Journal articles on the topic 'Lungs Immunology'
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1
Wilkes, D. S., K. M. Heidler, L. K. Bowen, W. M. Quinlan, N. A. Doyle, O. W. Cummings, and C. M. Doerschuk. "Allogeneic bronchoalveolar lavage cells induce the histology of acute lung allograft rejection, and deposition of IgG2a in recipient murine lungs." Journal of Immunology 155, no. 5 (September 1, 1995): 2775–83. http://dx.doi.org/10.4049/jimmunol.155.5.2775.
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Abstract The immunologic and histologic changes associated with lung allograft rejection are believed to result from the presentation of donor lung alloantigens to recipient lymphocytes resulting in up-regulated Th1 lymphocyte activity. The ability of allogeneic lung immune cells to induce the pathologic and immunologic changes associated with acute lung allograft rejection are unknown. The current study determined whether allogeneic (C57BL/6, I-a(b)) bronchoalveolar lavage (BAL) cells (> or = 97% macrophages), when instilled into the lungs of recipient BALB/c mice (I-a(d)), induced the histology and immunology associated with acute lung allograft rejection. BALB/c mice received BAL cells from either C57BL/6 mice (allogeneic instillate) or BALB/c mice (autologous instillate) or PBS (control) by nasal insufflation weekly for 4 wk. Allogeneic BAL cells resulted in a lymphocytic bronchitis and vasculitis analogous to grade 1 to 2 lung allograft rejection. The mice given allogeneic instillates had a greater percentage of lymphocytes in the BAL fluid than those given autologous instillates. After instillation of allogeneic BAL cells, the Th1 cytokines, IL-2 and IFN-gamma (IFN-gamma), were produced locally in greater quantities and more frequently than Th2 cytokine IL-10. IL-4, another Th2 cytokine, was not detected. The local production of IgG1 and IgG2a, which are dependent on IL-4 and IFN-gamma, respectively, were increased. However, only IgG2a was deposited in the perivascular and peribronchiolar tissues. These data show that installation of allogeneic BAL cells into the airways of recipient mice induced up-regulated Th1 lymphocyte activity and caused the histologic changes associated with lung allograft rejection.
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polikepahad, sumanth, Jad El-Daye, Arash Naghavi, Jonathan Miller, Preethi Gunaratne, and David Brian Corry. "Lung RNA profiling suggests an essential role for micro RNAs in regulating allergic lung disease (91.9)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S161. http://dx.doi.org/10.4049/jimmunol.178.supp.91.9.
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Abstract MicroRNAs (miRNAs) are small non-coding RNAs, which negatively regulate gene expression by translational inhibition of target mRNAs. In vertebrates, miRNAs are produced in most organs, including lungs. In the current study, we hypothesized that the expression of miRNAs would correlate inversely with expression of critically important target genes involved in the pathogenesis of allergic lung disease. After intranasal challenge of mice with a potent allergen derived from Aspergillus oryzae on alternating days for 2 weeks, lungs were isolated, high quality RNA was extracted and subjected to microarray analysis in comparison to naïve lungs obtained in parallel. In allergic lungs, ~ 30 known miRNAs were suppressed and ~100 were induced, including many new miRNA candidates uncovered through genome-wide predictions. Bioinformatics analysis revealed that miRNA 199a*, which was suppressed, and miR-144 which was induced in allergic lungs, are candidate regulators of STAT-6, GATA-3 and costimulatory factors, all of which are critical mediators of allergic lung disease. These studies suggest the existence of many new miRNAs and pivotal role for miRNA 199a* in controlling the expression of allergic lung disease.
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Kulkarni, Hrishikesh Satish, Fuyi Liao, Lina Ma, Xiaobo Wu, Daniel Kreisel, John P. Atkinson, and Andrew E. Gelman. "C3 expression by lung transplants reduces alloimmune-mediated injury." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 69.21. http://dx.doi.org/10.4049/jimmunol.202.supp.69.21.
