bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-15 Enables Septic Shock by Maintaining Natural Killer Cell Integrity and Function
Authors: Guo Yin , Luan Liming , Wang Jingbin , Patil Naeem , Bohannon Julia , Rabacal Whitney , Fensterheim Benjamin , Hernandez Antonio , Sherwood Edward 
Published: January 2023

Abstract
Interleukin-15 (IL-15) is essential for development, differentiation and function of natural killer (NK) and memory (m) CD8+T cells. Our lab previously showed that NK and CD8+T cells facilitate systemic inflammation and physiological dysfunction during septic shock. However, factors that regulate NK and CD8+T cell function during sepsis are not well characterized. We hypothesize that IL-15 promotes the pathogenesis of sepsis by maintaining NK and mCD8+T cell numbers and function. To test our hypothesis, the response of IL-15-deficient (IL-15 KO) mice to sepsis was assessed. IL-15 KO mice showed improved survival, attenuated hypothermia, and less pro-inflammatory cytokine production during septic shock caused by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS). Treatment with IL-15 superagonist (IL-15 SA, IL-15/IL-15Rα complex) regenerated NK and mCD8+ T cells and re-established mortality of IL-15 KO mice during septic shock. Preventing NK cell regeneration attenuated the restoration of mortality caused by IL-15 SA. If given immediately prior to septic challenge, IL-15 neutralizing IgG M96 failed to protect against septic shock. However, M96 caused NK cell depletion and conferred protection if given 4 days prior to septic challenge. IL-15 SA treatment amplified septic shock, which was prevented by NK cell or IFNγ depletion. IL-15 SA treatment also exacerbated septic shock caused by CLP if given after the onset of sepsis. In conclusion, endogenous IL-15 doesn’t directly augment the pathogenesis of sepsis but enables septic shock by maintaining NK cell numbers and function. Exogenous IL-15 SA exacerbates severity of sepsis by activating NK cells and facilitating IFNγ production.
Monocyte trans-differentiation in healthy and coronary artery disease patients is dependent on the affinity state of CD11c/CD18.
Authors: Hernandez Alfredo Alexander , Simon Scott I , Foster Greg , Fernandez Andrea , Singh Gagan 
Published: January 2023

Abstract
Mon2 CD14++CD16+subset of monocytes are central to the progression of coronary artery disease (CAD) by increasing their numbers in the circulation and upregulation of CD11c, which binds to endothelial VCAM-1 leading to recruitment to the nascent sites of plaque formation in arteries. In contrast, Mon1 CD14++CD16− monocytes are enriched within atherosclerotic plaques. We hypothesized that the number and affinity state of CD11c, which influences the capture efficiency and adhesion to inflamed endothelium, can regulate monocyte fate. Using a lab-on-a-chip assay to capture monocytes from whole blood samples under shear flow we examined the effect of antibodies that stabilize a high (HA) versus low affinity (LA) state of CD11c. In healthy subjects, we found that Mon2 have the capacity to differentiate into Mon3 CD14dimCD16++ (mean: .1 vs 6.79%, P&lt;.001) when stabilized with CD11cHA, or to a Mon1 monocyte (mean: 6.13 vs 36.82%, P&lt;.001) stabilized with CD11cLA. Healthy Mon1 spontaneously upregulate CD16, thereby taking on a Mon2 phenotype (~80% expansion to CD16+) in contrast to CAD Mon2 which progressively lose CD16 (50–60% reduction) and assume a Mon1 phenotype consistent with their fate in atherosclerotic plaques. Stabilizing CD11cHA maintained a Mon2 phenotype antagonizing the shift to Mon1 (mean: 62.37 vs 2%, P&lt;.01) in CAD monocytes. The loss of CD16 on adherent Mon2 monocytes and the conversion to Mon1 is consistent with the phenotype within atherosclerotic plaques. However, Mon2 gain of CD16 and progression to Mon3 in healthy patients suggests divergent pathway for homeostatic function. Taken together these data indicate a role for regulation of monocyte phenotype via outside-in signaling of CD11c on monocytes captured on VCAM-1.
Diversity of Human Monocyte Subsets Revealed by CyTOF Mass Cytometry
Authors: Hamers Anouk AJ , Thomas Graham D , Kim Cheryl , Hedrick Catherine C 
Published: January 2023

Abstract

Background
To date, 3 distinct human monocyte subsets have been identified based primarily on their expression of the surface markers CD14 and CD16. With the emerging knowledge of myeloid-derived suppressor cells and other myeloid subsets, we hypothesized that these monocytes were likely more heterogeneous in composition. Therefore, we set out to use the high dimensionality of mass cytometry to accurately identify and define monocyte subsets in blood of healthy humans.

