bluuebunny/crossref_metadata_2025_split huggingface dataset:
Innate Immune Signaling Pathways in Reactome (94.13)
Authors: Haw Robin , Caudy Michael , Croft David , Garapati Phani , Gillespie Marc , Jassal Bijay , Jupe Steven , Kanapin Alexander , Mahajan Shahana , Matthews Lisa , May Bruce , O'Kelly Gavin , Schmidt Esther , Shamovsky Veronica , Wu Guanming , Birney Ewan , Hermjakob Henning , D'Eustachio Peter , Stein Lincoln 
Published: January 2023

Abstract
Toll-like receptors (TLR) play a key role in the innate immune system, providing vertebrates with a critical first line of defense against invading microbial pathogens. With the increasing body of molecular data relating to TLR function, organizing this information is useful to biologists and immunologists. We have used Reactome (www.reactome.org), a manually curated pathway database, to organize TLR data so that it can be viewed like an electronic textbook. TLR signaling cascades were authored by experts, maintained by the Reactome editorial staff and cross-referenced to publicly available bioinformatics resources. The Reactome data model generalizes the concept of a biochemical reaction to encompass any transformation of an input set of physical entities into an output set, and thus allows us to integrate TLR cascades with other innate immune processes, adaptive immunity, metabolic pathways, and other signaling processes. Since TLR-signaling molecules and pathways and the signaling pathways they initiate are highly conserved, Reactome provides pathway inference for 22 species based upon improved orthology prediction methods. A new entity-level pathway viewer and pathway analysis tools facilitate searching and visualizing pathway data and the analysis of user-supplied high-throughput data sets. All data content and software can be freely used and redistributed under open source terms.
The Role of NK/DC cross-talk in HIV pathogenesis (94.5)
Authors: Valentin-Torres Alice , Bernstein Helene 
Published: January 2023

Abstract
NK and dendritic cells(DCs) interact with each other inducing reciprocal activation and maturation of both cell types. Interactions between NK cells and DCs are important in controlling viral and bacterial infections. Furthermore, NK/DC interactions potentially link the innate and adaptive immune response via NK cell maturation of DCs. Our laboratory previously identified CD4-expressing NK cells. Using an NK/DC co-culture system, we find that both autologous immature and mature DCs(mDCs) induce CD4 expression on NK cells. CD4 expression requires cell to cell contact and is dependent on the NK/DC ratio. Cellular activation is bidirectional, as CD4+ NK cells induce dendritic cell maturation as assessed by enhanced CD40, CD83, CD86, and HLA-DR expression. Moreover, CD4+ NK cells up-regulate co-stimulatory molecule and HLA-DR expression, better than CD4- NK cells, beyond levels seen in LPS matured DCs. These findings can impact HIV pathogenesis, as mDCs are capable of transferring HIV virus to T cells, a process called trans-infection. We also find that mDCs can trans-infect CD4+ NK cells with HIV, providing a potential mechanism for in vivo HIV-infection of NK cells. In summary, NK/DC crosstalk results in reciprocal activation, including induction of CD4 expression on NK cells and DC maturation. CD4+ NK cells are susceptible to HIV infection, and can be trans-infected by mDCs, supporting a critical role for NK/DC interactions in HIV pathogenesis.
Pigment epithelium-derived factor (PEDF) is an endogenous inflammatory factor (94.6)
Authors: Chavan Sangeeta , Hudson LaQueta , Li Jianhua , Ochani Mahendar , Tracey Kevin 
Published: January 2023

Abstract
Obesity is a major risk factor for conditions ranging from metabolic syndrome and type 2 diabetes mellitus to atherosclerosis. Low grade inflammation leading to insulin resistance is a central feature of the pathophysiology of most obesity-related disorders; however the factors linking these disorders are not well defined. Here a potential mediator of inflammation is identified and characterized in animal models. We identified pigment epithelium-derived factor (PEDF), a noninhibitory serine protease inhibitor, as a mediator released from cultured adipocytes. Adipocyte PEDF levels were elevated after treatment with TNF. Addition of adipocyte-conditioned media to macrophages resulted in increased proinflammatory cytokine production, and this activity was recapitulated by addition of recombinant PEDF to macrophages in culture. PEDF administration to mice mediated increased serum levels of TNF and IL6, and administration of neutralizing PEDF antibodies attenuated this cytokine release. Animals injected with recombinant PEDF developed insulin resistance. Considering these observations, in light of the recently reported elevated levels of circulating PEDF in patients with type 2 diabetes and metabolic syndrome, indicates that adipocyte secreted PEDF may contribute to the development of chronic inflammation and insulin resistance observed in obesity.
Cigarette smoke suppresses the anti-viral capacity of dendritic cells (94.7)
Authors: Castro Shawn , Guerrero-Plata Antonieta 
Published: January 2023

