bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inflammaging decreases the human B cell response to the influenza vaccine (P4524)
Authors: Frasca Daniela , Diaz Alain , Romero Maria , Landin Ana Marie , Blomberg Bonnie 
Published: January 2023

Abstract
Deficits in immune responses in the elderly contribute to their mortality and morbidity. In order to develop predictive markers for a beneficial humoral immune response, we evaluated the in vivo and in vitro response to the seasonal influenza vaccine in young and elderly individuals. We measured serum antibody response and associated this with the in vitro B cell response to the vaccine, measured by AID (activation-induced cytidine deaminase). AID is a measure of immunoglobulin class switch recombination, the process that generates protective antibodies, and is a good measure of B cell function. Both responses decrease with age and are significantly correlated. We hypothesize that the increased pro-inflammatory status of the elderly, called inflammaging, directly impacts B cell function, thus impairing the capacity of the individual to make protective antibodies and to respond to vaccination. Our data indicate that aged B lymphocytes themselves make TNF-α before vaccine challenge and this correlates with their impaired function, including reduced AID expression after B cell stimulation. Our results reveal new molecular mechanisms which contribute to reduced antibody responses in aging and suggest that these will have an impact for crucial development of effective vaccines to protect the elderly from infectious and other debilitating diseases.
Induction of linear and conformational V2-specific antibodies using HIV-1 gp145 clade B envelope protein as the immunogen (P4505)
Authors: Rao Mangala , Peachman Kristina , Jobe Ousman , Kuaban Alice , Billings Erik , Guao Guofen , Wieczorek Lindsay , Polonis Victoria , Pinter Abraham , Kim Jerome , Michael Nelson , Alving Carl , Rao Venigalla 
Published: January 2023

Abstract
TThe potential importance of binding antibodies (Abs) in preventing HIV-1 acquisition was recently demonstrated by the case control analysis of the RV144 phase III HIV-1 vaccine trial, which showed that binding Abs to a gp70 scaffolded V1V2 loop of gp120 correlated inversely with infection. We examined if immunization with a HIV-1 env trimer in the absence of any priming vector could induce functional V2-specific Abs. The clade B HIV-1 gp145 env protein consisting of gp120, gp41 ectodomain, and MPER, trimerized with foldon was expressed in 293F cells and purified. The protein adjuvanted with liposomes containing lipid A was used to immunize New Zealand white rabbits. Strong Ab binding titers (50,000-400,000) were induced to env epitopes including V2 and V3 peptides (linear) and MuLV gp70-scaffolded V1V2 protein (conformational) as measured by ELISA and Biacore. The sera neutralized infectious molecular clones and pseudoviruses in PBMC, monocyte-derived macrophage, and TZM-bl assays. Purified IgG neutralized primary US-1 in a dose-dependent manner in the macrophage assay. Depletion of linear V2 or V3 epitope-specific Abs retained the conformation-specific gp70 V1V2 binding Abs and did not completely abolish neutralization. Further depletion of gp70 V1V2-specific Abs significantly reduced neutralization. These data indicate that gp145 trimers induce linear as well as conformational V2-specific antibodies and might be a good candidate for designing a preventative HIV-1 vaccine.
Nanoparticle vaccines comprising the respiratory syncytial virus G Protein CX3C chemokine motif induce robust immunity protecting from challenge and disease (P4513)
Authors: Tripp Ralph , Choi Youngjoo , Powell Thomas , Boyd James , Palath Naveen , Haynes Lia , Anderson Larry , Jorquera Patricia 
Published: January 2023

