevated numbers of B-1a and B-1b cells in their primary niche, the peritoneal cavity, as well as in the bone marrow and spleen. Consistent with this finding, circulating IgM was elevated in TET2-KO mice compared to WT. We observed reduced expression in both heavy and light chain immunoglobulin genes, predominantly in B-1a cells from TET2-KO mice compared to WT controls. As expected, IgM was by far the most abundant isotype expressed by genes in B-1 cells. Yet, only in B-1a cells was there a significant increase in the proportion of IgM isotypes in TET2-KO mice compared to WT. Analysis of the CDR3 revealed an increased abundance of replicated CDR3 sequences in B-1 cells from TET2-KO mice, which was more clearly pronounced in B-1a compared to B-1b cells. The results from our study suggest that TET2 may regulate the pool of antigen-specific IgM-producing cells.
Modulation of neuromuscular function through extracellular traps in septic shock models
Authors: ADAM Lucille , Bourcier Camille , Emam Laila , Vinit Stéphane , Mansart Arnaud 
Published: November 2024

Abstract
Sepsis via innate immune system activation causes organ dysfunction. Among these, the central nervous system (CNS) is particularly affected by sepsis-associated encephalopathies. These symptoms are linked with the activation of microglia and leukocyte infiltration. These immune cells have been discovered to have the ability to produce extracellular traps (ETs). While these components capture and destroy pathogens, deleterious effects occur such as reduced neuronal excitability with excessive production. In this study, the objectives were to determine whether (1) immune cells form ETs in the CNS by using two models of sepsis: lipopolysaccharide (LPS) and cecal ligation and puncture (CLP); (2) ETs produce neuromuscular disorders, and (3) a threshold is necessary to produce these disorders. Our results demonstrate a systemic inflammation for both models. As expected, the LPS administration increases leukocyte infiltration into the CNS, activates immune cells and produces ETs, which directly impair the gastrocnemius motoneuron excitability. Sivelastat, an inhibitor of ET formation significantly decreases the production of ETs in immune cells and induces a preservation of the neuromuscular function without decrease of the inflammatory response. This infiltration of leukocytes and production of ETs is also observed using the CLP model, at a lower stage, without neuromuscular dysfunctions, suggesting that the CNS has an ET threshold in order to display these deleterious effects.
Allogeneic CD4+ iNKT cellular immunotherapy promotes anti-tumoral T cell responses in a human B-lymphoma xenograft model
Authors: Baiu Dana , Sharma Akshat , Schehr Jennifer , Basu Jayati , Smith Kelsey , Kenney Shannon , Gumperz Jenny 
Published: November 2024

Abstract
iNKT cells are innate-like CD1d-restricted T cells that mediate potent anti-tumor responses in murine models and have shown therapeutic potential in clinical trials. In humans, expression of CD4 delineates two functionally distinct iNKT cell subsets, with CD4- iNKT cells mainly producing TH1 cytokines and showing cytolytic activity, while CD4+ iNKT cells display a polyfunctional phenotype and are linked to regulatory pathways. Here, we used an EBV-driven B-lymphoma model to investigate the anti-tumor effects of these two iNKT subsets. In a live cell imaging system, CD4- iNKT cells carried out cell-mediated cytotoxicity and limited tumor spheroid growth in vitro, while CD4+ iNKT cells showed little anti-tumor activity. However, in a xenograft model, the effects of the two subsets were reversed. CD4- iNKT cells had no impact on tumor mass, which was likely due to down-regulation of CD1d by lymphoma cells in vivo. In contrast, administering CD4+ iNKT cells to tumor-bearing mice led to rapid reduction in tumor mass. CD4+ iNKT cells activated the expression of multiple co-stimulatory ligands by DCs, and human T cells from mice given CD4+ iNKT cell immunotherapy had enhanced responses against EBV. These results show that allogeneic CD4+ iNKT cell immunotherapy leads to potent anti-tumor activity in vivo that does not require tumor cell CD1d expression, and instead is associated with adjuvant-like activity that enhances anti-tumor responses by endogenous T cells.
Impaired NK cell-mediated antiviral responses to HIV following BCG vaccination: implications for neonatal vaccination
Authors: Gunasena Manuja , Alles Mario , Mulhern Will , Robinson Richard , Demberg Thorsten , Liyanage Namal 
Published: November 2024

