bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tick-borne flaviviruses impair IRF-1 and type I IFN signaling to inhibit IL-12 production by dendritic cells (170.6)
Authors: Robertson Shelly , Lubick Kirk , Freedman Brett , Best Sonja 
Published: January 2023

Abstract
Tick-borne encephalitis virus (TBEV), family Flaviviridae, is an emerging pathogen causing ~10,000 human cases of severe CNS disease annually. Dendritic cells (DCs) are early cellular targets of TBEV infection, which may contribute to viral pathogenesis. Here, we examined the cytokine response and maturation profile of murine bone marrow-derived DCs infected with LGTV, a naturally attenuated member of the TBEV serogroup. LGTV infection failed to induce DC maturation or a robust cytokine response. Treatment with LPS or LPS/IFNγ, strong inducers of inflammatory cytokines, resulted in enhanced production of TNFα and IL-6, but suppressed IL-12 in infected DCs when compared to uninfected "bystander" cells or mock-infected controls. Although late suppression of IL-12p40 involved antagonism of type I IFN signaling, early suppression was dependent on IRF-1, a key transcription factor required for anti-flaviviral immunity. LGTV infection did not affect IRF-1 mRNA expression, but rather diminished IRF-1 protein levels and nuclear localization in DCs and reduced IRF-1 transcriptional activity in Huh7 cells. The effect on IRF-1 was also observed in DCs infected with the virulent Sofjin strain of TBEV and in DCs isolated from skin-draining lymph nodes of LGTV-infected Ifnar-/- mice. Thus, IL-12p40 inhibition by LGTV involved coordinated impairment of IRF-1 function and type I IFN signaling. This work identifies IRF-1 as a novel target of flavivirus-mediated immune evasion.
Type I IFN Signature in plasmacytoid dendritic cells from young Sle 1,2,3 lupus prone mice. (171.1)
Authors: Sriram Uma , Varghese Linda , Xu Jun , Gallucci Stefania 
Published: January 2023

Abstract
The importance of the Type I Interferon (IFN) Signature in systemic lupus erythmatosus is well documented in patients and mouse models. We have earlier observed a distinct IFN gene Signature in the myeloid dendritic cells (mDC) of young Sle 1,2,3 lupus prone mice. In this study, we grew bone-marrow precursors in the presence of Flt3L to generate plasmacytoid dendritic cells (pDC) and analyzed the IFN Signature. The percentage of pDCs generated in culture did not differ between the Sle and the control C57BL/6 (B6) mice. We sorted pDCs (B220+CD11c+) and mDCs (CD11c+CD11b+) from the culture and analyzed the constitutive expression of IFN responsive genes (IFNb, IRF7, ISG15, Mx-1 and CXCL10) by real-time RT-PCR as sign of IFN Signature. There was minimal IFNb expression in both B6 and Sle pDCs; while the IFNb expression in mDCs was higher and much higher in Sle vs B6 mDCs like we observe in cultures supplemented with GMCSF. IRF7 gene expression was higher in pDCs than mDCs and much higher in Sle pDCs. The expression of the other genes in pDCs was lower than in mDCs in both strains, although in Sle pDCs their expression was higher than in B6 pDCs. Our results indicate that plasmacytoid DCs from young pre-diseased Sle1,2,3 lupus prone mice express an IFN Signature similarly to lupus myeloid DCs. Moreover, these results highlight the important role for IRF7 in the activation of lupus pDCs and suggest a probable mechanism for the hyper-activation of the IFN Signature in lupus.
Neutrophil expression of FasL and perforin in hapten challenged skin induce chemoattractants directing the infiltration of hapten-primed CD8 T cells into the skin (173.3)
Authors: Kish Danielle , Gorbachev Anton , Fairchild Robert 
Published: January 2023