Abstract
BALB/c mice immunized with nanoparticle vaccines comprising RSV G protein CX3C polypeptides in absence of adjuvant had a neutralizing antibody response associated with reduced lung titers following RSV challenge. These mice also had an increased level of RSV G protein-specific IL-4 and IFNγ secreting cells in the lung, and an increased level of RSV M2-specific IL-4 and IFNγ CD8 T cells. There was a significant increase in M2-specific CD8 T cells that trafficked to the lung following RSV challenge despite the mice being vaccinated with a G protein epitope. Pulmonary cell analysis revealed no significant increase in neutrophils (Ly6Ghi Ly6Cint CD125loSiglecF-) or eosinophils (Ly6Gint Ly6Chi CD125hi SiglecF+) in vaccinated mice before or after RSV challenge. The results show that RSV G protein nanoparticle vaccination is safe and effective, induces a neutralizing protective antibody response, increased RSV G protein- and M2-specific T cell responses, and is not associated with pulmonary disease pathogenesis.
Assessment of immune response against HIV-1 P24 antigen using Bacillus thuringiensis serovar dakota (H15) activated delta-endotoxin as an adjuvant (P4491)
Authors: Abouelhag Hussien , Safhi Mohammed 
Published: January 2023

Abstract
Bacillus thuringiensis var. dakota activated δ-endotoxin (BtDEAP) had many biological activity. Our previous experience recorded that BtDEAP had anti-malignancy activity in-vitro and in-vivo. There were many thoughts about the mode of action and one of them was their capability of immune modulation against tumor cell Ag. This work assesses the immune response in BALB/c mice immunized with HIV-1 P24 Ag individually and/or in combination with BtDEAP, complete Freund's adjuvant (CFA). The evaluation of the immune response against immunogenic preparations was carried out through estimating the immunoregulatory cytokines (IL-1α, Il-1β, IL-4, IL-10 and TNF-α) in the supernatant of splenocytes from mice that were immunized with HIV-1 P24 Ag alone and/or in combination with BtDEAP, CFA in relation to splenocytes from control mice. Also, the total IG level in the serum of tested and control mice were appraised. The results obtained conducted that the total IG level was raised remarkably by using CFA in comparing with BtDEAP while HIV-1 P24 Ag alone record the minimal raise in IG levels. These results was accompanied with raised levels of IL-4 and IL-10 by using CFA combination with HIV-1 P24 while IL-1 and TNF-α raised by immunization using BtDEAP in combination with HIV-1 P24 Ag over that recorded by HIV-1 P24 Ag alone. Based on the described above, BtDEAP, seems to be playing a significant role in preferential induction of Th1-dependent immune response against HIV-1 P24 Ag.
Hypothemycin inhibits tumor necrosis factor-α production by post-transcriptional regulation in lipopolysaccharide-stimulated RAW 264.7 cells (P5046)
Authors: Kang Jong Soon , Park Ki Hwan , Han Sang-Bae , Kim Youngsoo , Oh Soo Jin , Yun Jieun , Lee Chang Woo 
Published: January 2023

Abstract
Tumor necrosis factor-α (TNF-α) is a major inflammatory cytokine produced by activated macrophages and lymphocytes and involved in the development of many inflammatory diseases. Preventing the production or action of TNF-α is considered as a promising therapeutic strategy for various inflammatory diseases. The resorcylic acid lactone hypothemycin has been shown to exert an antitumor activity. In this study, we studied the inhibitory effects of hypothemycin on TNF-α production and underlying mechamisms. Hypothemycin dose-dependently suppressed lipopolysaccharide (LPS)-induced TNF-α secretion without affecting LPS-induced nitric oxide (NO) production in RAW 264.7 cells. Quantitative real-time reverse transcription polymerase chain reaction analysis revealed that TNF-α mRNA expression was only slightly reduced by hypothemycin in LPS-stimulated RAW 264.7 cells. Further study demonstrated that hypothemycin down-regulated the stability of TNF-α mRNA in LPS-stimulated RAW 264.7 cells. In addition, hypothemycin suppressed the phosphorylation of p38 MAPK and ERK in LPS-stimulated RAW 264.7 cells. Knockdown of tristetraprolin (TTP), a major component of TNF-α mRNA decay machinery and direct substrate of p38 MAPK, by small interfering RNA reversed the stability of TNF-α mRNA decreased by hypothemycin treatment. Collectively, these results suggest that hypothemycin inhibits TNF-α production, at least in part, by TTP-dependent reduction of mRNA stability in LPS-stimulated RAW 264.7 cells.
Predominant Th2 cytokine gene expression in lymph node cell cultures from Andes virus-infected deer mice (Peromyscus maniculatus) (P6316)
Authors: Schountz Tony , Haddock Elaine , Feldmann Heinz , Prescott Joseph 
Published: January 2023