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Abstract Allograft injury is a major risk factor for death in lung transplant recipients. Complement protein C3 is primarily synthesized in the liver. However, a recent study by our group has demonstrated that C3 present in pulmonary epithelial cells can be augmented to facilitate their own ability to withstand acute environmental stress. Here, we hypothesized that pulmonary C3 expression reduces the severity of allograft rejection. To address this question, C3−/−left lungs [on a C57BL/6 (B6) background] were orthotopically transplanted into wildtype (WT) fully MHC mismatched (CBA/J) recipients. The right lung, native to the recipient, served as an internal control. CBA/J lungs transplanted into C3−/− recipients, C3−/− lungs transplanted into C3−/− recipients and CBA/J lungs transplanted into WT B6 recipients were also employed as controls. One week after transplantation, recipients were euthanized and evaluated for C3 levels and graft injury. C3 protein in C3−/− recipients of WT B6 and CBA/J lungs was not detected in the peripheral circulation but was expressed within graft tissues suggesting locally expressed C3 is sequestered within the lung. Signs of graft tissue injury were only observed in allogeneic recipients. However, acute rejection severity was significantly higher in C3−/− allografts when compared to WT allografts. Additionally, C3−/− allografts had a distinct pattern of acute alveolar damage and increased cellularity not evident in WT allografts. Taken collectively, our data indicate that expression of C3 by lung allografts attenuates alloimmunedependent responses that are associated with reduced survival in humans.
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Barker, Kimberly A., Anukul T. Shenoy, Nicole Stauffer-Smith, Emad Isam Arafa, Carolina Lyon de Ana, Alex Barron, Fumiaki Aihara, et al. "Lung resident memory B cells are a common and functionally significant component of lung adaptive immunity." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 85.8. http://dx.doi.org/10.4049/jimmunol.204.supp.85.8.
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Abstract Resident memory B cells (BRM) in influenza-recovered mouse lungs were recently described, but whether other types of infections elicit these cells is unknown. The relevance of BRM in human lungs and to lung immune defenses also remains unexplored. Using flow cytometry and immunofluorescence, we found that respiratory pneumococcal exposures in mice elicited lung BRM without concurrent tertiary lymphoid structure formation. Additionally, flow cytometry analysis of normal human lung tissue showed that human lungs are enriched compared to human blood for B cells bearing a resident memory phenotype. These findings indicate that lung BRM are a common feature of antigen-experienced lungs. Multiple mouse models were used to address the contributions of B cell immunity to anti-pneumococcal lung defenses. Mice exposed to a low virulence pneumococcal strain 4 weeks previously were well-protected from a serotype-mismatched pneumococcal challenge. When previously exposed mice were depleted of circulating B cells (but not lung B cells) with anti-CD20 treatment before the challenge infection, there was no effect on the acquired lung immunity. However, a genetically engineered mouse strain allowed effective depletion of lung B cells bearing PD-L2 (a mouse memory B cell marker) from previously exposed mice, and doing so before the virulent pneumococcal challenge resulted in substantial defects in bacterial clearance compared to mice with lung B cells intact. These results provide the first direct evidence of a role for lung BRM in anti-bacterial lung immunity. Notably, this defense was pneumococcal serotype-independent, distinguishing it from the serotype-specific immunity elicited by current pneumococcal vaccines.
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Nishinakamura, R., R. Wiler, U. Dirksen, Y. Morikawa, K. Arai, A. Miyajima, S. Burdach, and R. Murray. "The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation." Journal of Experimental Medicine 183, no. 6 (June 1, 1996): 2657–62. http://dx.doi.org/10.1084/jem.183.6.2657.
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Mice mutant for granulocyte macrophage colony-stimulating factor (GM-CSF) or the common receptor component (beta c) for GM-CSF, interleukin (IL)-3, and IL-5 exhibit a lung disorder similar to human pulmonary alveolar proteinosis, a rare disease with congenital, infantile, and adult forms. Bone marrow transplantation and hematopoietic reconstitution of beta c mutant mice with wild-type bone marrow reversed the established disease state in the lungs, defining this disease as hematopoietic in nature. It is likely that the disease involves alveolar macrophages, as donor myeloid cell engraftment into the lungs of mutant recipient mice correlated with reverting both the disease and an abnormal macrophage morphology seen in the lungs of affected animals. Recombination Activating Gene-2 mutant donor bone marrow, which lacks the potential to develop lymphocytes, reversed the pathology in the lungs to the same extent as whole bone marrow. These data establish that certain lung disorders, if of cell-autonomous hematopoietic origin, can be manipulated by bone marrow transplantation.