Abstract
The innate immune system is the first line of host defense and against viral pathogens via effector molecules, such as type-I interferon (IFN-α/β). Plasmacytoid dendritic cells (pDC) and monocyte-derived DC (moDC) are potent producers of IFN in response to viruses through the respective activation of recognition toll-like receptors (TLRs) and cytosolic RNA helicases MDA5 and RIG-I. Exposure to environmental tobacco smoke (ETS) is a risk factor associated with an increase in the frequency and severity of respiratory infections. However, the mechanisms by which ETS alters innate immune responses have not been fully elucidated. Therefore, we investigated the ability of pDC and moDC to respond to respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) in the presence of cigarette smoke extract (CSE). In viral infected pDC and moDC, CSE led to a significant dose-dependent decrease in IFN-α production and in pDC alone cytokines IL-10 and IP-10. CSE treatment attenuated IFN induction by TLR agonists TLR7 and TLR9 in pDC and TLR3 in moDC. CSE also significantly decreased TLR7 and TLR9 gene expression in viral infected pDC. In hMPV infected moDC, the presence of CSE down regulated the gene and protein expression of both MDA5 and RIG-I and phosphorylation of PKR regulated eukaryotic initiation factor-2alpha (eIF2α). Overall, these findings provides novel evidence of the IFN signaling pathways abrogated by CSE in viral infected pDC and moDC.
Stress-induced increases in bacterial killing are p38 dependent (94.9)
Authors: Allen Rebecca , Stiner La'Tonia , Hufnagle Amy , Galley Jeffrey , Sheridan John , Bailey Michael 
Published: January 2023

Abstract
Social Disruption (SDR), a murine social stressor, results in an increased reactivity of splenic CD11b+ macrophages to inflammatory stimuli. For example, SDR leads to increased cytokine production and glucocorticoid insensitivity upon lipopolysaccharide stimulation. Moreover, SDR enhances the ability of these macrophages to kill Escherichia coli partly through TLR4-induced expression of inducible nitric oxide synthase (iNOS). The MAPK p38 has extensive known relationships to a number of these SDR characteristics and previous work has also shown that levels of phosphorylated p38 are increased in CD11b+ splenocytes following SDR. As such, p38 is a likely common link among these various stress-induced immunological changes in this model. These experiments were designed to test the hypothesis that inhibiting p38 would significantly reduce the stress-induced increase in killing of E. coli. SDR normally significantly (p &lt; 0.05) increases the percentage of bacteria killed; however, when p38 is inhibited, we found that the percentage killed is reduced to baseline. Additionally, iNOS expression in stressed animals stimulated with E.coli is significantly enhanced in SDR-exposed splenocytes but, p38 inhibition eliminated this increase. Taken together, the negation of the enhanced killing effect and significant decrease in iNOS expression following p38 inhibition supports the hypothesis that the MAPK p38 has an important role in the stress-induced increase in bacterial killing.
ISG15 as a Novel Target for Tumor Immunotherapy (95.13)
Authors: Wood Laurence , Seavey Matthew , Pan Zhen-Kun , Paterson Yvonne 
Published: January 2023

Abstract
Passive immunotherapy is widely used in the treatment of cancer, however, active therapeutic vaccination is achieving increased effectiveness in clinic trials and in preclinical models of cancer. Our laboratory specializes in constructing therapeutic cancer vaccines that utilize Listeria monocytogenes (Lm) as a vector to induce a strong CTL response against tumor-associated antigens (TAAs) when fused to non-hemolytic Listeriolysin O (LLO). Recently, elevated expression of ISG15, an ubiquitin-like protein, has been found in human breast cancer cell lines and clinical breast cancer. After confirming elevated expression of this potential TAA in murine breast cancer models, we constructed an Lm vaccine targeting cells with elevated expression of ISG15. Our recombinant Lm vaccine, Lm-LLO-ISG15, produces and secretes a fusion protein of LLO and ISG15 proficiently. After tumor implantation and subsequent vaccinations, Lm-LLO-ISG15 significantly slowed tumor growth and reduced metastatic lung lesions in comparison to a non-specific Lm control vaccine. In addition, prior vaccination with Lm-LLO-ISG15 offered some protection against implantable tumor challenge and reduced time to tumor progression in a mouse model for sporadic breast cancer. Further work has identified two hypothetical ISG15 H2d-restricted CD8 T cell epitopes. Additional work to determine the mechanism of Lm-LLO-ISG15 anti-tumor efficacy is being pursued.
TGFβ1 Modulation of Inflammation in Premalignant Squamous Lesions is IL-17-dependent and Independent (95.5)
Authors: Mohammed Javed , Ryscavage Andrew , Perez-Lorenzo Rolando , Gunderson Andrew , Blazanin Nicholas , Glick Adam 
Published: January 2023