Abstract
Deer mice (Peromyscus maniculatus) are the principal reservoir hosts of Sin Nombre virus (SNV), while long-tailed pygmy rice rats (Oligoryzomys longicaudatus) are the principal reservoir hosts of Andes virus (ANDV). These viruses cause the great majority of hantavirus cardiopulmonary syndrome cases in North and South America. The disease in humans is principally an inflammatory immunopathology that results in a pronounced capillary leak syndrome with a 36% fatality rate due to cardiogenic shock. In contrast, infection of rodent reservoirs with their hantaviruses results in life-long persistence, without signs of disease, that appears to be mediated by regulatory T cells. Deer mice are experimentally susceptible to ANDV; however, they clear infection within 56 days. We infected deer mice with SNV or ANDV for 14 days and examined the immune responses to each virus. Lymph node cells from infected deer mice were harvested and cultured with viral antigens to examine expression of 94 immune-related genes by real-time PCR. We found that most of the same genes were expressed in both SNV- and ANDV-infected deer mice; however, the magnitude of gene expression, particularly Th2 genes, were significantly greater in lymph node cells from ANDV-infected deer mice. Together, these results suggest a quantitative effect occurs in the host response to a reservoir hantavirus (SNV) compared to a nonreservoir hantavirus (ANDV) and is associated with persistence or clearance.
Circulating autoantibody and intrahepatic inflammation profiles in patients chronically infected with hepatitis C virus (P6328)
Authors: Yu Qigui , Ghabril Marwan , Meng Zhefeng , Hu Sishun , Amet Tohti , Byrd Daniel , Lan Jie , Hu Ningjie , Chalasani Naga 
Published: January 2023

Abstract
The liver injury in hepatitis C virus (HCV) infection is thought to be mainly due to immunological disorders and attacks of inflammatory factors rather than a direct cytopathic effect of the virus itself. To investigate whether intrahepatic inflammation and immunological disorders are correlated in HCV-infected patients, we used a real-time RT-PCR-based array and a slide-based autoantigen array to analyze intrahepatic inflammation gene profiles in liver biopsy specimens from HCV-infected (n=16) and uninfected (n=8) individuals and their circulating autoantibody profiles, respectively. Compared with uninfected individuals, HCV infection markedly altered expression of 59.5% of 84 inflammation-related genes tested. Among these genes affected, the CXCR3-associated chemokines (CXCL9, CXCL10, and CXCL11) were among the most up-regulated genes. Patients chronically infected with HCV have 2-fold or greater increase in circulating autoantibodies of IgG and IgM to 28 and 23 of 84 autoantigens tested, respectively, than that in uninfected individuals. The antinuclear antibody IgG titers correlated significantly with the levels of intrahepatic CXCR3-associated chemokines (p = 0.002). Given that CXCR3-associated chemokines are involved in the development of autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), these chemokines may also play a key role in the pathogenesis of HCV-related liver disease through enhancement of autoimmune responses.
Involvement of type I IFN signaling in lymphocyte migration and lymphoid structure during viral infection (P6306)
Authors: Ng Cherie , Teijaro John , Schreiber Robert , Oldstone Michael 
Published: January 2023