Abstract
Bacillus Calmette-Guérin (BCG) vaccine is the only approved vaccine against tuberculosis (TB). BCG has been shown to elicit nonspecific protection as well as detrimental effects during diseases unrelated to TB. We investigate the impact of BCG on modulating NK cell responses and its effect on altering susceptibility to HIV acquisition. The C57BL/6 mouse model was used to compare splenic NK cell responses of control (n=4) and BCG vaccinated mice (n=4) following subsequent exposure to Mycobacterium bovis (Mtb) and HIV Gag peptide antigens. Statistical comparisons were made using Wilcoxon ranked sum test. The data acquired though flowcytometry suggested that mature, BCG trained memory-like (KLRG1+ Ly49H+) NK cells showed increased proinflammatory cytokine responses and polyfunctionality upon re-exposure to Mtb antigens. However, when these trained cells were exposed to HIV Gag antigen, we observed a significant reduction in cytokine production and polyfunctionality. Specifically, these BCG trained NK cells showed marked decrease in IFNγ, TNFα, IL1β and Granzyme B production alone or in combination (p&lt;0.05). Furthermore, negative correlations between NK polyfunctionality and mature BCG trained NK cells were observed, following HIV Gag peptide exposure. This suggests that NK cells are impaired in their antiviral effects during HIV exposure, soon after BCG vaccination. This may suggest higher risk of HIV acquisition in BCG vaccinated neonates that are frequently exposed to HIV.
Function of tissue-resident helper T cells in chronic lung sequelae following viral pneumonia
Authors: CHEON In Su , SON Youngmin , Narasimhan Harish , Im Jun-Sub , Vassallo Robert , Sun Jie 
Published: November 2024

Abstract
Respiratory viral infections such as influenza and SARS-CoV-2 can lead to the development of chronic lung disease and impaired lung function long-term after the recovery from acute morbidity. However, the mechanisms underlying the development of chronic diseases post-acute respiratory viral infection are largely elusive.
Using a model of age-related development of chronic lung disease after acute influenza infection, we found that a population of lung resident PD1HiCD4+ T helper cells (TRH), which exhibit characteristics of both follicular helper T cells and resident memory cells, was greatly increased after primary influenza pneumonia. Furthermore, TRH cells were located near the dysplastic/inflammatory lung parenchyma after the resolution of primary viral pneumonia. Strikingly, genetic ablation of TRH or the blockade of TRH-derived IL-21 signaling diminished chronic lung pathology and improved lung function following viral pneumonia in aged animals. Moreover, TRH cell presence was associated with worse lung function and increased lung pathology in COVID-19 convalescents. Our data suggest that exuberant TRH responses contribute to the development of chronic lung sequelae following viral pneumonia. Additionally, our findings may pave the way to develop novel preventive and/or therapeutic options treating chronic lung diseases following acute viral pneumonia including long COVID.
Intestinal ILC3 Activation by Commensal Bacteroides thetaiotaomicron: Implication for Liver Protection in Alcohol-Induced Liver Disease
Authors: Sriwastva Mukesh Kumar , Lei Chao , Xu Zhishan , Tan Yi , Deng ZhongBin 
Published: November 2024

