bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatic Stellate Cells Directly Inhibit B Cells via Programmed Death-Ligand 1
Authors: Li Yan , Lu Lina , Qian Shiguang , Fung John J , Lin Feng 
Published: January 2023

Abstract
We previously demonstrated that mouse hepatic stellate cells (HSCs) suppress T cells via programmed death-ligand 1 (PD-L1), but whether HSCs exert any effects on B cells, the other component of the adaptive immune system, remains unknown. In this study, we found that mouse HSCs directly inhibited B cells and that PD-L1 was also integrally involved. We found that (a) HSCs inhibited the upregulation of activation markers on activated B cells; (b) HSCs inhibited the proliferation of activated B cells and their cytokine/immunoglobulin production in vitro; and (c) pharmaceutically or genetically blocking the interaction of PD-L1 with programmed death-1 (PD-1) impaired the ability of HSCs to inhibit B cells. To test the newly discovered B-cell-inhibitory activity of HSCs in vivo, we developed a protocol of intrasplenic artery injection to directly deliver HSCs into the spleen. We found that local delivery of wild-type HSCs into the spleens of mice that had been immunized with 4-hydroxy-3-nitrophenylacetyl-Ficoll, a T-cell-independent antigen, significantly suppressed antigen-specific IgM and IgG production in vivo, whereas splenic artery delivery of PD-L1-deficient HSCs failed to do so. In conclusion, in addition to inhibiting T cells, mouse HSCs concurrently inhibit B cells via PD-L1. This direct B-cell-inhibitory activity of HSCs should contribute to the mechanism by which HSCs maintain the liver’s immune homeostasis.
Step-wise formation of germinal center B cells is completed by a requisite phase of Th cell disengagement and CD40 signaling abstinence
Authors: Zhang Ting-ting , Gonzalez David , Haberman Ann M 
Published: January 2023

Abstract
There are conflicting reports on the role of CD40 signaling in the initiation and maintenance of germinal centers (GC). CD40 signaling invokes the nuclear translocation of RelB, a transcription factor that promotes IRF4 expression. We examined the early stages of GC B cell differentiation without any phenotypic preconceptions by the adoptive transfer of tagged antigen-specific B cells. As expected, B cells were first observed to express intermediate levels of BCL6 within the interfollicular (IF) zone shortly after immunization. However, these GC B cell precursors had only a partial GC phenotype and co-expressed RelB and IRF4, transcription factors known to repress BCL6 transcription. This initial co-expression of mutually antagonistic transcription factors is short-lived: follicular BCL6hi GC B cells with diminished levels of RelB and IRF4 emerge shortly thereafter, coupled with the disappearance of the immediate precursors as a function of cell division. Interestingly, potentiating T cell help at the GC initiation stage blocks this transition and diverts the fate of GC immediate precursors towards plasma cells, suggesting that ongoing T cell engagement discourages GC B cell formation. Consistent with this idea, we found that reducing the amount of antigen at the time of immunization accelerates GC B cell formation. Similarly, discontinuing T-cell derived factors in an in-vitro culture system promotes the generation of BCL6hi RelB− IRF4− cells with GC B cell properties. Taken together these results suggest that CD40 signaling in B cells is necessary to generate the immediate precursors of GC B cells, but transition to the BCL6hi follicular state is completed by a period of abstinence from Th cell CD40L.
TLR9 limits mouse and human B cell responses
Authors: Sindhava Vishal , Oropallo Michael , Moody Krishna , Naradikian Martin , Zhou Lin , Higdon Lauren , Green Nathaniel , Nündel Kerstin , Stohl William , Schmidt Amanda , Kambayashi Taku , Marshak-Rothstein Ann , Cancro Michael 
Published: January 2023

Abstract
TLR9 can augment B cell activation, but also prevents autoimmune pathogenesis through an unknown mechanism. Herein we describe a cell-intrinsic mechanism that limits the extent of B cell activation by TLR9 ligands delivered by the B cell antigen receptor. This self-limiting response requires that TLR agonists be linked with B cell receptor ligands, as it is not observed with independent B cell receptor and TLR9 ligation. The underlying mechanism involves p38 dependent G1 cell cycle arrest that precedes intrinsic mitochondrial apoptosis, and is shared by all pre-immune murine B cell subsets and CD27− human B cells. B cells can be rescued from this death mechanism by survival or inflammatory cytokines, and preferentially switch to IgG2c producing cells both in vitro and in vivo. These findings reveal a previously unappreciated system of crosstalk that limits responses to antigens containing TLR9 ligands, and suggest that circumventing this response-limiting process can promote sustained autoantibody production.
Type I interferon and TNF signaling plays key synergistic role in programmed necrosis
Authors: Brault Michelle , Stetson Daniel B , Oberst Andrew 
Published: January 2023