Methods
Heparinized blood from 12 healthy humans was obtained and analyzed by CyTOF mass cytometry. We employed the Phenograph algorithm to cluster and identify all monocyte subsets based on their phenotypes using a 40-marker mass cytometry panel.

Results
Phenograph identified a total of 15 monocyte clusters based on cell phenotype. By performing hierarchical clustering, we were able to group the 15 clusters into 6 larger meta-clusters and found that most of these meta-clusters fall within the CD14hi classical monocyte population, illustrating significant heterogeneity among the classical CD14hi monocyte population in humans. We also identified two subsets of nonclassical monocytes of which one was high for both CD61 and CD9 expression, pointing to a possible role in cell adhesion/migration and platelet activation.

Conclusion
Monocytes are highly diverse with the conventional classical subset showing the most diversity. Studies of these new subsets should lead to greater understanding of functions of monocyte subsets in diseases.
Neonatal MDSCs compromise macrophage control of encapsulated bacteria
Authors: Robinson Cory , Gleave-Parson Madeline , Grimmett Juanita , Lyda Logan , Labuda Christopher 
Published: January 2023

Abstract
Limitations in innate and adaptive immunity have been described early in life that contribute to susceptibility to microbial infection. Interleukin (IL)-27 is a heterodimeric cytokine produced primarily by antigen presenting cells and suppressive toward a variety of immune cell types. We have shown in humans and mice that neonatal macrophages express IL-27 at an elevated level as compared with adults. In mice this was shown to be maintained through infancy. Using the mouse as a model system, we have recently shown that myeloid-derived suppressor cells (MDSCs) are more abundant in the spleens of neonatal and infant mice and contribute to elevated IL-27 levels in young mice. Functional studies demonstrate that these MDSCs express active nitric oxide synthase, phagocytic oxidase complex, and arginase-1. Few studies have investigated the influence of MDSCs on innate immune function during bacterial infection. Streptococcus agalactiae and Escherichia coli are significant concerns for newborns as common causes of sepsis. We investigated the influence of neonatal and infant MDSCs cultured with infected macrophages and show impaired macrophage control of S. agalactiae and E. coli. Furthermore, the suppressive effect of MDSCs on macrophage function requires IL-27. Inclusion of a soluble receptor to neutralize IL-27 promotes increased control of bacterial growth. Our data suggests that the effect of MDSCs and IL-27 involves a direct influence on macrophage effector functions since inflammatory cytokines such as TNF and IL-6 are not significantly altered by the presence of MDSCs. Taken together these results suggest that the increased abundance of MDSCs and IL-27 production may contribute to some of the limitations in early life immunity.
Using the Circulating Proteome to Assess Type I Interferon Activity in Systemic Lupus Erythematosus
Authors: Smith Michael Alexander , Chiang Chia-Chien , Sinibaldi Dominic , Zerrouki Kamelia , Manna Zerai , White Wendy I. , Kaplan Mariana J. , Hasni Sarfaraz , Siegel Richard M. , Sanjuan Miguel A. , Casey Kerry A. 
Published: January 2023

Abstract
Type I interferon (IFN) signaling drives pathology in systemic lupus erythematosus (SLE) and can be tracked via IFN-inducible transcripts present in whole blood as described by several IFN gene signatures. As SLE is a complex disease affecting diverse organ systems, we examined whether measurement of circulating proteins, which can infiltrate the bloodstream from afflicted tissues, might also offer insight into global IFN activity. The presence of anti-DNA autoantibodies in patient serum has prevented effective use of SOMAmers for the evaluation of circulating proteins in SLE. Here, we adapted protocols to mitigate for those autoantibodies and report high reproducibility and accuracy with 100% QC pass rate and improved correlation with previously validated multi-analyte platform results. Using SOMAmers together with the IFN 21-gene signature1 (IFNGS), we derived an IFN protein signature that can approximate the IFNGS score. In a cohort of 82 SLE patients and 48 healthy donors, the protein signature was found elevated above healthy donors for most of IFNGS-high patients (49/55, 89%) and also for a subgroup of IFNGS-low patients (7/27, 26%). The protein signature correlated with global disease activity (median SLEDAI score of 4 for the cohort) in both lymphopenic and non-lymphopenic patients. Significant associations with skin involvement, low complement, anti DNA auto-antibodies, and thrombocytopenia were also observed. In sum, our results suggest blood derived protein measurements may complement validated gene signatures to monitor IFN activity.
A combined genome-wide DNA methylation and mRNA expression analysis identified aberrant gene regulatory pathways in inflammatory myositis
Authors: Li Quanzhen , Luo Hui , Zhu Honglin , Zhu Chengsong , Wang Li , Zhang Huali , Zuo Xiaoxia 
Published: January 2023