Abstract
In recent years, there has been a growing recognition of the intricate interplay between the commensal bacteria Bacteroides thetaiotaomicron (Bt) and immune system. Among the various immune cell subsets, innate lymphoid cells (ILCs), group 3 ILCs (ILC3s) have particularly piqued the interest of researchers, as they appear to wield a significant influence in maintaining gut homeostasis. In order to understand if Bt mediates the crosstalk between intestinal epithelial cells (IECs) and ILC3 that prevents gut dysbiosis and liver injury in alcoholic liver disease (ALD), a disorder that causes lipid accumulation, liver damage, gut bacterial overgrowth and gastrointestinal mucosa dysfunctions, this study narrowed to the exploration of intricate relationship between Bt and ILC3s activation in the modulation of ALD. Bt supplementation leads to lower liver triglyceride content, prevent liver from steatosis, inflammatory lesions, relieves liver fat lesions and enhance intestinal. Bt enhances the Ahr activity and IL23 expression in IEC. The beneficial effect of Bt was abrogated in mice supplemented with Bt lacking capsular polysaccharides (CPS) and diminish AhR dependent IECs IL23 production and activation of type 3 innate lymphoid cells (ILC3). IL22-producing ILC3 cells improved gut homeostasis and this cascade ultimately results in enhance Mucin secretion, reduced systemic inflammation, hepatocyte apoptosis, and subsequently acute liver injury through the gut-liver axis.
LRRK2 Kinase Function Regulates NLRC4 Inflammasome Activity and Thereby Modulates Intestinal Inflammation
Authors: Deloer Sharmina , Fuss Ivan , Strober Warren , Suebsuwong Chalada , Kumar Kunal , Peter Inga , Devita Robert J 
Published: November 2024

Abstract
The LRRK2 protein associated with increased risk of IBD. Recently described, this protein influences NLRC4 inflammasome phosphorylation. This LRRK2 function, however, has uncertain significance since it is not clear how NLRC4 phosphorylation affects NLRC4 inflammasome function.This study utilizes commercially available LRRK2 inhibitors, to clarify this knowledge gap. In vitro studies showed that inhibition of LRRK2 kinase activity inhibits both its binding to NLRC4 and phosphorylation upon activation with needle protein, thus establishing that LRRK2 has an indispensable role for NLRC4 phosphorylation. later using THP-1 cells with ASC deletion or human PBMC-derived dendritic cells with shRNA ASC- KD showed that ASC deficiency retards NLRC4 phosphorylation. Finally, we found that inhibition of NLRC4 phosphorylation by LRRK2 inhibitors has a major negative effect on NLRC4 mediated IL-1b cleavage but, surprisingly, it has minor effect on IL-18 cleavage. This indicated that IL-1b expression requires ASC-caspase binding whereas IL-18 expression does not. Next, systemic administration of NLRC4 activator (flagellin protein) caused increased intestinal permeability and that co-administration of inhibitor reversed the increased permeability. These findings concluded that inhibition of IL-1b production with the preservation of IL-18 via LRRK2 kinase inhibition blocks the potentially harmful effects of NLRC4 activity on intestinal permeability during intestinal inflammation.
Highly multiplex volumetric imaging Ce3D-IBEX reveals commensal-induced immune clustering along sensory nerves in the lung
Authors: Ichise Hiroshi , Hor Jyh Liang , Arroyo-Mejías Armando , Jin Hao , Belkaid Yasmine , Ronald Germain 
Published: November 2024