Abstract
Pathogen detection and downstream signaling events are important for protection against disease and clearance of infection. Upon sensing pathogen-associated molecular patterns (PAMPs), cells often produce interferons (IFNs), which drive multiple transcriptional changes, allowing a cell to enter an antiviral state. Intriguingly, the IFN-α/β receptor (IFNAR) has recently been shown to be important in triggering the cell death program necroptosis (or programmed necrosis), although the mechanism is unclear. Unlike apoptosis (which relies on caspase activation), necroptosis requires the activation of receptor interacting kinase 3 (RIP3) and leads to the swelling and bursting of the cell. Death receptor or Toll-like receptor signaling can activate RIP3 in certain cellular contexts, leading to cellular destruction by necroptosis. Furthermore, RIP3-deficient mice are highly susceptible to multiple viral infections, highlighting RIP3’s antiviral role. How IFN signaling interfaces with programmed necrosis remains to be discovered. My studies have illuminated the requirement of TNFα production downstream of IFN signaling to trigger necroptosis. We believe promoting necroptosis through the production of TNFα may be an underappreciated role of the IFN-driven antiviral response.
TLR3 signaling is impaired in small airway epithelial cells following cigarette smoke exposure.
Authors: Duffney Parker , Nogales Aitor , Thatcher Thomas , Martinez-Sobrido Luis , Phipps Richard P , Sime Patricia J 
Published: January 2023

Abstract
Mainstream and second hand cigarette smoke exposures increase the risk of respiratory viral infections, especially in children and those with underlying lung disease. Epithelial cells are the primary targets for viral infection and recognize foreign pathogens through multiple Toll-like receptors (TLR). TLR3 recognizes double stranded RNA, a common intermediate in virus replication, and activates antiviral signaling pathways. We hypothesized that cigarette smoke exposure impairs TLR3 signaling in airway epithelial cells leading to an increase in susceptibility to viral infection. Primary human small airway epithelial cells were cultured at the air-liquid interface and exposed to whole cigarette smoke. Following cigarette smoke exposure, cells were treated with the TLR3 ligand polyinosinic-polycytidylic acid (poly I:C), a mimic of RNA viral infection. Levels of interferon gamma induced protein 10 (IP-10) and antiviral interferon bioactivity were measured in culture supernatants. TLR3 cleavage was investigated using the cathepsin inhibitor z-FA-FMK and protein lysates were analyzed by western blot. Our data shows that cigarette smoke exposure causes a decrease in the production of IP-10, as well as a decrease in the interferon bioactivity of culture supernatants. Western blot data indicates that cigarette smoke inhibits cleavage of TLR3. Inhibitor studies confirmed that cleavage of TLR3 was important for the production of IP-10 and interferons. These data show that cigarette smoke disrupts the production of anti-viral signaling molecules by disrupting cleavage and activation of TLR3, as well as provides a mechanistic explanation for increased susceptibility to viral infections in smokers.
Augmentation of salivary IgA production in healthy subjects by fucoidan-agaricus mix ingestion
Authors: Miyazaki Yoshiyuki , Nakamizo Masaji , Kawahara Kazuhiro , Takeuchi Hideaki , Tachikawa Daisuke , Yamada Koji 
Published: January 2023

