bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptome analysis reveals distinct immune response profiles in HBeAg+ and HBeAg− HBV infection and in HBV/HDV co-infection
Authors: Park Heiyoung , Heller Theo , Rehermann Barbara 
Published: January 2023

Abstract
In chronic hepatitis B virus (HBV) infection, HBeAg positivity is associated with an increase in liver inflammation and progression to liver cirrhosis and cancer. Super-infection with hepatitis D virus (HDV) results in more severe liver disease. The causative factors are unknown. To understand the unique immunopathogenesis of HBeAg+ chronic HBV infection and chronic HBV/HDV co-infection, we performed a comparative transcriptome analysis using peripheral blood mononuclear cells of 12 HBV infected patients (6 HBeAg+ vs. 6 HBeAg−), 10 HBV/HDV co-infected patients, and 12 uninfected controls using NanoString human immunology V2 panel.
About half of the differentially expressed genes in HBeAg+ versus HBeAg− HBV patients were interferon-stimulated genes (ISGs), and 83% of these ISGs (5/6) were upregulated. Ingenuity Pathway Analysis identified IFNA2 and IFNL1 as the most activated upstream regulators associated with HBeAg+ status.
In contrast, only 7 out of 31 differentially expressed genes in chronic HBV/HDV co-infection compared to chronic HBV infection were ISGs, which were either upregulated or downregulated, indicating that IFN-signature is marginally involved in the pathogenesis of chronic HBV/HDV co-infection. Instead, Ingenuity Pathway Analysis identified CD40LG and IL18 as the most activated upstream regulators, and IRF activation by cytosolic pattern receptors and B cell receptor signaling as the top canonical pathways associated with chronic HBV/HDV co-infection.
Our data suggest that IFN signaling may play a role in the enhanced liver disease found in chronic HBeAg+ HBV infection, and that CD40LG and IL18 signaling may contribute to unique immunopathogenesis of chronic HDV/HBV co-infection.
Fecal microbiota transplantation provokes systemic host immune changes that drive the clearance of lethal disseminated pathogens
Authors: Kim Sangman Michael , DeFazio Jennifer , Hyoju Sanjiv , Krezalek Monika , Khodarev Nikolai , Sangwan Naseer , Gilbert Jack , Zaborina Olga , Jabri Bana , Alverdy John 
Published: January 2023

Abstract
After several iterations across medical disciplines, fecal microbiota transplantation (FMT) is now widely and effectively used to treat recurrent C. difficile infection. FMT normalizes the composition of the gut microbiota and is widely thought to mediate its protective effects by displacing pathogens in the context of the gut.
We have previously shown that the microbiome of patients with severe sepsis consists of a low-diversity pathobiome dominated by multi-drug resistant pathogens. To test the hypothesis that treatment with FMT would protect against sepsis, we employed a gut-derived sepsis model that involves inoculation of a pathogen community (PC) into the gut of surgically-stressed mice. Septic mice receiving FMT derived from healthy mice via enema exhibited a dramatic increase in survival accompanied by restoration of gut microbial diversity. Intriguingly, we observed that treatment with FMT led to alterations to the host transcriptome in extra-intestinal tissues.
Given the systemic effects of FMT administration, we next investigated whether FMT could influence survival in a model in which the PC was acutely disseminated via i.p. injection. Remarkably, administration of FMT in the gut markedly increased survival and drove the systemic clearance of pathogens. This suggests that the effects of FMT are not merely mediated by gut-confined colonization resistance, but also through the modulation of systemic host physiology in a way that is detrimental to pathogens. Comparative transcriptomics suggested that in both models the FMT rescue effect depends on the upregulation of the IRF3/Type I IFN signaling pathways, and using knockout mice we demonstrated that IRF3 is required for FMT-mediated protection and pathogen clearance.
Protein immunization induces T follicular helper memory cells and uncommitted Th0- like memory cells
Authors: Hale J. Scott , Harrison-Chau Malia , Novis Camille Leite 
Published: January 2023