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Lund, Sean J., Kathryn A. Patras, Jacqueline M. Kimmey, Asami Yamamura, Gilberto Hernandez, Omar Lakhdari, Alyssa M. McCoy, Victor Nizet, and Lawrence S. Prince. "Polysaccharide capsule allows Group B Streptococcus to avoid killing in a newborn pneumonia model." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 117.30. http://dx.doi.org/10.4049/jimmunol.200.supp.117.30.
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Abstract Group B Streptococcus (Streptococcus agalactiae, GBS) causes severe infections in neonates. While not a common adult pathogen, GBS is the leading cause of congenital pneumonia. To determine the molecular mechanisms of neonatal susceptibility, we developed a murine GBS pneumonia model. Neonatal, juvenile, and adult C57BL/6 mice were inoculated intranasally with 2800 CFU/g of GBS (COH1). After 7 d, survival was 100 % in adults and juveniles, with 10 % of neonates dying within 3 d after infection. Histopathological assessments showed severe lung injury scores 24 h after infection, with adult and juvenile mice demonstrating resolution of injury at 3 d post infection and normal histology after 7 d. In contrast, neonatal lungs had persistent lung injury up to 7 d post infection. By FACS, GBS induced rapid neutrophil recruitment into adult lungs and increased CD11b expression on adult lung macrophages. In neonatal lungs, GBS neither increased neutrophil numbers nor altered macrophage marker expression. Confocal imaging showed GBS in adult lungs almost entirely localized to alveolar macrophage phagolysosomes. However in neonatal lungs, GBS was only rarely phagocytosed by macrophages. These data were consistent with GBS killing data, which showed complete GBS killing within 24 h in adult and juvenile mice, but persistent GBS viability within the lung for up to 3 d in neonates. Defective GBS killing in neonates appeared to require the GBS capsule. Neonatal mice were much more efficient in killing the ΔcpsD capsule mutant compared to wild type GBS. Adult mice showed equal killing of ΔcpsD or wild type GBS. Our data suggest that the GBS capsule prevents killing by the newborn lung innate immune system, leading to neonatal disease susceptibility.
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Park, Juwon, Christina Lee, and Michelle D. Tallquist. "PDGFRα ablation leads to alteration of ECM and immune cell composition in the lung." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 74.20. http://dx.doi.org/10.4049/jimmunol.204.supp.74.20.
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Abstract Fibroblasts are the major cells responsible for tissue homeostasis, repair, and remodeling. In particular, PDGFRα is expressed by mesenchymal progenitors in the lung that constitute the myofibroblast population which transiently express α-SMA during alveologenesis. In the fibrotic lungs, PDGFRα+ lineages can differentiate into subpopulation of myofibroblasts which regulate tissue repair and remodeling. Although the contribution of PDGFRα+lineage to lung development and fibrosis are particularly well-known, their roles in the lung parenchyma at baseline are less characterized. To explore how PDGFRα+ fibroblasts affect extracellular matrix in baseline lung, we used genetic ablation of PDGFRα+ fibroblasts using Pdgfrα-CreERT2-driven expression of diphtheria toxin A. Histologically, thin mesenchyme was observed in fibroblast-ablated adult lungs. A majority of PDGFRα+ lineages are Col1a1-GFP+ cells, but PDGFRα-ablated lungs showed a significant decrease in the number of PDGFRα lineage and Col1a1-GFP+ cells. In addition, decreased expressions of ECM genes, such as Col1a1, Col1a2, and fibronectin-1 were observed in PDGFRα-ablated lungs. These data indicated that PDGFRα+ cells are a major source of extracellular proteins and PDGFRα ablation leads to alteration of ECM homeostasis in the baseline lung. Flow cytometry analysis of the lung tissues revealed that PDGFRα ablation resulted in elevated numbers of leukocytes and neutrophils. However, fibroblast loss did not affect macrophage numbers. These data suggested that fewer PDGFRα+ cells or loss of ECM or both can affect the recruitment of immune cells in the lung. In summary, changes in ECM environment by PDGFRα ablation leads to altered immune cell composition in the lung.
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Lorenzo, Erica, Jacob Hopkins, Julie Lefebvre, and Laura Haynes. "Vaccination does not protect aged mice from influenza-induced lung inflammation (VAC9P.1062)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 145.2. http://dx.doi.org/10.4049/jimmunol.194.supp.145.2.