Abstract
The proinflammatory functions of TGFβ1 are dependent on the local cytokine milieu. Overexpression of TGFβ1 in epidermis provokes an inflammatory response in the skin while its role in skin tumors is still not clear. To evaluate the effects of TGFβ1 in modulating inflammatory cytokine production, we overexpressed TGFβ1 in premalignant primary keratinocytes derived from an inducible TGFβ1 transgenic mouse. TGFβ1 induced expression of TNFα, IL-1β and IL-23a in vitro and conditioned media from these cells polarized naïve T cells to a Th17 phenotype that was dependent on TGFβ1 signaling. Overexpression of TGFβ1 in premalignant squamous lesions resulted in an increase in IL-17 production by CD4+ and γδ+ T cells as well as rapid regression of the tumors. Microarray analysis of gene expression following induction of TGFβ1 in premalignant skin tumors indicated a significant upregulation of proinflammatory genes at day 2. This was followed by an increase in MPO+, F4/80+ and CD8+ cells in the tumors and increase in CD8+ effectors and IFNγ+ cells in the skin draining lymph nodes at day 5. Concomitantly, the percentage of tumor CD11b+Ly6G+ cells was reduced in TGFβ1 overexpressing tumors. Neutralization of IL-17 blocked TGFβ1 induced CD11b+Ly6g- macrophage infiltration in the tumor but did not alter the reduction of CD11b+Ly6g+ cells or tumor regression. Thus, TGFβ1 overexpression causes IL-17 dependent and independent changes in the premalignant tumor inflammatory microenvironment.
Effective prevention and therapy of ovarian cancer with sperm protein 17 vaccination (95.7)
Authors: Chiriva Maurizio , Yu Yuefei , Mirandola Leonardo , Jenkins Marjorie , Chapman Caroline , Cannon Martin , Cobos Everardo , Kast W. Martin 
Published: January 2023

Abstract
Sperm protein (Sp17) is an attractive target for cancer vaccines because of its over-expression in primary and metastatic ovarian cancer (OC). Our studies suggest that a Sp17-based vaccine can induce an enduring defense against OC development in C57BL/6 mice with ID8 OC cells, following prophylactic and therapeutic treatments. Our results show that a SP17 protein based vaccine combined with CpG induced an effective CD8 mediated immune response against Sp17 protein. This is the first time that a mouse counterpart of a cancer testis antigen (Sp17) was shown to be expressed in an OC mouse model. and that vaccination against this antigen significantly controlled tumor growth . The CpG-adjuvanted vaccine are activating Th17 cells while inhibiting immunosuppressive T-reg cells, suggesting a reprogramming of active cellular-mediated response against Sp17-expressing tumor cells. Taken together, these results indicate that prophylactic and therapeutic vaccinations can induce long-standing protection against OC and delay tumor growth, suggesting that this strategy may provide additional treatments of human OC and the prevention of disease onset in women with a family history of OC.
Cannabinoid receptors as novel targets in the treatment of T cell-mediated fibrosis (96.26)
Authors: Kanada Shunsuke , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
Liver diseases are one of the main causes of mortality in the world, especially chronic hepatitis leading to the development of liver cirrhosis or liver cancer. Previous studies have shown that natural cannabinoids such as Δ9-tetrahydrocannabinol (THC) exhibit immunosuppressive and anti-inflammatory properties. In this study, we investigated the effect of THC on chronic hepatitis caused by repeated toxic insult. For the chronic hepatitis, ConA or CCl4 was administered to the C57BL/6 mice for several weeks. THC was injected after every toxic insult. Livers were collected for the histological assessment and hepatic cells were harvested for flow cytometric analysis to characterize the nature of hepatic inflammatory cells. Fibrosis related gene expression in injured liver was investigated by real time PCR. The results showed that THC treatment suppressed the mRNA expression of liver fibrosis markers and flow cytometric analysis suggested that THC treatment decreased the inflammatory cell accumulation in the liver in ConA-induced model. On the contrary, THC did not suppress the progression of fibrosis in CCl4-induced model. Together, these results demonstrated that THC can suppress chronic autoimmune hepatitis but not chemical-induced hepatitis and that cannabinoid receptors can be the new therapeutic targets preventing immune cell-mediated liver injury (Supported in part by NIH grants R01AI053703, R01ES09098, R01 AI058300, R01DA016545, R01HL058641, R01ES019313 and P01AT003961)
OR3: an anti-TCR autoantibody and immunomodulation (96.7)
Authors: Ranganathan Parvathi , Schluter Samuel 
Published: January 2023