Abstract
We have previously demonstrated that viral infection generates lineage-committed T helper 1 (Th1) and T follicular helper (Tfh) memory cells that preferentially recall their lineage-specific functions following secondary reencounter with virus. In this study, we analyzed antigen-specific T helper cell differentiation and memory differentiation following glycoprotein in adjuvant immunization and compared it to differentiation induced by acute LCMV infection. Similar to viral infection, protein immunization induced CXCR5+ memory Tfh cells that rapidly recalled Tfh cell function following reactivation, while differing in their expression of certain transcription factors such as Tbet. Protein immunization also induced CXCR5- non-Tfh effector and memory cells. Surprisingly, these non-Tfh memory cells had undergone memory differentiation, but had not undergone polarization toward any particular T helper cell lineage. Upon challenge with virus, these Th0-like memory cells were able to generate Th1 effector cells. Together, these data demonstrate that protein-immunization generates Tfh memory cells, in addition to Th0-like memory cells that are relatively undifferentiated toward the T helper cell lineages.
A 2nd generation antiviral T cell product for sustained immunological regeneration
Authors: Amini Leila , Schmueck-Henneresse Michael , Volk Hans-Dieter , Reinke Petra 
Published: January 2023

Abstract
Reactivation of persisting viruses is one major complication in immunosuppressed patients. Despite the availability of potent antiviral drugs for CMV infection/reactivation, sufficient T cell response is required to control the infection sustainably, particularly in case of drug resistance development. In these cases, novel treatment strategies such as adoptive T cell therapy are indispensable.
We developed an autologous approach of antiviral T cell therapy which efficiently reduced viral load and symptoms, however, CMV disease relapsed in about half of patients. Back-to-bench, we could figure out that the relapses were presumably due to the biased composition of this 1st generation T cell product which almost exclusively consisted of short-lived effector memory T cells (TEM). Therefore, a 2nd generation protocol was developed which enriches for more long-lived and highly proliferative central memory T cells (TCM) which showed better engraftment and survival in animal models.
We characterized this 2nd generation T cell product employing different cytokine regiments in long-term culture with regard to stability, expansion, specific killing abilities, metabolic properties and could show its superiority with regard to cell survival and resistance to Fas-induced apoptosis.
Furthermore, we showed that TCM enrichment mainly resulted from preferred expansion and inhibited differentiation of TCM from the starting population, but partially also from reprogramming cells from “later” memory subsets, i.e. TEM and RA expressing effector T cells, into the TCM phenotype.
Finally, we demonstrated the applicability of this protocol to blood samples from kidney transplant patients who were undergoing immunosuppressive treatment.
Title: Human mucosal-associated invariant T (MAIT) cells in inflamed tissues
Authors: Berkson Julia D , Slicter Chloe , Dutta Mukta , Oberbillig Haley , Prlic Martin 
Published: January 2023

Abstract
Mucosal-associated invariant T (MAIT) cells recognize bacterial metabolites via a semi-invariant T cell receptor (TCR) presented by MHC-like molecule MR1. Once activated, MAIT cells are a potent effector population with cytotoxic and pro-inflammatory properties. We recently reported that a TCR signal is not sufficient to elicit effector function, instead pro-inflammatory cytokines in addition to a TCR signal are required for sustained MAIT cell effector functions. We proposed that this requirement allows MAIT cells to distinguish between commensal (TCR signal only) and pathogenic bacteria (TCR signal + inflammation). We next wanted to address how MAIT cells function within an inflamed tissue environment. Specifically, if inflammation resulted in increased MAIT effector function or an exhausted phenotype because of the sustained stimuli. We obtained gingival tissue and matched blood from donors undergoing periodontic surgery for various inflammation-related diseases. MAIT cells within inflamed mucosa showed increased effector function directly ex vivo compared to blood including expression of granzyme B and TNFa. RNAseq analysis of MAIT cells from inflamed mucosal tissue revealed a distinct transcriptional signature compared to MAIT cells in the blood. We observed a significant upregulation of chemotaxis and activation genes as well as inhibitory genes from multiple immune-modulatory pathways. Our data suggest that MAIT cells in inflamed tissues can maintain effector function, but also express immunomodulatory genes that presumably serve to avoid unwanted tissue damage.
High mobility group box 1 (HMGB1)-RAGE interaction mediates ectopic Intestinal inflammation in NAFLD.
Authors: CHANDRASHEKARAN VARUN , SETH RATANESH K , DATTAROY DIPTADIP , ALHASSON FIRAS , ZIELONKA JACEK , CARSON JAMES , BERGER FRANKLIN , KALYANARAMAN BALARAMAN , Diehl Anna Mae , Chatterjee Saurabh 
Published: January 2023