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Abstract Aging predisposes individuals to increased susceptibility to influenza infection and delays in viral clearance. Importantly, we show that age-related delays in viral clearance are correlated with lingering inflammation in the lungs of aged mice. This is critical since inflammation in the lungs is associated with an enhanced susceptibility to secondary bacterial infection, which is a significant sequela to flu infection and often causes death. Inflammation in young lungs following flu infection can be significantly reduced by prior flu immunity, such as that generated following vaccination with recombinant influenza nucleoprotein (rNP). This protection is characterized by reduced lung inflammation, reduced lung damage, reduced susceptibility to flu challenge and also correlates with increased levels of IL-10 and anti-NP antibodies. In contrast, vaccination of aged mice with rNP does not reduce lung inflammation and shows no protection from weight loss and no reduction in viral titers in the lungs following subsequent flu infection. Additionally, aged mice generate lower levels of NP-specific antibodies, which are absolutely critical for reducing lung inflammation. Consequently, unlike young mice, these NP vaccinated aged mice are not protected from death due to secondary bacterial infection. Thus, when considering a universal flu vaccine such as rNP, it is important to understand how efficacious it can be in highly susceptible populations such as the elderly.
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Chapoval, Svetlana P., Ann E. Kelly-Welch, Elizabeth Smith, and Achsah D. Keegan. "Complex role of STAT6 in allergic airway inflammation (39.11)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S27. http://dx.doi.org/10.4049/jimmunol.178.supp.39.11.
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Abstract STAT6 plays a critical role in Th2 cell differentiation and in allergic lung inflammation. Using a chimeric mouse model, we observed alternative lung pathology in STAT6 KO mice even when WT bone marrow or Th2 cells were provided. Thus, we hypothesized that STAT6 contributes to inflammation in a complex manner. To detail STAT6 function, WT and STAT6 KO mice were subjected to OVA priming and challenges. Broncho-alveolar lavage (BAL) cell composition, lung histology, and FACS analysis of digested lungs were assessed 48h after the last challenge. As expected, eosinophils composed a majority of BAL cells in WT mice and less than 2% in STAT6 KO mice. The OVA-induced inflammation in STAT6 KO lungs was composed mainly of macrophages with small fractions of neutrophils and lymphocytes. The OVA-treated WT lungs showed strong although divergent expression of F4/80, Mac-2, and CD11b molecules; this was significantly reduced in STAT6 KO mice. However, the numbers of dendritic cells, B cells, CD4+ and CD8+ T cells in the lungs of OVA-treated mice were unaffected by STAT6 deficiency. Interestingly, STAT6 KO mice showed enhanced basal airway reactivity to methacholine and numbers of Mac-2+ cells as compared to WT mice, suggesting that STAT6 deficiency altered lung homeostasis. Taken together, our studies demonstrate STAT6-dependent and –independent features of asthma phenotype which may impact treatments targeting STAT6. (AI38985)
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Singh, Ram Raj, and Isela Valera. "Plasmacytoid dendritic cells contribute to pro-inflammatory and pro-fibrotic milieu in lung fibrosis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 182.76. http://dx.doi.org/10.4049/jimmunol.202.supp.182.76.
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Abstract Fibrosis, the end-result of tissue injury in a wide range of diseases, contributes to >40% of mortality in the US. Plasmacytoid dendritic cells (pDC) are reduced in the peripheral blood, but increase in the lungs and skin of patients with systemic sclerosis, a prototypic fibrotic disease (JCI Insight 2018). The frequency of pDCs in the lungs of patients correlated with the severity of lung disease and with levels of proteins implicated in inflammation and fibrosis. Importantly, depletion of pDCs ameliorated lung and skin fibrosis in the bleomycin-induced animal model. pDC depletion also altered the expression levels of proteins and genes implicated in chemotaxis, inflammation, and fibrosis in the lungs. To test if pDCs directly contribute to inflammatory/profibrotic milieu in fibrosis, we injected C57Bl/6 mice with bleomycin, harvested lungs, and analyzed lungs for proteins by Western blot, ELISA, and flow cytometry. CD36 that is implicated in platelet-collagen adhesion, oxidative stress and inflammation was increased on pDCs but not on mDCs, other myeloid cells, B cells and T cells in the lungs of bleomycin-injected mice as compared to control mice. TLR7 was also increased more on pDCs than on all other immune cells examined, whereas TLR2 was increased more on mDCs and other myeloid cells but not on pDCs and B cells. TGFβ-latent peptide was higher on all immune cells examined in the lungs of bleomycin-injected animals than in controls. Among chemokine receptors, CCR2, CCR3, CCR6, CCR9 and CXCR4 were higher on pDCs than other cells. In summary, pDCs elicit profibrotic milieu in the development of systemic fibrosis. These observations identify the increased trafficking of pDCs’ to the affected organs as a therapeutic target in fibrosis.