Abstract
Inflammatory myositis (IM) is an immune-mediated inflammatory process primarily involving skeletal muscle and the etiology is still poorly understood. Clinical and molecular evidence indicated that the epigenetic regulation on mRNA transcription of immune cells may drive the pathogenic processing. In this study, we performed genome-scale DNA methylation and mRNA transcription profiling using Illumina HumanMethy450 and HumanHT-12 Beadchips on PBMC of 24 IM patients and matched normal controls (NC). We identified 617 genes showing altered DNA methylation between IM and NC. By integrating DNA methylation and mRNA expression data, we found 108 hypomethylated genes showing concurrent up-regulation and 43 hypermethylated genes showing decreased expression. Integrated pathway analysis indicated that these genes are involved in Th1/Th2 cell activation, arginine degradation, chemotaxis of neutrophils, granulocyte adhesion, cytotoxic T cell-mediated apoptosis, etc. Comparison of DNA methylation profile between dermatomyositis (DM) and polymyositis (PM) identified 66 altered genes which were shared in both DM and PM, 51 genes altered only in PM and 32 genes only DM. The genes which showed most significant hypomethylation and up-regulated are DYSF, IL1R2, OLFM4, ARG1, PDE6H, PPARG, MYB, and the most hypermethylated and down-regulated genes include CXCR6, ABLIM1, LAX1, PRKCH, CD3G and SLFN5. DYSF is a gene encoding dysferlin protein which may involve in the pathogenesis of myositis by interfering membrane repair in muscular dystrophy. Our analysis lays the groundwork for further molecular studies of IM by identifying novel epigenetically dysregulated genes potentially involved in the immune activation and muscular dystrophy.
Our Own Worst Enemy: Psychosomatic effects of perceived stress on IgA levels
Authors: Redmond Sarah , Biggs Erick , Blevins Kasey , Brimer Kelsey , Brown Cameron , Bryan Sandra , Burger Haley , George Anna , Hunt Mckenzie , Jannise Caitlin , Kesterson Melissa , Kwan Anthony , Marshall Jacob , Miller Kenzie , Mohamed Attia , Rajashekara Arpitha Mysore , Pagan Rachael , Peters Mary , Saenz Allison , Steeves Gregory , Stowers Samuel , Welch Nate , Williams Alexis , Williams Devonn , Wingfield Kyle , Zimmermann Krista 
Published: January 2023

Abstract
Our study is to determine and compare human IgA levels to self reported stress levels of college students and faculty at the beginning of the college semester, when stress levels are expected to be low, as compared to a later point in the semester, when stress levels are expected to be higher. This study is significant because the data will provide us with information regarding whether or not people are as biologically stressed as they report at different periods of the semester. Individuals are expected to be at a lower stress level at the beginning of the semester than at the end of the semester. Biological stressors are indications that the psychological and physical aspects of an organism are attempting to maintain an equilibrium in order to function properly. We are interested in quantifying biopsychological stressors between mental and physical stress responses and the effect of psychosomatic influence. To analyze samples for IgA molecules levels in comparison to proclaim stress levels to determine if students are as physically stressed as they are mentally feeling stressed. Stress was reported on a zero to ten scale and these reports will be compared to actual levels of human IgA attained from saliva samples. Geospatial coordinates have been taken to relate the data to location across campus. After a regression test, showing a P value of 0.206, it was clear that there was no significant correlation in the data. This tells us that, overall, the levels of IgA, and therefore stress, did not relate to the reported level of stress from the participants.
Macrophage Migration Inhibitory Factor Serves As an Upstream Regulator of NLRP3 Expression and Subsequent IL-1beta Production in Human Monocytes in Response to Lupus U1-snRNP Immune Complex
Authors: Shin Min Sun , Kang Youna , Leng Lin , Bucala Richard , Kang Insoo 
Published: January 2023