Abstract
Recent clinical studies found a strong association of colonic inflammation with NAFLD yet the mechanisms remain largely unknown. The present study identifies HMGB1 as a key mediator of intestinal inflammation in NAFLD and outlines a detailed redox signaling mechanism for such a pathway. NAFLD mice showed liver damage and release of higher HMGB1 in systemic circulation, increased intestinal tyrosine nitration that was dependent on NADPH oxidase. Intestines from NAFLD mice showed higher TLR4 activation and proinflammatory cytokine release, an outcome strongly dependent on the existence of NAFLD pathology and NADPH oxidase. In vitro experimentation using IE6 cells showed the HMGB1 activation of Toll like receptor (TLR-4) was both NADPH oxidase and peroxynitrite dependent with the latter being formed from the activation of NADPH oxidase. Proinflammatory cytokine production was significantly blocked by the specific peroxynitrite scavenger Phenyl Boronic Acid (FBA), AKT inhibitor (LY294002) and NADPH oxidase inhibitor Apocynin suggesting NADPH oxidase-dependent peroxynitrite as a key mediator in TLR-4 activation and cytokine release via an AKT dependent pathway. Studies to ascertain the mechanism of HMGB1-mediatied NADPH oxidase activation showed a distinct role of RAGE as the use of inhibitors targeted against RAGE prevented NADPH oxidase activation, peroxynitrite formation, TLR4 activation and finally cytokine release. Thus in conclusion, the present study identifies a novel HMGB1 mediated inflammatory pathway that is RAGE and redox signaling dependent and helps promote ectopic intestinal inflammation in NAFLD.
Silencing Mutated Cxcr4 in Mouse Hematopoietic Stem Cells as a Genetic Cure Strategy Obviating Bone Marrow Conditioning in WHIM Syndrome
Authors: Gao Jiliang , Yim Erin , Siwicki Marie , McDermott David H , Murphy Philip M 
Published: January 2023

Abstract
Genetic cure of diseases caused by autosomal dominant (AD) gain-of-function (GoF) mutations could require full correction of the disease allele; however, selective inactivation of the disease allele might suffice or even be superior. To test the relative efficacy of these two strategies in WHIM syndrome, a rare combined primary immunodeficiency disease caused by AD GoF mutations in chemokine receptor CXCR4 leading to impaired release of mature leukocytes from bone marrow, we have performed competitive bone marrow transplantation experiments with Cxcr4+/+, Cxcr4+/o and Cxcr4+/S338X (WHIM model) mice. Here we show a whole bone marrow donor genotype rank order of Cxcr4+/o &gt;Cxcr4+/+&gt; Cxcr4+/S338X for repopulating the blood of lethally irradiated recipient mice. Importantly, the strong competitive advantage of transplanted Cxcr4 haploinsufficient bone marrow cells is durable, intrinsic to hematopoietic stem cells (HSCs) and evident in the blood at the level of cell frequency and total cell numbers in both the myeloid and lymphoid lineages in both irradiated and unconditioned congenic recipients. Mechanisms included enhanced engraftment of hyperproliferative Cxcr4+/o HSCs in irradiated recipients and enhanced release of mature Cxcr4+/o leukocytes to the blood in unconditioned recipients. These results provide proof of principle that inactivation of the CXCR4 disease allele in HSCs may be a safe, effective and superior genetic cure strategy able to obviate toxic bone marrow conditioning in patients with WHIM syndrome.
Identification of lysophosphatidylserine receptor P2Y10 as a novel G-protein coupled receptor mediating eosinophil degranulation
Authors: Chung Il Yup , Jeong Kim Hye , Mi Hwang Sae 
Published: January 2023

Abstract
P2Y10, along with GPR34 and GPR174, is a G protein-coupled receptor that is activated by lysophosphatidylserine (LysoPS), and its expression and function have not yet been described. We have previously shown that P2Y10 is one of the highly upregulated genes at the late differentiation stage during in vitro eosinophilopoiesis. In the present study, we examine the expression and functions of P2Y10 in human eosinophils. P2Y10 is increasingly expressed, as cord blood (CB) CD34+ cells differentiate toward eosinophils. Analysis of its expression in peripheral blood (PB) leukocytes shows that P2Y10 is the most highly expressed in the granulocytes among the major leukocytes in numbers, including lymphocytes, monocytes, and granulocytes. Importantly, PB eosinophils express this receptor much more strongly than PB neutrophils. In contrast, GPR34 and GPR174 are negligible on PB eosinophils, while being comparable to P2Y10 in PB neutrophils. LysoPS activates CB eosinophils to induce a robust ERK phosphorylation as profoundly as IL-5. LysoPS is able to trigger degranulation of eosinophil cationic protein (ECP) in PB eosinophils, and its capability of degranulation is significantly blocked by inhibitors of signaling or receptor molecules including ERK, TACE, and EGFR. Taken together, our data suggest that LysoPS provokes a proinflammatory functions of eosinophils likely through P2Y10, proposing P2Y10 as a potential therapeutic target to control eosinophil-associated diseases.
Identification of Interleukin 40, a novel B cell-associated cytokine.
Authors: Catalan-Dibene Jovani , Vazquez Monica Ivonne , Luu Van Phi , Nuccio Sean-Paul , Maravillas-Montero Jose Luis , Villalta Sergio Armando , Ushach Irina , White Clayton , Pone Egest , Raffatellu Manuela , Hernandez Marcela , Zlotnik Albert 
Published: January 2023