Abstract
During many chronic viral infections, the stromal cells of secondary lymphoid organs (SLO), essential to lymphocyte migration, activation, and survival, are disrupted, suggesting abrogation of necessary immune cell interactions. Little is known why and how these changes occur. To study the changes in these scarce stromal populations, we immortalized fibroblastic reticular cells (FRCs), which are stromal cells of T cell zones that are targeted by multiple viruses, and tested the effect of type I and II interferon (IFN). In reaction to IFN-γ, FRCs expressed MHC II, along with co-stimulatory ligands, and activated naïve CD4+ and CD8+ T cells but limited expansion of effector T cells. To IFN-I, interestingly, FRCs responded differentially, upregulating PD-L1 and MHC I in reaction to IFN-β but not IFN-α. To assess the effect of IFN-I on stromal cells, including FRCs, we blocked IFN-I signaling during persistent lymphocytic choriomeningitis virus infection in mice. Surprisingly, IFN-I blockade protected from the SLO destruction that occurs with chronic infection. FRC structure and T cell (and B cell) zones remained intact despite higher viral load and greater numbers of anti-viral T cells. IFN blockade increased FRC expression of T cell/DC chemokines, resulting in significant differences in naïve T cell homing. These data suggest that IFN-I signaling alters lymphocyte migration via stromal cells and regulates pathways that are involved in maintaining SLO architecture.
Novel mouse models reveal how expression of NKG2D and its ligands on various cell subsets affects immune responses (P4351)
Authors: Morvan Maelig , Champsaur Marine , Johnson Natrina , Sexl Veronika , Lanier Lewis 
Published: January 2023

Abstract
NKG2D is an activating receptor expressed by all Natural Killer (NK) cells, a subset of T cells, and activated macrophages. NKG2D and its ligands, which are expressed on stressed or damaged cells, play important roles during viral infections, cancers, and autoimmune diseases, both in mouse and human. While NKG2D is well studied in NK cells, its function on other cells remains unclear, particularly in vivo. In this study, we examine the consequences of cell-specific ablation of NKG2D, or tissue-specific expression of its ligand Rae-1, on innate and adaptive immunity, using two novel mouse models. By crossing Cre expressing strains to our two newly generated mice bearing a floxed allele of NKG2D, or a Rosa26-LSL-Rae-1 transgene, we obtain conditional knockouts of NKG2D, or mice that express Rae-1 in a cell-specific manner. We are now able to dissect the contribution of each cell subset expressing NKG2D in models of viral infection, tumor rejection, and autoimmunity. In addition, we observed that NK cells chronically interact with myeloid cells in vivo, since expression of Rae-1 on these subsets, but not others, leads to down-modulation of NKG2D expression and impaired NKG2D-dependent functions. Data from these two new mouse models provide a better understanding of the role of NKG2D by defining its impact on different immune cell functions, and by mimicking physiopathological situations of patients in which a human counterpart of Rae-1 is expressed on various tissues.
NKG2C+CD57+ CD56dim NK cells are enriched following Epstein-Barr virus transformed lymphoblastoid cell line co-culture with peripheral blood mononuclear cells from cytomegalovirus+ donors (P4359)
Authors: Saghafian-Hedengren Shanie , Sohlberg Ebba , Theorell Jakob , Queiroz-Carvalho Claudia , Nagy Noémi , Nilsson Caroline , Bryceson Yenan , Sverremark-Ekström Eva 
Published: January 2023