Abstract
Contact hypersensitivity (CHS) is a CD8 T cell mediated response to hapten sensitization and challenge of the skin. Hapten-primed CD8 T cell infiltration into the skin challenge site is observed 12-16 h post-challenge and requires prior neutrophil infiltration and activation within the site. The neutrophil activities required to direct this T cell infiltration have remained undefined. Absent CHS responses to 2, 4-dinitrofluorobenzene (DNFB) in gld/perforin-/- (dKO) mice are caused by the absence of T cells in the hapten challenged skin of sensitized dKO mice at 18 h despite the presence of neutrophils 6 h after challenge. The absence of T cell infiltration into the hapten challenged skin of sensitized dKO mice was accompanied by absent expression of the T cell chemoattractants CCL1, CCL2, and CCL5 in the site at 6 h after challenge. Gr-1+ cells purified from WT bone marrow expressed high levels of FasL and perforin mRNA. Transfer of these wild-type Gr-1+ cells to sensitized dKO at time of hapten challenge restored expression of CCL1, CCL2 and CCL5 in the challenged skin as well as T cell infiltration into the site at 18 h after challenge and the edema of the CHS response. These results indicate the requirement for neutrophil expression of FasL and perforin in hapten challenged skin to induce the chemoattractants for activated T cells and other leukocytes that direct hapten-primed T cells into the challenged skin site to mediate the edema of CHS responses.
Specific antigenic recognition shifts a balance from tolerance to effector immune responses in lupus cerebritis (173.34)
Authors: Dasgupta Subhajit , Molano Ivan 
Published: January 2023

Abstract
Lupus cerebritis is a distinct mid brain specific disease with unknown etiology. The MRL/MpJ (Fas lpr/Faslpr) mice are used to study systemic lupus as well as organ specific lupus cerebritis. We found a decrease in CD3+CD4+CD25+ regulatory T cells (Treg) in 22 weeks lupus prone female MRL/MpJ (Faslpr/Faslpr) than asymptomatic 6 weeks old mice. Such attenuation of tolerance specific Treg cells was inversely related with CD3+CD1d+ T cells. We found, at 22 weeks of disease, there was an increase of CD3+CD1d+ T cells than 6 weeks old asymptomatic mice. We also found that, the TLR2 ligand LTA and TH17 cytokine IL17 play a role in activation of CD19+ B cells in spleen mononuclear cells. These CD19+ B cells were also found positive for CD1dgalactosylceramide. The LTA injection in female MRL/lpr mice increased expansion of CD1d+CD19+ B220+CD5- activated B cells in spleen. However, there was a decrease in CD19+CD1d+CD5+ regulatory B (Breg) cells at the acute stage of disease. The observations suggested a possibility of switch in balance from tolerance to effector immune responses in MRL mice during progression of disease. Studies are undertaken to determine the mechanism of raise in antigen specific Breg responses in maintenance of Treg tolerance and attenuation of TH17/ IL17 responses as a way to prevent mid brain inflammation in lupus cerebritis.
CD13 regulates immune cell trafficking to solid tumors. (P641) (173.5)
Authors: Vernier Kaitlyn , Shapiro Linda 
Published: January 2023

Abstract
While solid tumor growth clearly triggers an inflammatory response, the tumors are often able to evade attack from the innate immune system by establishing both an immunosuppressive and tumor promoting microenvironment. Moreover, increases in infiltrating myeloid cells in tumors correlates with poor prognosis suggesting a role for these cells in the control of the tumor microenvironment. The peptidase CD13 acts as a homotypic adhesion molecule expressed on myeloid cells and activated endothelium (including tumor blood vessels) that regulates the transport of myeloid cells to sites of inflammation. Naive wild type or CD13 null mice show identical immune cell profiles but display significant differences in the number and ratio of myeloid subsets recruited to the sites of disease upon inflammatory challenge prompting our investigation into its role in myeloid cell control of the tumor microenvironment. We found that allografts grown in CD13 null mice have more infiltrating monocytes and macrophages as well as an increase in tumor growth rate. Paradoxically, although tumor growth is more rapid, tumor angiogenesis is markedly decreased suggesting tumor vessels are more patent in the absence of CD13 and can more efficiently supply the growing tumor. Therefore, CD13 has a role in immune cell trafficking, infiltration into solid tumors, and tumor angiogenesis. The knowledge gained from this study will broaden our understanding of immune cell contribution to cancer progression.
Role of microRNA in 3,3-diindolylmethane (DIM)-mediated amelioration of SEB-induced acute lung injury (173.6)
Authors: Elliott David , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: January 2023