Abstract
The pathologic hallmarks of systemic lupus erythematosus (SLE or lupus) are altered immune responses to nuclear autoantigens with autoantibody production and subsequent tissue injury. TLR7/8 recognize the ssRNA of the self-antigen U1-small nuclear ribonucleorprotein (U1-snRNP) that is targeted by anti-U1-snRNP antibodies (Abs) in lupus. Recently, we showed IL-1β production from human monocytes (MO) exposed to a combination of U1-snRNP and anti-U1-snRNP Abs (snRNP immune complexes) via the NLRP3 inflammasome. Macrophage migration inhibitory factor (MIF), primarily produced from MO and macrophages, promotes the production of IL-1β, IL-6 and TNF-α, which are increased in lupus patients. Data showed an association between serum MIF levels and MIF gene polymorphisms with lupus-related organ damage and decreased glomerulonephritis in lupus-prone mice treated with MIF antagonists. Here we investigated the possible mechanisms underlying the functional link between MIF and the NLRP3 inflammasome. The snRNP immune complexes (ICs) induced high levels of MIF and IL-1β from freshly purified human MO. The small molecule MIF inhibitor MIF098, which interferes the binding of MIF to its receptor complex, decreased the production of IL-1β from MO in response to the snRNP ICs. The inhibitor substantially reduced the expression of NLRP3 and caspase-1 activation. This phenomenon is likely mediated in part by the suppression of NF-kB activation. Plus, exogenous MIF increased IL-1β production by the MO. Our results first show the production of MIF from MO by the lupus snRNP IC and the regulation of the NLRP3 inflammasome by MIF in human, providing a scientific rationale for translating animal studies targeting MIF into human lupus.
The Benzathine Penicillin G (BPG) reformulation preferences study - towards a new Pencillin for Rheumatic Fever and Rheumatic Heart Disease
Authors: Sika-Paotonu Dianne , Tiatia Ramona , Sung Yun K , Lander Lynette , Haira Tia , Thornley Craig , Betty Bryan , Wineera-Parai Ranei , Eddie Barbara , Baker Michael , Chrzan Keith , Maloney Margaret , Felix Manuel , Spector Jonathan , Carapetis Jonathan 
Published: January 2023

Abstract
Acute rheumatic fever (ARF) is an autoimmune condition caused by untreated Group A Streptococcal (GAS) infection of the upper respiratory tract (and possibly skin). Multiple or severe attacks of ARF can cause cardiac damage known as rheumatic heart disease (RHD). The most effective recommended treatment of ARF requires monthly intramuscular injections of Benzathine Penicillin G (BPG) known as secondary prophylaxis. The goal of secondary prophylaxis is to prevent GAS infections that may lead to the recurrence of ARF. Rates of adherence to secondary prophylaxis schedules are usually low due to the frequency and duration of injection, pain and access to proper and timely healthcare services. A less painful and longer acting BPG formulation would ideally help prevent ARF recurrence and improve compliance rates to this schedule. The purpose of this work is to explore the BPG reformulation preferences of children and teens currently receiving monthly BPG intramuscular injections, in addition to their families and healthcare providers. A software application has been developed that will explore the experiences of the groups who will then choose their ideal BPG formulation from a range of plausible formulations and associated dosing regimens. The software application has been optimized for use to ensure age and cultural appropriateness and also efficient data collection. Pretesting of the software has been undertaken which has received positive responses with the piloting stage initiated. This is the first time a software application has been successfully developed to collect qualitative and quantitative data on individual preferences for BPG formulations and dosing regimens.
A Fast, Flexible and Low Cost Process for Neo-Epitope Based Immune Monitoring
Authors: Castro Aaron , Derhovanessian Evelyna , Luxemburger Ulrich , Beck Michaela , Gehring Franziska , Wenschuh Holger , Zerweck Johannes , Kern Florian , Reimer Ulf , Sahin Ugur 
Published: January 2023