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Donkor, Michael A., Jamie Choe, Byron Quinn, and Harlan P. Jones. "Abstract A53: Intranasal nanoparticulate PLGA cancer vaccine administration prevents secondary lung metastasis." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): A53. http://dx.doi.org/10.1158/2326-6074.tumimm22-a53.
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Abstract The lung is one of the most frequent sites of cancer metastasis. Because metastatic lung disease is usually associated with poor survivorship, decreasing secondary lung metastasis will decrease morbidity and mortality associated with cancer. Mitigating tumor immunosurveillance at metastatic sites such as the lung is essential for tumor progression and metastasis. As such, tumors developing elsewhere in the body take advantage of the natural tolerogenicity of the lung to establish immunosuppressive niches via tumor burden induce pre-metastatic niche formation to support lung metastasis. Here we tested the ability of an intranasal nano-vaccine administration to prevent the seeding of tumor cells in the lungs by pre-emptying tumor burden induced immunosuppression. Our hypothesis is that intranasal administration of cancer nano-vaccine will prevent secondary lung metastasis from an existing primary tumor. Because breast cancer is the one of the primary tumors with high propensity to metastasize to the lung, we used the syngeneic mouse breast tumor model to test our hypothesis. Our results showed that intranasal administration of our engineered nano-vaccine protected the lungs of female BALB/c mice from secondary lung metastasis after orthotopic implantation of murine 4T1 tumors. The protection was as a result of nano-vaccine induced antitumor immunity in the lungs. Mice that received the intranasal nano-vaccine had increased frequency of effector T-cells and increase accumulation of lung resident memory T-cell in their lungs. This coincided with increased frequency of IFN-g and granzyme B producing CD8+ T-cells following ex-vivo restimulation of lymphocytes from the lungs of previously immunized mice with tumor cell. These results demonstrate that cancer vaccines can still be part of an integrated cancer therapy where they can be used as a prophylactic approach to prevent secondary lung metastasis. Citation Format: Michael A Donkor, Jamie Choe, Byron Quinn, Harlan P Jones. Intranasal nanoparticulate PLGA cancer vaccine administration prevents secondary lung metastasis [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A53.
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Block, Katharine E., Koji Iijima, Daniel A. Walsh, Mark Pierson, Sara E. Hamilton, Hirohito Kita, and Stephen C. Jameson. "Lung ILC2 responses to Alternaria alternata fungal allergen are blunted in “dirty” mice with physiologically transmitted murine microbes." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 147.2. http://dx.doi.org/10.4049/jimmunol.204.supp.147.2.
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Abstract The objective of this study was to test the hypothesis that the increasing global incidence of allergy and atopy are due in part to improved hygiene and decreased microbial exposure. We have adopted a novel mouse model of normalized microbial exposure to test the impact of immune experience on subsequent responses to airway allergens. In this model, specific pathogen free (SPF) B6 mice are cohoused with mice from pet stores and become “dirty” – many commensals and pathogens are transmitted through cohousing and influence the immune cell populations systemically and in the lungs. We treated mice intranasally with a single dose of A. alternata fungal extract (Alt) and assessed production of type 2 cytokines. IL5 and IL13 levels in the lungs and bronchoalveolar lavage fluid were dramatically elevated by Alt in SPF mice but were not significantly increased by Alt in dirty mice. Type 2 innate lymphoid cells (ILC2) are the cells responsible for IL5 and IL13 after acute Alt treatment, and interestingly the number of lung ILC2 was unaltered by cohousing and their activation status appeared similar in both housing conditions. We treated mice with recombinant IL33, the alarmin released by lung epithelial cells in response to allergens, and the results suggest an impaired response to IL33 by dirty lung ILC2. In a repeated Alt exposure model, ILC2 cells expanded in SPF lungs and recruited eosinophils, neutrophils, and T cells. Most dirty mouse lungs contained these cell populations at steady state but were only modestly recruited with repeated Alt exposure. Lung function experiments are in progress. This study suggests that increased microbial exposure leads to more type-2 associated immune cells in the lungs, however responses to airway allergens are dampened.