Abstract
Staphylococcal enterotoxin B (SEB) is a CDC select agent of bioterrorism and a public health threat during nosocomial infections. A deleterious effect of SEB exposure is acute lung injury (ALI) and acute respiratory distress syndrome characterized by pulmonary infiltration. 3,3-diindolylmethane (DIM) found in cruciferous vegetables, has been shown to have anti-inflammatory properties. We studied the mechanism underlying the ameliorative effects of DIM on SEB-induced ALI. Mice were exposed to SEB [50 mg; intranasal] and administered DIM [100 mg/kg] via oral gavage. Forty-eight hours after SEB exposure, serum, lung tissue and lung infiltrating cells were collected. DIM treatment led to a decrease in lymphocytic infiltration, specifically CD4+, CD8+ and Vβ8+ T cells as well as NKT cells. DIM also led to a reduction of fluid leak in lungs. DIM [10, 25, 50 µM] induced apoptosis in splenocytes and CD3+ T cells treated in vitro with SEB in a dose-dependent manner. DIM treatment led to downregulation in microRNA, miR-706 and miR-494 that target pro-apoptotic genes, and upregulation of miR-22 and miR-34a targeting anti-apoptotic genes in lung-infiltrating cells. Thus, studies are underway to examine whether in T cells, DIM treatment leads to modulation in the expression of genes involved in apoptosis. Together, these studies demonstrate that DIM treatment may suppress SEB-mediated ALI by induction of apoptosis in T cells via alteration in expression of miRNA.
A non human primate gamma Interferon assay for quantitation of cellular immune responses to therapeutic specific and measles antigen specific responses (174.11)
Authors: Jawa Vibha , Deshpande Meghana , Zhou Lei , Wullner Danika , Chirmule Naren 
Published: January 2023

Abstract
We have developed and optimized an in vitro functional assay using whole blood derived peripheral blood derived mononuclear cells (PBMC) from non-human primates. The assay was used to quantitate therapeutic specific T cell responses following dosing with a fully human antibody based therapeutic. Measles-specific response from same animals was used as a control. The drug product specific response was evaluated using 50 monkeys dosed with the therapeutic. The PBMC were tested for reactivity to the therapeutic and to a control measles peptide cocktail, using an IFN-gamma ELISPOT assay and a Luminex based cytokine secretion assay. The optimization and qualification experiments describe: i) evaluation of number of cells to be plated in culture, ii) pre-resting of cells before plating, iii) viability of cells, and iv) impact of co-stimulatory cytokines (IL2, IL7, and IL15) on elicitation of antigen-specific responses. An assay specific cut point and stimulation index was calculated to distinguish responders from non-responders. Using this qualified assay, therapeutic specific responses and measles-specific T cell responses were evaluated in 56 and 50 monkeys respectively. These assays may provide an assessment of antigen-specific T cell function in vivo, and have various applications, such as evaluation of immune competence status of animals, immunomodulatory effects of drug products, and understanding the T cell dependence of anti-drug-antibody immune responses.
Effect of delay from sample collection to umbilical cord mononuclear cell isolation on T cell phenotype and function. (174.20)
Authors: Scheible Kristin , Secor-Socha Shelley , Wightman Terry , Wang Hongyue , Mariani Thomas , Topham David , Pryhuber Gloria , Quataert Sally 
Published: January 2023

Abstract
Background: The unpredictable nature of deliveries makes it difficult to control timing of umbilical cord mononuclear cell (UCMC) isolation. Our study tested the effect of time delay from umbilical cord collection to UCMC isolation on T cell phenotype and function. Methods: Cord blood was drawn from 15 healthy term deliveries using a standardized collection method. Each sample was divided and processed immediately, 24 hours and 48 hours after collection. Samples were analyzed using flow cytometry for phenotype and cytokine secretion, with and without in vitro stimulation. Comparisons were made to determine differences in variation and median cell frequencies over time. Results: Viability and recovery were &gt;92% for all time-points. There was a decrease after 48 hours for CD56+ and CD3+ frequencies. CD4+ T cells showed differences after 24 hours in 4 of 23 subpopulations, and 8 subpopulations after 48 hours. No differences were seen with cytokine positive frequencies for IFNg, TNFa, IL17, or IL4/5/13 after 24 and 48 hours, but there was a decrease in IL2 and increase in MIP1β frequencies for CD4+ T cells. IL2 alone was increased for CD8+ T cells after 24 and 48 hours. Variation analysis showed high assay reproducibility, and subject-subject variation exceeded time delay variation for most populations. Conclusion: A 24-hour delay prior to UCMC isolation does not significantly change phenotype or function of most cord T cell subsets. A 48-hour delay may affect study results.
The Alarmin Interleukin-33 is a Notch Target in Quiescent Endothelial Cells (174.6)
Authors: Haraldsen Guttorm , Jetne Reidunn , Hol Johanna , Sponheim Jon , Küchler Axel , Kasprzycka Monika , Sundlisæter Eirik 
Published: January 2023