Abstract
The presence of low levels of circulating self-reactive autoantibodies (AAbs) is a normal feature of a healthy immune system. One suggested function for autoantibodies is the control of autoreactivity and immune homeostasis. Healthy humans spontaneously express low levels of serum AAbs directed against defined epitopes of the T Cell Receptor (TCR) Vβ chains that can be markedly elevated in individuals with autoimmune diseases such as Rheumatoid Arthritis (RA). Here, we describe a monoclonal IgM AAb, OR3, derived from peripheral blood B cells of a patient with RA. OR3 was selected for its ability to bind to residues 23-38 of the complementarity determining region 1 (CDR1) segment of human Vβ8.1. It binds to Jurkat T cells expressing human Vβ8.1 and to ovalbumin-specific transgenic murine DO11.10 T cells. OR3 significantly reduces ova peptide stimulated activation of DO11.10 CD4+ T cells and inhibits IFN-γ, IL-2 and IL-10 cytokine secretion by antigen specific DO11.10 T cells. OR3 also blocks antigen induced proliferation of DO11.10 T cells, but does not initiate apoptosis. The interaction between the TCR and MHC:peptide is a critical point in the activation of the adaptive immune response, disruption of which, can lead to a global dampening of the immune response. We show evidence for the development of a unique anti-TCR autoantibody that binds to only a subset of T cells and possesses potent blocking and anti-inflammatory properties that can be harnessed for therapeutic use.
Induction of regulatory T cells by a novel immunoregulatory therapy suppresses the development of allergic airways disease (97.10)
Authors: Thorburn Alison , Foster Paul , Gibson Peter , Hansbro Philip 
Published: January 2023

Abstract
Evidence suggests that exposure to Streptococcus pneumoniae may be protective against asthma. We have identified key S. pneumoniae components that form an immunoregulatory therapy (IRT) and suppress the development of allergic airways disease (AAD) using mouse models. AAD was induced in adult BALB/c mice by intraperitoneal sensitization and intranasal challenge with ovalbumin. At the time of sensitization, the IRT was administered intratracheally. IRT treatment suppressed hallmark features of AAD including eosinophil influx, local and systemic Th2 cytokines, airways hyperresponsiveness and mucus hypersecretion. A time course analysis showed that the IRT induced CD4+CD25+Foxp3+ Tregs in the lymph nodes 4 days post treatment. This was associated with increased IL-2, TGF-β and Foxp3 expression in the lungs. IRT treatment also increased the proportion of CD4+CD25+/- cells expressing Foxp3 in the lungs and expression of markers associated with Treg function, during the induction of AAD. Anti-CD25 administration 3 days before IRT treatment abolished the suppressive effects on AAD. However, anti-CD25 administration 9 days after IRT treatment had no effect. This indicated a requirement for IL-2 signalling via CD25 (IL-2R) during the induction of Tregs by the IRT treatment. In conclusion, a S. pneumoniae-based IRT induces CD25-dependent Tregs, suppresses the development of AAD and may be useful as a novel therapy for asthma.
Role of IL-17 in a murine model of allergen immunotherapy for allergic asthma (97.5)
Authors: Boehm Livia , Soo-Becker Kinga , Übel Caroline , Schuster Petra , Karwot Roman , Lehr Hans-Anton , Schild Hansjörg , Finotto Susetta 
Published: January 2023