Abstract
The airway mucosa is a primary site of the immune response to inhaled antigens. However, how immune homeostasis is maintained in this organ during continuous exposure to airborne particles and microbial antigens is not known. Previous studies have shown that the spatial organization of immune components in relationship to each other and to non-hematopoietic components in tissues is critical to their proper function. To interrogate such relationships in the lung, 3D information is required. However, current methods for fluorescence 3D imaging do not provide the marker depth afforded by high-content 2D imaging.
To overcome this constraint, we created Ce3D-IBEX, which enables the visualization of 30+ markers in an optically cleared 3D sample. Using Ce3D-IBEX, we have identified a previously uncharacterized immune cluster in the lung of naïve SPF mice that is enriched with T cells and dendritic cells (DCs) and is localized in close proximity to vagal sensory nerves. Agonistic denervation of the sensory nerves reduced the number of clusters, and that cluster formation was disrupted in germ-free mice as well as OT-I and OT-II TCR transgenic mice. These findings indicate that the clustering requires sensory nerve-derived signals and TCR-mediated recognition of bacterial antigens. Functional studies in virus-infected animals suggest that the T cells in these clusters behave like tissue resident memory T cells, providing acute antigen-independent effector activity.
Pre-clinical Pharmacology and Tolerability Characterization of a Novel KIRxICOS Targeting Bispecific CD8 Treg Modulator
Authors: Pham Thi Minh Nguyet , Bogatzki Lisa , Boster Dan , Bowser Justin , Childs Monica , Crane Courtney , Gardell Jennifer , Hermansky Gleda , Julien Susan , Meengs Brent , Quach Phoenicia , Tan Cathy , Therriault Jon , McMahan Catherine J , Swiderek Kristine M 
Published: November 2024

Abstract
Here we present an Fc-based bispecific CD8 Treg modulator that binds in cis to inhibitory KIR and ICOS receptors co-expressed by CD8 Treg designed to restore CD8 Treg functions. CD8 Treg dysfunctions include impaired cytotoxicity and insufficient longevity in autoimmune disease affected tissues. The KIRxICOS targeting bispecific molecule selectively enhances CD8 Treg killing, promoting their recruitment to and survival within disease affected tissues.
Through in vitro, ex vivo, and in vivo evaluations in humanized mouse models, we assessed binding, specificity, and function of the KIRxICOS CD8 Treg Modulator, which boosted ICOS signaling in KIR-expressing CD8 Treg, without activating immune cells expressing only ICOS. It extended survival and reduced disease score in a humanized acute GvHD model, marked by a reduction of activated CD4 T cells and an increase of CD8 Treg. In antigen stimulated tissues, the KIRxICOS CD8 Treg modulator reduced CD4 derived proinflammatory cytokines and epithelial cell death. In vivo, the KIRxICOS molecule demonstrated antibody-like PK parameters. Repeat dose studies in huNSG(IL15Tg) mice indicated good tolerability without terminal toxicity or induction of proinflammatory serum cytokines. The evaluation of binding, impact on immune cell phenotypes, and pharmacology revealed immune cell binding without activation.
Our preclinical data supports development of the KIRxICOS CD8 Treg modulator as a therapeutic in autoimmune disease.
Advancing CD19 CAR T Cell Therapy for Treatment of Primary Biliary Cholangitis
Authors: Sokke Umeshappa Channakeshava , Babu Kolla Harish , Hebbandi Nanjundappa Roopa 
Published: November 2024

Abstract
CD19 Chimeric Antigen Receptor (CAR) T cell therapy is emerging as a revolutionary approach in autoimmune disease management, offering a promising alternative to conventional treatments like anti-CD20 antibody therapy. Unlike challenges associated with existing therapies, CD19 CAR T cells, engineered to recognize CD19 molecules on B cells, exhibit remarkable efficacy in achieving targeted B cell depletion. Upon target recognition, they become activated, efficiently eliminating the harmful B cells. Furthermore, the CAR T cells exhibit a propensity for proliferation upon target recognition, thereby ensuring their prolonged presence within the body. Our findings unequivocally establish the effectiveness of CD19 CAR T cells in specifically targeting and depleting B cells, both in vitro and in vivo. In a well-established PBC model involving NOD.c3 mice, the application of CD19 CAR T cell therapy led to a remarkable reduction in liver pathology scores, indicating a substantial decrease in tissue damage and inflammation compared to control groups. Beyond liver autoimmunity, our research holds promise for treating other autoimmune conditions where B cells play a detrimental role. These insights pave the way for innovative therapies that have the potential to revolutionize autoimmune disease management, offering a hope for affected individuals and improving their quality of life.