Abstract
Fucoidan is a series of sulfated polysaccharides derived from brown algae, and have reported to have various biological activities. Previously, we demonstrated that fucoidan derived from Cladosiphon okamuranus and Undaria pinnatifida effectively augmented anti-tumor immunity in combination with Agaricus blazei mycelia extract. In this study, we evaluated the capacity of the fucoidan-agaricus mix (FAM) to enhance oral mucosal immune function. Fifteen healthy volunteers (mean age, 41.2 years old; range, 22–56 years old; 8 males, 7 females) ingested 4 capsules each containing 250 mg FAM powder every day for 12 weeks. As a result, the mean of secretory rates of salivary secretory immunoglobulin A (sIgA) tended to be increased by the FAM administration for 4 and 12 weeks as compared with the initial value. The enhanced salivary sIgA secretion was more distinctly observed in subject group whose initial values of salivary sIgA secretory rate were lower than the total average. Furthermore, the intake of FAM led to significant augmentation in the salivary sIgA secretion (by 1.3-fold) in the group of subjects under 40 years of age. On the other hand, concanavalin A-induced blastogenic response of peripheral blood mononuclear cells and serum IgA concentration was not elevated during this trial. Therefore, it was suggested that FAM stimulated functional maturation rather than expansion of B lymphocyte. The intake of FAM did not significantly affect NK cell activities. In addition, the safety of FAM consumption was confirmed because no abnormal findings were observed in general clinical tests. From the results, it was suggested that intake of FAM was useful in augmentation of oral mucosal immune defense via enhancing salivary sIgA production.
The development of WX486, a novel inhibitor of BTK, to treat rheumatoid arthritis in China
Authors: Xu Yong , Tu Ronghua , Chen Hailiang , Yue Yang , Huang Lu , Wang Xuehai , Wu Chengde , Shen Chunli , Shen Liang , Wu Dongdong , Wu Jiahu , Wang Lexi , Li Jian , Chen Shuhui 
Published: January 2023

Abstract
BTK inhibition has been shown to be a potential approach to treat rheumatoid arthritis. We sought to develop an oral small molecule inhibitor in China market for rheumatoid arthritis. Our medchem group discovered a novel PCC WX486 which demonstrated superior in vivo anti-arthritic activity in two animal models. We studied WX486’s metabolic pathway in different species, and evaluated its genotoxicity, MTD, 7 day acute toxicity and 28 day GLP toxicity in rats and dogs. Our studies have shown that WX486 is effective in preclinical animal models, and with high safety window suitable to be developed for rheumatoid arthritis. IND for this indication will be filed with CFDA in early 2016.
Modulation of tumor vasculature promotes tertiary lymphoid organogenesis.
Authors: Weinstein Aliyah M , Chen Lu , Storkus Walter J 
Published: January 2023

Abstract
The tumor vasculature has been shown to have pro-tumorigenic effects, leading to the use of anti-angiogenic drugs as therapy. However, the importance of tumor vasculature in recruiting immune cells to the tumor microenvironment (TME), leading to the formation of tertiary lymphoid structures (TLS) within the TME, has also been shown. TLS are aggregates of immune cells that develop at site of chronic inflammation and function as local sites of immune priming. The presence of TLS in the TME is a positive prognostic marker in many human tumors, suggesting that modulation of the tumor vasculature to promote increased TLS formation may serve as a novel therapeutic modality for solid tumors.
We have previously shown that intratumorally-injected dendritic cells (DC) engineered to overexpress the Type 1 transactivator Tbet (DC.Tbet) slow tumor progression in a mouse model dependent on T and NK cell recruitment to the TME. Our recent work indicates that DC.Tbet treatment of established murine sarcomas and colon carcinomas leads to an upregulation by d5 following treatment of peripheral node addressin (PNAd) on CD31+ vascular endothelial cells, marking high endothelial venules (HEV) similar to those found in lymph nodes. Dense infiltrates of T cells and DC surround these HEV; however, T cells and DC are observed proximal to tumor vasculature before PNAd upregulation is observed, indicating that while HEV mark mature TLS, PNAd does not initiate TLS formation. Instead, we observe that DC.Tbet but not unmodified DC express CCL21, CXCL13, lymphotoxin (LT) α, and LIGHT. In vivo these can recruit and activate DC, T cells, NK cells, and B cells, which can modulate the vasculature via LT signaling axes to upregulate PNAd and propagate immune cell recruitment to TLS.
Impact of microbiome manipulation on age-related inflammation and immune system dysfunction
Authors: Kodroff Lauren Hillary , Norton Elizabeth B 
Published: January 2023