Abstract
Human studies have demonstrated that allergen specific immunotherapy (IT) is validated for allergic diseases. IT involves repeated subcutaneous administration of the allergen following allergen sensitization. We now established a mouse model in which subcutaneous applications with allergen suppressed the asthma-like manifestations. In this model we found an antigen dependent decrease of airway hyperresponsiveness, IgE and lung eosinophils mediated inflammation as compared to untreated mice. Consistently, Th2 as well as Th17 type cytokines were found to be reduced in the lung of antigen treated mice. Moreover, we found that this established subcutaneous immunotherapy decreased the number of lung gamma-delta (γδ)+IL17+ T cells. IL-17 production by αβ T helper cells (Th17) and the conditions of their development received much attention over the last few years, however the role of IL-17-producing γδ T cells was not fully investigated. In fact, it has been recently reported that γδ T cells represent a vast majority of IL-17-producing cells in murine lung. Revealing the role of IL-17 and lung γδ+ IL17+ T cells in asthma and in an immunotherapy model will probably lead to therapeutical improvement for this disease.
Serum but not secreted Ag-specific IgA inhibits oral Ag induced anaphylaxis. (97.6)
Authors: Strait Richard , Mahler Ashley , Hogan Simon , Khodoun Marat , Finkelman Fred 
Published: January 2023

Abstract
Epidemiologic evidence suggests that IgA, the main mucosal Ig isotype, inhibits allergy, but it is not known whether it suppresses anaphylaxis. We used mouse models to evaluate whether IgA can suppress systemic anaphylactic responses to ingested allergens by neutralizing them before or after their systemic absorption. Passive systemic anaphylaxis (PSA), measured as hypothermia, was induced by sensitizing mice with IgE anti-TNP mAb, then challenging them orally (og) with TNP-OVA. The ability of IgA to inhibit PSA by neutralizing Ag prior to or after systemic absorption was evaluated by pretreating mice with IgA anti-TNP mAb either og or iv. TNP-OVA was detectible in serum by 5 min after og administration. PSA developed within 5 min and was inhibited by iv, but not og IgA. Extent of inhibition was proportional to the IgA dose and Fcα/μR- and FcγRIIb-independent. Intestinal anaphylaxis (IA), defined as diarrhea &lt;60 minutes after OVA challenge, was induced by priming mice ip with OVA/alum, then challenging them og 3x/wk with OVA. IA development was delayed in J-chain- and PIgR-deficient mice, which have markedly increased serum IgA and decreased intestinal IgA. Thus, Ag-specific IgA acts in the blood but not the gut to inhibit systemic and intestinal anaphylaxis. This indicates that ingested antigen must be absorbed systemically to induce systemic anaphylaxis and suggests that immunotherapy should aim at increasing blood, rather than gut levels of non-IgE Abs to food allergens.
Administration of dendritic cells signaled via the neurokinin 1 receptor favors type-1 cellular immunity by mechanisms involving exogenous and endogenous dendritic cell populations (98.12)
Authors: Janelsins Brian , Mathers Alicia , Tkacheva Olga , Erdos Geza , Shufesky William , Morelli Adrian , Larregina Adriana 
Published: January 2023

Abstract
Induction of type-1 immunity is the focus of current dendritic cell (DC)-vaccination approaches for tumors and intracellular infections. The pro-inflammatory neuropeptides, substance P and hemokinin-1, favor cell-mediated immunity by binding the neurokinin 1 receptor (NK1R). DCs express functional NK1R; however, the ability of NK1R agonists to modulate the T cell stimulatory and biasing functions of DCs remains unknown. In the present work, we analyzed the effects of ex vivo-generated DCs signaled via the NK1R to exert T cell stimulatory and type-1 biasing functions. We demonstrate that agonistic signaling via the NK1R promotes the maturation of murine bone marrow-derived DCs (BMDCs) and inhibits their secretion of IL-10. Adoptive transfer of NK1R-signaled BMDCs favors enhanced Ag specific type-1 CD4+ (Th1) and CD8+ (CTL/Tc1) responses in vivo. The individual roles of adoptively transferred BMDCs and endogenous DCs, under our experimental conditions, were further addressed by comparing the development of type-1 immunity in C57BL/6 wild type, IL-12p35-/- and CD11c+DTR mice (the latter depleted of endogenous DCs). Our results demonstrate that generation of type-1 immunity required inhibition of IL-10 by transferred BMDCs and secretion of IL-12p70 by endogenous DCs. Together, our data strongly suggest that adoptive transfer of NK1R-signaled BMDCs promotes type-1 immunity by mechanisms involving both the adoptively transferred and endogenous DC populations.