Abstract
We have identified a novel mouse and human cytokine. IL-40 is normally produced in the bone marrow and fetal liver, and by activated B cells. Its sequence predicts a small (~27kDa) secreted protein unrelated to other cytokine gene families, that we have called Interleukin 40 (IL-40). IL40 is only present in mammalian genomes, suggesting a role in mammalian immune responses. Accordingly, IL-40 expression is induced in the mammary gland upon the onset of lactation, and an IL-40−/− mouse exhibits reduced levels of IgA in the serum, gut, feces, and milk. Furthermore, the IL-40−/− mouse has smaller and fewer Peyer’s patches and IgA secreting cells. The gut microbiome of IL-40−/− mice also exhibits altered composition, reflecting the reduced levels of IgA in the gut. We have also determined that B cell precursor populations are altered in the IL-40−/− mouse. Taken together, these observations indicate that IL-40 represents a novel B cell associated cytokine, that plays an important role in the development of humoral immune responses. IL-40 is also expressed by human activated B cells and by several human B cell lymphomas. The latter observation suggests that it may play a role in the pathogenesis of these diseases.
The impact of IL-27 on human T cells is altered in multiple sclerosis patients
Authors: Clénet Marie-Laure , Beauseigle Diane , Devergne Odile , Duquette Pierre , Prat Alexandre , Arbour Nathalie 
Published: January 2023

Abstract
IL-27 exhibits pro- and anti-inflammatory properties. This cytokine dampens the severity of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Whether IL-27 plays a role in pathobiology of the human disease is still unresolved. We recently showed that both IL-27 and IL-27Receptor (IL-27R composed of IL-27Rα and gp130 chains) are elevated in MS brains compared to controls. We reported expression of IL-27R by brain-infiltrating CD4 and CD8 T cells in MS tissues. To determine whether IL-27 contributes to altered immune responses in MS, we investigated the impact of this cytokine on peripheral blood T cells obtained from untreated MS patients and age/sex-matched healthy donors. Surface IL-27R is present on lower proportions of effector memory (CCR7−) CD4 and CD8 T cells compared to naïve (CCR7+CD45RA+) and central memory (CCR7+CD45RO+) counterparts in all donors. However, reduced proportions of all CD4 T cell subsets but enhanced percentages of CD8 T cell subsets express IL-27R in MS patients compared to controls. IL-27 triggers rapid phosphorylation of STAT1 and STAT3 in all T cell subsets. The percentage and intensity of pSTAT1 detection in all T cell subsets were similar in both donor groups. In contrast, increased proportions of all CD4 and CD8 T cell subsets express pSTAT3 in response to IL-27 compared to cells from controls. Finally, elevated amounts of both IL-27 and its recently identified natural antagonist (soluble) IL-27Rα are present in serum from MS patients compared to controls. Thus, our results reveal that IL-27 has an altered impact on T cells from MS patients which could contribute to aberrant immune responses associated with this inflammatory/autoimmune disease of the central nervous system.
Modulation of Inflammation Induced by Recombinant MOMP of Chlamydia in Mouse Macrophages by IL-10 is Mediated by Skewing M1 to an M2 Polarizing Macrophage Phenotype
Authors: Duncan Skyla A. , Sahu Rajnish , Martin David , Singh Shree R , Dennis Vida 
Published: January 2023