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Hwang, Ji Young, Javier Rangel-Moreno, Maria de la Luz Garcia-Hernandez, and Troy Randall. "Inducible bronchus-associated lymphoid tissue reduces Th2-driven pathology by redistributing leukocytes within the lung (P6214)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 62.6. http://dx.doi.org/10.4049/jimmunol.190.supp.62.6.
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Abstract Inducible bronchus-associated lymphoid tissue (iBALT) is an ectopic lymphoid tissue formed in the lung after pulmonary infection or inflammation. This local lymphoid tissue is structurally similar to conventional secondary lymphoid organs, with separated B and T cell areas, specialized stromal cells and lymphoid dendritic cells (DCs). Here, we tested whether the presence of iBALT affects pulmonary immune responses to allergens. We induced iBALT formation in neonatal mice by pulmonary administration of LPS, and when the mice were adults, challenged them intranasally with OVA. We found that although mice with iBALT had more lymphocytes in their lungs, they had fewer eosinophils, less goblet cells and had reduced Th2 cytokine production in bronchoalveolar (BAL) fluid and lung tissue after OVA challenge. Surprisingly, using IL-4 reporter and by transferring OVA-specific OT-II cells, we found that the presence of iBALT did not reduce the number of Th2 cells that accumulated in the lung. Despite similar numbers of Th2 effectors in the lungs of mice with and without iBALT, we found that Th2 cells were differentially distributed in these two groups of mice. Those in the lungs of mice without iBALT were more widely dispersed, whereas the cells in the lungs of mice with iBALT were predominantly concentrated in the lymphoid tissue. These results suggest that the reduction in Th2-driven pathology with iBALT is due to the redistribution of leukocytes within the lung after iBALT formation.
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Lawrence, Donald W., and Jacki Kornbluth. "E3 ubiquitin ligase NKLAM is important for bacterial killing in a murine model of streptococcal pneumonia." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 77.10. http://dx.doi.org/10.4049/jimmunol.198.supp.77.10.
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Abstract Natural killer lytic associated molecule (NKLAM) is an important component of the innate immune system. Previous in vitro studies using NKLAM-KO macrophages have demonstrated that NKLAM positively affects the transcriptional activity of STAT1, a transcription factor crucial for proper immune function. Therefore, we hypothesized that NKLAM-KO mice would be unable to mount an effective immune response when exposed to Streptococcus pneumoniae. Using a nasal inhalation infection model we found that the lungs of NKLAM-KO mice had a significantly higher bacterial load than WT mice. This observation was associated with increased lung phosphatase activity and decreased STAT1 phosphorylation. STAT1 regulates a large number of genes, including iNOS and MCP-1, which are important for successful pathogen eradication. In our model, we observed that NKLAM-KO mice expressed less iNOS in their lungs at 24 and 48 hr post-infection in comparison to WT mice. Additionally, infected NKLAM-KO lungs contained less TNF-alpha, IL-12, IFN-gamma and MCP-1 than lungs from WT mice. NKLAM-KO mice had significantly less neutrophil lung infiltration than WT mice, an effect that is likely due to the decreased expression of chemokines including MCP-1. In summary, these novel findings demonstrate the importance of NKLAM in innate immunity and begin to define a role for NKLAM in leukocyte trafficking to the lung upon S. pneumoniae infection.
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Shan, Ming, Han-Fang Cheng, David Corry, and Farrah Kheradmand. "Lung antigen presenting cells in human emphysema (93.21)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 93.21. http://dx.doi.org/10.4049/jimmunol.184.supp.93.21.
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Abstract Exposure to tobacco smoke activates innate and adaptive immune responses that in long-term smokers have been linked to diseases of the lungs, cardiovascular system, joints, and other organs. The destruction of lung tissue that underlies smoking-induced emphysema has been associated with T helper 1 cells that recognize the matrix protein elastin. Factors that result in the development of such autoreactive T cells in smokers remain unknown but are crucial for further understanding the pathogenesis of systemic inflammatory diseases in smokers. Here, we show that lung myeloid dendritic cells were sufficient to induce T helper 1 and T helper 17 responses in CD4 T cells. T helper 1 and 17 cells are invariably present in lungs from patients with emphysema but not in lungs from normal individuals. Interleukin-17A, a canonical T helper 17 cytokine, enhanced secretion of CCL20, a chemoattractant for dendritic cells, and matrix metalloproteinase 12, a potent elastolytic proteinase, from lung macrophages. Thus, although diverse lung factors potentially contribute to T helper effector differentiation in vivo, lung myeloid dendritic cells direct the generation of pathogenic T cells and support a feedback mechanism that sustains both inflammatory cell recruitment and lung destruction. This mechanism may underlie disease in other elastin-rich organs and tissues.