Abstract
The aging process can be described as a disease characterized by increasing inflammation and declining immune function. Gut microbiota may impact this process, as it is altered with both disease and advanced age. We examined if gut microbiota from young animals could reduce inflammation, cellular senescence, and immune system dysfunction in older animals. To do so, we performed fecal microbiota transplants (FMT) from young (14 weeks) to groups of young, middle-aged (50 weeks), and old (100 weeks) Balb/c mice. Groups (n=5) were pre-treated with ampicillin for 3 weeks followed by oral gavage with freshly homogenized fecal material (FMT groups) or PBS and euthanized 3 weeks later. Fecal samples were collected over time for microbial analyses. Small intestines, cecum, and colons were collected for gross and microscopic analyses. To examine changes to systemic immunity, splenic and whole blood B- and T-cells were stained for surface and intracellular marker expression (i.e. activation levels, senescence) by flow cytometry.
Overall, PBS control groups showed classic age-related effects. This included signs of molecular dysfunction in oldest mice with altered levels of the NfkB inhibitor IkBz and increased senescence subsets (P16INK4a+, β-gal+). A single FMT treatment had the most dramatic effects vs. PBS controls in older mice compared to other age groups. While treatment significantly reduced IkBz and microbial-sensing TLR2 expression, FMT did not have visible impact on cellular senescence. These results reinforce a critical role for the microbiome in age-related immune decline and suggest a regimen of FMT from healthy young subjects may be a potential strategy to lower chronic inflammation and improve immune function in the elderly.
A multivariate approach to data analysis of vaccine clinical trials.
Authors: Coccia M , Nozay F , De Mot L , Deyati Avisek , Jogert E , van der Most R , van den Berg R 
Published: January 2023

Abstract
Despite significant progress in prevention, diagnosis and treatment, Malaria and Tuberculosis (TB) remain major health challenges. In 2014 WHO estimated that ≈438000 people died from Malaria and ≈1.5 million from TB, mainly in resource-poor countries. Vaccines represent a cost-effective and efficient method of preventing infectious diseases. The development of vaccines for TB and Malaria would significantly contribute to reducing disease burden, particularly with the emergence of drug-resistant pathogens. GSK’s Malaria vaccine, Mosquirix™ (RTS,S/AS01), received a positive opinion from European regulators for the prevention of Malaria in young children in sub-Saharan Africa. GSK’s candidate vaccine for TB (M72/AS01) induces robust TB-specific CD4 T-cell responses in humans, and it is undergoing phase IIb clinical trials. System biology approaches can support vaccines at different stages of development by identifying molecular signatures that drive responses to vaccination. Here, we describe the application of systems vaccinology to the analysis of gene expression data from clinical trials for Malaria and TB candidate vaccines. Our analysis aimed to identify early predictors of vaccine efficacy in Malaria clinical trials and to detect signatures associated with reactogenicity in the early development of a TB vaccine. To better capture the multidimensional nature of the data, we used multivariate analysis approaches such as Partial Least Squares regression. Additionally, biological interpretation of our results allowed us to pinpoint biological processes linked with response to vaccination, advancing our understanding of vaccine mode of action.
The impact of cytomegalovirus on naive lymphocytes in a novel non-human primate model.
Authors: Willis Erin L. , Eberle Richard , Wolf Roman F. , White Gary L. , McFarlane Dianne 
Published: January 2023

Abstract
Immunosenescence causes changes in the immune system, such as losses of naïve T-cells, which can lead to immune impairment in the elderly. Cytomegalovirus (CMV) is a common chronic herpesvirus that has been implicated in immunosenescence, although its direct effects have remained unclear. Therefore, we wanted to test the impact of CMV on immunosenescence in a recently validated baboon model. To assess the effects of CMV on the immune system over time, we determined lymphocyte populations and CMV load in age-matched baboon groups representing variable CMV exposure and shedding pressures: specific pathogen free (SPF; CMV−); small-group conventionally housed (SMConv; CMV+); and large-group conventionally housed (LGConv; CMV+) baboons (7animals/group). All baboon groups showed a decrease in naïve cells over time (P≤0.5). However at Year 1, between-group comparisons revealed 50% fewer CD8+ naïve cells in LGConv animals compared to SPF and SMConv. In Year 2, the number of naïve cells in SMConv was intermediate to that of SPF and LGConv; and by Year 3, CD8+ naïve cells were decreased in both Conv groups compared to SPF (P≤0.5). Preliminary results also revealed that a greater proportion of LGConv baboons shed CMV compared to SMConv. These data indicate that all baboons, independent of pathogen status and environmental conditions, show signs of immunosenescence at this age (9.6–11.6 years); however, LGConv baboons appear to be aging more quickly. Ongoing work includes the addition of more animals, further characterization of viral shedding and load, and infection of SPF baboons with CMV to help verify these differences. Results of this project will lead to a better understanding of the role of CMV in immunosenescence.
‘Role of IL-28A in Herpes Stromal Keretitis’.
Authors: Jaggi Ujjaldeep 
Published: January 2023