Abstract
Advances in genomic technologies have paved the way to developing personalized cancer vaccines targeting neo-antigens. Patient-specific vaccines, targeting several neo-antigens in one go have already entered the clinic. Such personalized, multi-target approach poses a challenge for immune monitoring of vaccine-specific T-cell responses in a fast, flexible and cost-effective fashion.
Most immune monitoring protocols use 9–15-mer synthetic peptides originating from the vaccine target antigen. In contrast to detection of shared antigen-specific T-cells, for which the same peptide batch can be used for several patients, immune monitoring of individual neo-antigen-specific T-cell responses requires small amounts of large numbers of peptides (e.g. 40 × 15-mer peptides for 10 neo-epitopes of 27 amino-acids), which can only be used for one single patient. Therefore, standard peptide synthesis approaches applying commercial peptide synthesizers not only lack required throughput and speed but also generate peptides at prohibitive costs. Here, we present data demonstrating the flexible application of our high-throughput, low cost FastTrack peptide synthesis approach in comparison with different specifications of standard peptides in ex-vivo ELISPOT to monitor neo-antigen specific immune responses in patients participating in the IVAC MUTANOME Phase I clinical trial (NCT02035956). Application of the new peptide synthesis method enables the assembly of up to 1200 peptides in less than 3 weeks at appr. 20% of standard synthesis costs.
Development of a powerful next-generation immunoassay platform for low level detection of serum based analytes
Authors: Bourdon David M , Meng Lihao , Alohali Madhawi , Freeman Alisha , Le Lucas , Messina Jessica 
Published: January 2023

Abstract
Early detection of protein biomarkers is critical to the study of human disease (e.g. cancer, inflammation/autoimmunity, neurodegeneration). Basic research scientists as well as translational investigators require powerful protein quantitation tools that provide sensitive low-level detection of disease relevant protein analytes.
ELISAs first developed in the 1970s and slightly improved upon over the years are still considered the gold standard, yet large sample consumption, limited sensitivity, and laborious workflows, leave room for improvement and innovation.
Thermo Fisher Scientific, the worldwide leader in life science tools for researchers, is unveiling an affordable new platform for the next generation of high-sensitivity, ready-to-use immunoassays. Featuring serum compatible, TaqMan™ based Proximity Ligation Assay (PLA) and SiteClick™ antibody labeling technologies, this new assay combines the analyte specificity of high affinity antibody-antigen binding with the signal detection and amplification of real-time PCR.
Key benefits of this platform include: - Greater sensitivity and dynamic range than traditional methods- Smaller sample consumption than traditional methods: 1–2 uL per sample- A fast, simplified workflow - 2 hr. sample-to-answer with no wash steps- The inclusion of an intuitive, robust multi-OS data analysis software- Workflow compatibility with any real-time PCR instrument
Here, we highlight the immunoassay performance including sensitivity, dynamic range, spike-recovery, parallelism, linearity of dilution, and benchmarking to ELISA, all analyzed using a new software available through the Thermo Fisher Cloud.
Enhancement of antigen-specific Natural Killer cell ‘memory’ by removal of a viral innate immune signalling inhibitor
Authors: Ren Hongwei 
Published: January 2023

Abstract
Previous analysis of the vaccinia virus (VACV) K7 protein showed that this protein has a Bcl-2 structure, inhibits the pathways leading to activation of IRF3 and NF-κB and contributes to virus virulence. Here we show that infection with a VACV lacking the K7 protein (vΔK7) induced weaker VACV-neutralising antibody responses 1 month post infection, but still provided better protection against intranasal challenge with VACV. This implied a role for cellular immunity. By transfer of NK cells or CD8+ T cells to recipient mice and subsequent challenge with VACV, it was demonstrated that the NK cells from mice infected with vΔK7 induced better protection against challenge, compared to NK cells derived from wild type immunised mice. In contrast, adoptive transfer of CD8+ T cells from mice immunised with either virus conferred equal protection. In recipient mice, the NK cells transferred from vΔK7-infected mice were more responsive to homologous virus challenge and showed enhanced migration to the site of infection. By staining donor cells with CFSE prior to adoptive transfer, it was seen that donor NK cells proliferated greater in response to VACV than influenza challenge, and NK cells from vΔK7-immunised mice enhanced this effect compared to NK cells from wild type immunised mice.
This study shows that VACV-specific NK memory cells can confer protection against VACV challenge and that the production of these memory cells is enhanced by deletion of the VACV K7 protein.