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McGill, Jodi, Nico Van Rooijen, and Kevin L. Legge. "IL-15 trans-presentation by pulmonary dendritic cells promotes effector CD8 T cell survival during influenza virus infection." Journal of Experimental Medicine 207, no. 3 (March 8, 2010): 521–34. http://dx.doi.org/10.1084/jem.20091711.
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We have recently demonstrated that peripheral CD8 T cells require two separate activation hits to accumulate to high numbers in the lungs after influenza virus infection: a primary interaction with mature, antigen-bearing dendritic cells (DCs) in the lymph node, and a second, previously unrecognized interaction with MHC I–viral antigen–bearing pulmonary DCs in the lungs. We demonstrate that in the absence of lung-resident DC subsets, virus-specific CD8 T cells undergo significantly increased levels of apoptosis in the lungs; however, reconstitution with pulmonary plasmacytoid DCs and CD8α+ DCs promotes increased T cell survival and accumulation in the lungs. Further, our results show that the absence of DCs after influenza virus infection results in significantly reduced levels of IL-15 in the lungs and that pulmonary DC–mediated rescue of virus-specific CD8 T cell responses in the lungs requires trans-presentation of IL-15 via DC-expressed IL-15Rα. This study demonstrates a key, novel requirement for DC trans-presented IL-15 in promoting effector CD8 T cell survival in the respiratory tract after virus infection, and suggests that this trans-presentation could be an important target for the development of unique antiviral therapies and more effective vaccine strategies.
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Lindell, Dennis, and Maria White. "Allergic lung disease is enhanced by antigen-specific B cells (P6033)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 120.17. http://dx.doi.org/10.4049/jimmunol.190.supp.120.17.
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Abstract Previous studies from our laboratory have demonstrated that B cells play an important role in the initiation and maintenance of chronic allergic lung disease (asthma), and ascribed much of this role to antigen presentation (Lindell et al. PLoSONE 2008). Although present at higher frequency than other organs, antibody secreting B cells in the lungs represent a small proportion (<0.1%) of the overall B cells in the lungs. As alternative strategies to study the role of B cells in this disease, we have used novel flow cytometric techniques to detect the de novo expansion of antigen-specific B cells during allergic lung disease, as well as utilizing adoptive transfer of naive antigen-specific B cells. Mice were immunized with hen egg lysozyme and a cohort of these mice received adoptive transfers of HEL-specific B cells from MD4 mice. Our data indicate that the addition of antigen-specific B cells augmented mucus production in the lungs. Mechanistically, this was associated with increased T cell responses in the lungs (a 4-fold increase in CD69+ CD4+ and CD8+ T cells), significantly higher levels of IL-13 and IL-17a, as well as overall inflammation, although very few HEL+ B cells were found in the lungs, and we observed no increase in HEL-specific antibodies. These data suggest that B cells predominantly contribute to allergic disease by amplification of the T cell response, rather than via the production of antibodies.
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Quintero, Eric A., Katherine A. Gott, and Julie A. Wilder. "Evidence of Murine Alternatively Activated Lung Macrophages are Associated with Failure to Clear Pulmonary Cryptococcus neoformans (133.54)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 133.54. http://dx.doi.org/10.4049/jimmunol.182.supp.133.54.