Abstract
The major outer membrane protein (MOMP) of Chlamydia trachomatis (CT) is a very desirable vaccine candidate against CT because it stimulates robust T- and B-cell protective responses. Conversely, we showed that MOMP contributes to CT inflammation by stimulating macrophages to secrete pro-inflammatory cytokines that play pivotal roles in the pathogenesis of chlamydial diseases, and whose secretion levels are modulated by IL-10. We also showed that MOMP induced marked expression of the Socs3 gene in macrophages, correlating with its induction of pro-inflammatory cytokines, and its triggering of an M1 macrophage phenotype. Our goal in this study is to understand the inflammatory nature of MOMP by focusing on key chemokines (CCL5 and CXCL10), NO and Nod1/2 receptors, which are implicated in CT inflammation. We also evaluated their inhibition by IL-10 and its effect on M1 and M2 macrophage phenotypes. Mouse J774 macrophages were stimulated with recombinant MOMP (0.01–10 ug/mL) with/without exogenously added IL-10 (10 ng/mL); supernatants and RNA were collected for cytokine ELISAs, NO production and TaqMan gene expression analyses. Our results showed that rMOMP induced expression of CCL5, CXCL10, NO and Nod1/2 receptors that recognize and activate key inflammatory pathways, which were all modulated by IL-10. Characterization of macrophages revealed that rMOMP increased Nos2 expression, an M1 phenotypic marker, which was modulated by IL-10, suggesting skewing of the M1 phenotype whereas IL-10 upregulated M2 markers including, Arg 1 (and its isoform Arg 2) and Mrc1. Overall, our data helps in understanding the inflammatory nature of MOMP and the potential role played by M1 and M2 phenotypes in mediating IL-10 regulation of CT inflammation.
GM-CSF upregulates IL-15 expression on specific human myeloid cells.
Authors: Farzam-kia Negar , Duquette Pierre , Prat Alexandre , Arbour Nathalie 
Published: January 2023

Abstract
Although the salience of the immune system in multiple sclerosis (MS) pathology has been established, the mechanisms and mediators involved are incompletely characterized. We have identified IL-15, which aids in the development, activation, and survival of immune cells, as a relevant contributor to MS neuropathology. We previously showed that greater proportions of myeloid cells, including peripheral monocytes and brain macrophages/microglia, from MS patients express IL-15 versus controls. Thus, we aim to identify the factors that contribute to these elevated IL-15 levels in the context of MS. Primary human monocytes from MS patients and age/sex matched healthy donors are treated with M-CSF to trigger differentiation into macrophages (considered M0 macrophages) prior to being polarized into M1 or M2 macrophages. While a small proportion of M0 macrophages express IL-15, M2 polarization significantly enhances the percentage of IL-15+ macrophages. In contrast, M1 polarization does not affect IL-15 levels although it significantly increases MHCI and CD80 expression. GM-CSF is produced by pathogenic encephalitogenic T cells; monocytes and macrophages express the corresponding receptor (GM-CSF receptor). GM-CSF induces a major increase in the proportion of IL-15+ M0 and M2 macrophages from both donor groups. In contrast, GM-CSF does not modify IL-15 expression by monocytes although it induces STAT5 phosphorylation. In conclusion, GM-CSF is a potent trigger for IL-15 expression on M0/M2 macrophages but not monocytes. Moreover, M2 polarization of macrophages increases IL-15 expression. Identification of IL-15 triggers and further characterization of IL-15+ immune cells may provide novel targets for therapies for MS patients.
The CD8+ T-cell receptor (TCR) repertoire in extremely preterm neonates is highly shared and convergent
Authors: Carey Alison J , Hope Jennifer L , Fike Adam J , Mueller Yvonne M , Nguyen Linda T , Kumova Ogan K , Van Zessen David BH , van der Burg Mirjam , Katsikis Peter D 
Published: January 2023

Abstract
Neonates have an immunological immaturity which persists from fetal life into the newborn period and can result in a poorly protective response to intracellular pathogens. We have previously shown a less complex TCR repertoire may be responsible for reduced CD8+ T cell immunity in a neonatal murine model of influenza virus infection. Therefore, we sought to determine if there were similar differences in the TCR repertoire across the human life span. High-throughput sequencing of the TCRβ CDR3 regions was performed in sorted, naïve CD8+ T cells from extremely preterm (23–27 weeks gestation), term (39–40 weeks gestation), children aged 16 months to 4 years old, and adults aged 25–50 years (n=5 in each group). There were differences in the CDR3 length across the life span, with preterm infants having a shorter CDR3 length, which was due to fewer N1 and N2 additions (p&lt;0.01) than their term counterparts, which inherently decreases junctional diversity. There was no increase in trimming at the 5′ and 3′ ends of the VDJ genes across the lifespan. Preterm neonates had a striking number of shared clonotypes (8% of total clonotypes) versus their term counterparts (3%) and adults (1%). Convergent recombination describes the phenomenon that identical TCR specificities at the amino acid level can be obtained through different nucleotide sequences. Upon analysis of the most highly shared clones (common to at least 4 samples/age group), the preterm neonate had 12 nucleotide rearrangements per highly shared amino acid sequence, compared to 6 rearrangements at term and 5 in the adult. Our analysis demonstrates the prevalence of shared, convergent clonotypes within the preterm TCR repertoire suggestive of an antigen-driven shaping of the TCR repertoire in utero.