Abstract
The molecular mechanisms that induce and maintain expression of the alarming interleukin-33 (IL-33) in endothelial cells are unknown. Based on the observation that IL-33 is also a marker of endothelial cell quiescence, we hypothesized that the Notch signaling pathway might be involved in regulation of IL-33 expression. Here we show that activation of Notch1 by immobilized Notch ligands was sufficient to induce nuclear IL-33 expression in human umbilical vein endothelial cells (HUVECs). Furthermore, IL-33 expression in confluent HUVECs was inhibited by the γ-secretase inhibitor DAPT or by blocking antibodies to Dll4, Jagged1 or Notch1, as well as by knockdown of the transcription factor RBP-Jκ. In vivo, expression of Dll4 but not Jagged1 was generally observed in all segments of quiescent vessels in healthy organs in both human and rat tissue, and therefore well correlated with expression of IL-33. Moreover, subcutaneous injections of DAPT markedly reduced expression of vascular IL-33, compatible with a role for Notch signaling in driving vascular IL-33 expression in vivo. Taken together, our data demonstrate that the alarmin IL-33 is a target of Notch and serve to further establish Notch signaling in innate immune defense.
Environmental exposure during pregnancy modulates fetal Treg development with consequnces for the allergy risk of the child (175.10)
Authors: Herberth Gunda , Hinz Denise , Bauer Mario , Röder Stefan , Olek Sven , Hühn Jochen , Sack Ulrich , Borte Michael , Simon Jan , Lehmann Irina 
Published: January 2023

Abstract
Regulatory T cells (Treg) are characterized by a specific demethylated region in the FOXP3 gene. There is evidence that prenatal exposure and lifestyle factors may have the potential to cause alterations in DNA methylation. The aim of the present study was to analyze the influence of prenatal environmental exposure on Treg numbers in cord blood due to demethylation of FOXP3 and the subsequent risk for the development of allergic disease. Analyses were performed in blood samples from pregnant women in the 34th gestational week and in cord blood (n=346 mother-child pairs) in the LINA study. DNA methylation of the Treg specific demethylated region (TSDR) of the FOXP3 gene in cord blood and total and specific IgE to food (fx5) and inhalant (sx1) allergens were determined. Exposure and disease outcomes were assessed by detailed questionnaires. Prenatal exposure to tobacco smoke and the usage of disinfectants during pregnancy were associated with decreased Treg numbers in cord blood. Children with low Treg numbers in cord blood had a significantly higher risk to develop an atopic dermatitis (adj. OR 1.55, 95% CI 1.00-2.41) and sensitization to food specific allergens (adj. OR 1.55, 95% CI 1.06-2.25) during the first year of life. These results indicate that environmental exposure during pregnancy may have the potential to influence the Treg number at birth. Low numbers of Treg in cord blood may predict the development of atopic dermatitis.
CD8+ T cells are not essential for the development of murine allergic airway disease (AAD). (175.13)
Authors: McKnight Christopher , Perkins Charles , Finkelman Fred 
Published: January 2023

Abstract
Murine models of asthma have shown that some cell types, including CD4+ T cells, are essential for induction of AAD. The importance of other T cell subtypes, including CD8+ T cells, is controversial. Although CD8+ T cells are reported to have little importance of AAD induction in rats, CD8+ T cells are reported to contribute substantially to AAD induction in mice. Notably, the murine experiments used transfer of T cells, ovalbumin (OVA) as antigen and peritoneal sensitization with adjuvant to induce disease and primarily studied C57BL/6 mice. We investigated this disparity with the more direct approach of antibody-mediated CD8+ T cell depletion in BALB/c and C57BL/6 mice. We find that CD8+ cells are irrelevant when inducing airway hyperresponsiveness (AHR) in BALB/c mice with house dust mite (HDM) in the absence of adjuvant or with OVA plus alum, but contribute to the development of eosinophilia in both strains of OVA-immunized mice. Our OVA immunization protocol only induced AHR in BALB/c mice. Thus, CD8+ T cells do not appear to be required for AAD induction when a potent allergen relevant to human asthma is used to immunize mice that are relatively prone to develop Th2 responses, but may promote AAD in a less Th2-biased mouse strain. These observations may have relevance to the possible role of CD8+ T cells in human allergy and asthma.
Chemokines mediate ethanol exacerbation of murine cockroach-allergen induced asthma. (175.15)
Authors: Bouchard Jacqueline , Beal Dominic , Allen Jessica , Kim Jiyoun , Vaickus Louis , Remick Daniel 
Published: January 2023