Abstract
Cytomegalovirus (CMV) is a persistent herpesvirus that promotes NKG2C+ Natural Killer (NK) cell differentiation. Highly mature CD57+ NKG2C+ NK cells have been proposed as the equivalent of mouse memory-like NK cells, which have features as long-term persistence and enhanced recall responses. AIM: To examine if co-infection with another common herpesvirus, Epstein-Barr virus (EBV), affects the NKG2C+ CD56dim NK cell population. METHODS: PBMCs from 45 five-year old children with known EBV and CMV serostatus were phenotyped. Further, PBMCs from 6 CMV sero+ EBV sero- infants were used for co-culture with EBV+ lymphoblastoid cell-lines (LCLs) during 72 hours. EBV- LCLs (Ramos) served as controls. Anti CD3, CD14, CD19, CD56, CD57, NKG2C and ki-67 antibodies were used for flow cytometric analysis. RESULTS: EBV and CMV co-infection was related to higher proportions of NKG2C+ and NKG2C+CD57+ CD56dim NK cells compared to infection with CMV or EBV alone, or seronegativity. In contrast to co-culture with Ramos, PBMC co-culture with EBV+ LCLs generally led to enrichment of NKG2C+CD57+ NK cells (stimulation index median 1.23, range 0.87-1.30), which was not related with higher NK cell proliferation. CONCLUSIONS: EBV co-infection seems to promote the existence of higher proportions of memory-like NK cells. Our data herein indicate that this is not due to enhanced proliferation of these cells; rather it suggests that memory-like NK cells may be maintained by EBV co-infection.
Zosteriform spread of Herpes simplex virus 1 as a model to study the role of leukocyte subpopulations in the mortality induced during acute infection (P4373)
Authors: Salinas Nohemí , Becerril-García Miguel , Hisaki-Itaya Emiliano , Estrada-Parra Sergio , Pavón-Romero Lenin , Velasco-Velazquez Marco , Pérez-Tapia Sonia 
Published: January 2023

Abstract
Immune response against Herpes simplex virus 1 (HSV-1) has been studied by various routes of inoculation in models of herpes. Zoteriform spread of HSV-1 infection occurs after primary inoculation of the skin of mice. This inoculation route has been used for study the pathogenesis of infection at nervous system level but little is known about the mechanism of immune response in this model. The aim of this work is to study the infiltrated of leukocytes in the inguinal lymph nodes (ILN) and correlate changes in leukocyte subpopulations with mortality in BALB/c mice cutaneously infected with HSV-1. We observed that infected mice showed 70-100% mortality during the acute infection. We removed inguinal and mesenteric lymph nodes (MLN) from infected mice and analysed phenotype of CD3, CD4, CD8, and CD19 cells from 0 to 15 days post-infection. The percentage of CD19+ cells and CD3+ cells in the ILN from infected mice changed from 20% to 50% and from 70% to 40% respectively. In contrast, such changes were not observed in MLN, suggesting that during acute infection immune response is elicited only at the region of the infection. Kinetic analysis of CD4+ and CD8+ T cells showed that the HSV-1-infection induced the expression of CD11c in T cells. Our findings show that HSV-1 infected mice retain a CD11c+ leukocyte infiltrate that could be involved in mortality. The role of CD11c+ cells will be further studied using immune-modulators that modify the percentage of those populations.
Type I interferon inhibits phosphorylation of AKT to impair T cell proliferation induced by interleukin-7 (P6315)
Authors: Sieg Scott , Bazdar Douglas 
Published: January 2023

Abstract
Type I interferons (IFN-I) have anti-proliferative activity and are elevated in chronic HIV infection. We hypothesized IFN-I may adversely affect T cell homeostasis by limiting T cell proliferation in response to interleukin-7 (IL-7). Peripheral blood mononuclear cells (PBMC) or purified CD4+ T cells were CFSE-labeled and incubated with IL-7 (5ng/ml) plus or minus interferon alpha (30-500 U/ml) in X-vivo serum-free medium. T cell proliferation was assessed by CFSE dye dilution at 7 d. T cell function was examined by stimulating cells with SEB and measuring IFN-g, IL-2 and CD40L expression by intracellular flow cytometry. Intracellular expression of P-STAT5 and pAKT were measured at 1-3 d. CD4+ T cells incubated with IL-7 proliferated less efficiently in the presence of IFN-I (n=10; p&lt;0.05). Moreover, these cells were less functional as indicated by reduced IL-2, CD40L and IFN-g production, with the greatest impairments observed for IL-2 production. Inhibition of either pAKT or P-STAT5 with chemical inhibitors also blocked T cell proliferation indicating that these pathways are both important in IL-7-induced proliferation of T cells. Analyses of IL-7-induced signaling pathways indicated that IFN-I impaired pAKT signaling (p&lt;0.05) but had limited effect on P-STAT5 signaling. These results suggest that IFN-I has the potential to interfere with T cell homeostatic proliferation by inhibiting pAKT activation.
Study of the PBMC response to TGN1412 and visilizumab in the “lymph node like” cytokine release assay format (P6327)
Authors: Serna Daniel , Scesney Susanne , Ibraghimov Alexander 
Published: January 2023