Abstract
Ocular infection with herpes simplex virus (HSV) can result in a chronic immune-inflammatory lesion that is a significant cause of human blindness. A key to controlling SK lesion severity is to identify cellular and molecular events responsible for tissue damage. Interferons are key cytokines in the establishment of a multifaceted antiviral response. Although all IFNs are important mediators of antiviral protection, their roles in antiviral defence vary. Interferon lambda which is a type III cytokine is capable of inducing an antiviral response both in vitro as well as in vivo. This family consists of three structurally related interferon lambda subtypes called IFN-λ (IL-29), IFN-λ2 (IL-28A) and IFN-λ3 (IL-28B). Here, we show that IFN-λ2 (IL-28A) has a prominent role in HSK. The binding of IFN-λ to their cognate receptors induces a common signaling cascade that results in the activation of STAT1 and STAT2, which promotes MX1, OAS1 and IRF7 which in turn mediate the antiviral activity of the type-III IFNs. Here we show that IL-28A appears to specifically target neutrophil function and cause a major reduction in the total number of CD4 and γδT cells and also in TH17 cells in DLN. Also, we found that the serum levels of IL-1β were reduced at the early stage of treatment. Administration of IL-28A effectively reduces the HSK lesions and can prove to be a very reliable therapeutic agent.
Human astrocytes and microglia-like cells constitutively express the novel cytosolic viral DNA sensor cGAS
Authors: Martins Angelica N , Jeffries Austin M , Marriott Ian 
Published: January 2023

Abstract
Evidence is accumulating that the innate immune response to HIV-1 within the central nervous system (CNS) plays a critical role in neuroAIDS disease pathology. Microglia and astrocytes are uniquely positioned to respond to CNS pathogens, and these cells produce key inflammatory, neurotoxic, and antiviral mediators following exposure to retroviruses such as HIV-1. This virus infects glia but the mechanisms by which these cells perceive intracellular replicative HIV-1 have not been defined. However, it has become apparent that innate immune sensing of nucleic acids underpins many physiological and pathological responses to viral pathogens. Cyclic GMP-AMP synthase (cGAS) has been identified as a cytosolic DNA sensor and this molecule has recently been demonstrated to have a key role in sensing replicative HIV-1 DNA intermediates and eliciting responses in human monocytic cell lines. Furthermore, cGAS and its downstream adaptor molecule STING have been found to be expressed by murine microglia and astrocytes. Here, we have characterized cGAS mRNA and protein expression by human glial cells. Microglial and astrocytic cell lines and primary human astrocytes were found to constitutively express robust mRNA and protein levels of cGAS and such expression could not be elevated further by transfection with viral nucleic acid motifs. Importantly, cGAS mRNA and protein expression was maintained despite the successful establishment of pseudotyped HIV-1 infection. As such, the identification of robust levels of cGAS in both microglia and astrocytes that are maintained even in the face of HIV-1 challenge may indicate an important mechanism by which human glial cells can respond to this pathogen.
Gp96 initiates DNA methylome remodeling in dendritic cells and facilitates interaction with T cells.
Authors: Kinner Lauren , Sedlacek Abigail L , Watkins Simon C , Binder Robert J 
Published: January 2023

Abstract
Tumor-derived immunogenic heat shock protein gp96 represents a promising vaccine strategy for the treatment of cancer. It is well established that immunization with gp96 elicits Th1 and CTL favoring conditions leading to rejection of the tumor from which gp96 is derived. It is unclear, however, how higher doses of gp96 leads to priming of Treg and suppression of the anti-tumor effect. Previous studies have confirmed that gp96 is endocytosed by CD91+ dendritic cells (DCs), and suggest that uptake by plasmacytoid DCs (pDCs) contributes to suppressive responses. Here, we focus on the molecular events which control gene transcription and drive this dose-dependent dichotomy in responding DCs. Our data demonstrates that stimulation of CD91+ conventional DCs (cDCs) and pDCs with gp96 results in accumulation of nuclear DNA methyltransferase (DNMT) punctae. These events correlated with methylome remodeling following gp96 immunization in vivo. Gene ontology analysis revealed that the bulk of differential methylation occurred within gene sets involved in cell-cell adhesion, signaling, and angiogenesis. Specifically, methylation and expression of target gene Nrp1 is modified in gp96-conditioned pDCs but not cDCs, suggesting that these genetic events are cell type specific. Finally, we show that gp96 stimulation facilitates increased pDC-Treg interaction in a Nrp1-dependent manner. These findings demonstrate a previously unknown role of pDCs in driving the tolerogenic response to gp96 via methylome remodeling, and can be applied to current clinical trials to improve their efficacy.