Abstract
Contributors to the development of atopic asthma can be multifactorial, with severe cases often requiring several stimuli, including allergen, LPS, and environmental factors. Here we show that alcohol intoxication concurrent with cockroach allergen (CRA) exposure will cause significant asthmatic exacerbations in mice pre-sensitized to CRA. CRA exposures were given on days 0 and 14, then outbred mice were gavaged with water or 32% ethanol on day 21 and challenged with CRA 30 minutes post-gavage. Kinetics of asthmatic inflammation were investigated. Ethanol intoxication significantly increased eotaxins and CXC chemokines in the bronchoalveolar lavage (BAL), peaking 90 minutes post-CRA challenge. Ethanol-gavaged mice displayed 2-fold increases in BAL eosinophils and 3-fold increases in BAL neutrophils over water-gavaged controls by 16 hours post-allergen challenge. Ethanol also resulted in significant respiratory impairment, including an acute 3-fold increase in airways mucin, increased mucus plug formation and bronchiole occlusion, and a 2-fold increase in airways hyperreactivity 14 hours post-CRA challenge. Pre-administration of a cocktail of neutralizing antibodies to eotaxins and CXC chemokines reduced BAL cellular infiltrate to baseline levels and decreased airways hyperreactivity by 50%. These data provide evidence that alcohol intoxication can exacerbate asthmatic inflammation and respiratory function, which may be mediated by ethanol-induced chemokine production.
Constitutive IL-13 promotes respiratory chlamydial infection and infection-induced chronic airway hyper-responsiveness (175.18)
Authors: Starkey Malcolm , Kim Richard , Horvat Jay , Essilfie Ama-tawiah , Beagley Ken , Mattes Joerg , Foster Paul , Hansbro Philip 
Published: January 2023

Abstract
We have previously shown that chlamydial lung infections in early-life drive the development of chronic airway hyper-responsiveness (AHR). To elucidate the mechanisms involved, we used a murine model of chlamydial lung infection, to investigate the influence of IL-13 on infection and infection-induced AHR. Infected IL-13-/- mice had less severe infection, reduced inflammation (neutrophils, dendritic cells, macrophages and T cells), less mucus secreting cells (MSCs) in the airways and attenuated AHR. More severe infection in wild-type (WT) mice was associated with the development of alternatively activated macrophages (increased Arg-1, FIZZ-1 and Ym-1), which were suppressed in IL-13-/- mice. Surprisingly, infection of WT mice did not induce any detectable increase in IL-13 expression. However, infection decreased the level of the IL-13 decoy receptor (IL-13Rα2), which may allow constitutive IL-13 to signal. Interestingly, reconstitution of IL-13 in IL-13-/- mice restored infection-induced inflammation and MSC formation, but not AHR. Furthermore, infection-induced inflammation and mucus were Stat-6-independent, whilst infection-induced AHR was dependent upon Stat-6. Thus, early-life respiratory chlamydial infection results in decreased decoy receptor expression, which allows constitutive IL-13 to signal and promote more severe infection, which drives the development of chronic AHR that persists into adulthood.
Allergic lung inflammation decreases the anti-viral response to vaccinia virus (175.3)
Authors: Walline Crystal , Sehra Sarita , Fisher Amanda , Guindon Lynette , Wilkes David , Brutkiewicz Randy , Kaplan Mark , Blum Janice 
Published: January 2023

Abstract
Despite the global eradication of smallpox following widespread vaccination with vaccinia virus (VV), other members of the poxviridae family persist and continue to infect animal and human hosts. Although the lung is the most lethal route of poxvirus infection, there is little known about the local immune response to pulmonary VV infection. Moreover, VV vaccination is contraindicated in patients with atopic dermatitis as the pro-allergic milieu diminishes anti-VV responses. Our goal was to determine the role of allergic airway disease (AAD) on the local immune response to VV infection. Our studies demonstrated increased weight loss, airway hyperreactivity, mucus gene expression, lung pathology and virus titer in mice with AAD. In contrast to observations from cells exposed to pro-allergic cytokines, expression of antimicrobial peptide genes in the lung tissue of infected mice was similar in control mice, and mice with AAD. At 4 days post infection (dpi) there was a more robust innate response in mice with AAD as evidenced by increased infiltration of lung macrophages and granulocytes. By 10 dpi, there were increased numbers of IL-10+CD8+ and IFNγ+CD8+ T cells and enhanced secretion of IL-10 and IFNγ in the bronchoalveolar lavage fluid of mice with AAD, compared to controls. Mice with AAD also had increased VV-specific IgG1 and IgM serum antibodies. These studies suggest the allergic lung microenvironment may influence the anti-viral immune response to pulmonary VV infection.