Abstract
Recently, a new format for the cytokine release assay (CRA) used to predict the in vivo safety of therapeutic antibodies was developed. In this assay, normal donor PBMCs are pre-incubated at high density for two days to make the cells more “lymph node like” (LNL) and then are incubated with soluble antibody. The assay was developed in response to the failure of previous in vitro stimulation formats to predict the strong cytokine storm shown in humans by TGN1412, a CD28 superagonist human IgG4 antibody. Similar to TGN1412, previous formats failed to predict the strong cytokine response elicited in human patients by visilizumab, a human IgG2a anti-CD3 specific antibody. Here we compare and contrast the PBMC response in the LNL format to TGN1412 and visilizumab. Activation of PBMC subset populations, cytokine profile and cellular source of cytokines were analyzed. For the majority of donors tested, the LNL format of CRA detected PBMC cytokine responses to both TGN1412 and visilizumab, which were consistent with those cytokine responses previoulsly observed in vivo. Our study of two human IgG antibodies targeting different T cell activating receptors suggests that the LNL format of CRA may be a valuable predictor of in vivo cytokine release by T lymphocyte specific biologics.
Interleukin 37 employs the IL-1 family orphan receptor SIGIRR and the alpha chain of the IL-18 receptor to inhibit innate immunity (P6293)
Authors: Nold Claudia , Nold Marcel , Rudloff Ina , Lo Camden , Mangan Niamh , Rotter Bjoern , Zepp Jarod , Azam Tania , Li Suzhao , Mansell Ashley , Bufler Philip , Garlanda Cecilia , Mantovani Alberto , Dinarello Charles 
Published: January 2023

Abstract
IL-37 is a powerful anti-inflammatory IL-1 family member with activity against a broad spectrum of inflammatory assaults. One mechanism by which this beneficial effect is mediated is via intracellular association with Smad3; however, the cell surface receptor for IL-37 remains unknown. Here, we show that to block inflammation, IL-37 requires IL-18Rα and SIGIRR, a so-far orphaned member of the IL-1R family. In PBMC, which naturally express IL-37, knockdown of SIGIRR increased IL-1β and IL-6 threefold. Silencing of SIGIRR in THP-1 cells significantly attenuated the anti-inflammation of IL-37 (83% less IL-1β with IL-37 and SIGIRR, only 34% less without SIGIRR). Similar effects were observed when IL-18Rα was depleted. To study SIGIRR’s contribution to IL-37 function in vivo, we created a strain of SIGIRR-/- mice that express IL-37. The protective effect imparted by IL-37 was markedly reduced in these crossbred mice when they (and wild-type, IL-37-transgenic and SIGIRR-/- animals) were injected with LPS. Using proximity ligation assays and FRET in PBMC, thus exploring interactions of the naturally occurring pairs IL-37-SIGIRR, IL-37-IL-18Rα and SIGIRR-IL-18Rα, we showed sub-40nm colocalization of each complex. The association peaked 30min after LPS stimulation and decreased to background by 4h. Thus, IL-37 limits inflammation by employing the properties of SIGIRR and by associating with IL-18Rα, suggesting that SIGIRR-IL-18Rα functions as the cell surface receptor for IL-37.