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Abstract We have previously shown that murine pulmonary immunity to the fungal pathogen Cryptococcus neoformans (Cne) is genetically regulated. C.B-17 mice efficiently clear the organism from the lung following intranasal inoculation whereas C57BL/6 mice do not. The ability to clear Cne from the lungs of C.B-17 mice is dependent upon the development of a Type 1 immune response. In contrast, infected C57BL/6 mice mount a Type 2 immune response. As alternatively activated macrophages (AAMs) have been associated with the development of a Type 2 immune response, we reasoned that Cne-infected C57BL/6 mice may have more AAMs in their lungs as compared to infected C.B-17 mice. We tested our hypothesis by analyzing the expression of four transcripts generally over-expressed in AAMs (YM1, FIZZ1, ARG1, and ARG2) in whole lung homogenate samples via PCR. Our data show increased expression of these markers over time post-Cne infection in both strains (increasing from 6 hours - 14 days) with greater expression in C57BL/6 mice at all time points. Lungs from naïve C57BL/6 mice also showed higher expression of ARG1, FIZZ1 and YM1 compared to naïve C.B-17 lungs. These data support our hypothesis that there are more AAMs in the lungs of Cne-infected C57BL/6 mice as compared to similarly infected C.B-17 mice. This research was supported by Lovelace Respiratory Research Institute internal funds.
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Kuan, Emma Lo, and Steven F. Ziegler. "Thymic stromal lymphopoietin promotes interplay between breast tumor cells, neutrophils and Ly6Chi monocytes to regulate breast tumor progression." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 72.2. http://dx.doi.org/10.4049/jimmunol.196.supp.72.2.
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Abstract Various human cancers display a T helper type 2 (Th2)-like inflammation. One possible mechanism suggested in human breast cancers is thymic stromal lymphopoietin (TSLP) secreted by breast tumor cells which can drive Th2 responses via tumor-associated dendritic cells. However, the interactions between TSLP, tumor cells, and other immune cells remain unclear. We found in breast tumor-bearing mice TSLP can also be produced by two pro-tumor myeloid cell populations, neutrophils and Ly6Chi monocytes. This non-tumor derived TSLP is crucial for both primary breast tumor growth and its metastasis to lungs. One important mechanism is myeloid derived TSLP can directly act on tumor cells and promote survival and TSLP production of tumor cells. Mice transplanted with TSLPR deficient breast tumor cells developed smaller primary breast tumors and fewer lung metastases. Conversely, mice that constitutively express TSLP in lungs transplanted with breast tumor cells had markedly increased lung metastases. Blocking TSLP in lungs resulted in a reduction in the number of lung metastases. We further discovered that TSLP signaling in Ly6Chi monocytes is crucial for their suppressor functions and their ability to differentiate into macrophages in tumors. Transfer of TSLP receptor deficient Ly6Chi monocytes significantly reduced lung metastases in tumor-bearing mice by changing T cell populations in lungs and in tumors. Our work is the first to show myeloid cell derived TSLP plays an important role in promoting breast tumor progression via maintaining tumor cell survival. We also provide a novel mechanism of the requirement of TSLP signaling in differentiation and suppressor functions in Ly6Chi monocytes.
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Mattingly, Cameron, Jennifer L. Elliott, Jeronay K. Thomas, Jenna L. Lobby, Sarah E. Michalets, and Jacob E. Kohlmeier. "Examining effector functions of lung CD8+ tissue resident memory T cells in humans." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 182.23. http://dx.doi.org/10.4049/jimmunol.208.supp.182.23.
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Abstract Due to their position in the lung tissue, CD8+ tissue resident memory T cells (TRM) act as sentinels of the respiratory tract that rapidly respond to, and mediate protection against, respiratory viruses. In mice, TRM have been shown to mediate protection at barrier sites by producing cytokines, chemokines, and performing cell lysis. In the lungs specifically, our lab has shown that influenza-specific CD8+ TRM rapidly produce IFNγ, but airway TRM are poorly cytolytic in mice. In humans, less is known about the effector functions of virus-specific CD8+ TRM in the lungs, and thus this study seeks to fill that gap in knowledge. Using cells from healthy human lungs, we first identified and quantified the frequency of antigen-specific cells in our lung donors by performing intracellular cytokine staining (IFNγ+) and activation induced marker assays (CD137+ CD25+). Then, by performing a series of in vitro peptide stimulation and cytokine neutralization experiments, we investigated which cytokines are produced by lung CD8+ TRM, and how those cytokines impact local innate and epithelial cells. Initial results show that, when stimulated with their cognate antigen, lung CD8+ TRM produce cytokines that directly activate innate immune cells. Results of this study suggests that human CD8+ TRM in the lungs act to rapidly reprogram local immune cells, and these data will ultimately help us understand how CD8+ TRM fit into the overall immune response to respiratory viruses. Supported by grants from the NIH/NHLBI (R35 HL150803) and by NIH/NIAD through the Centers of Excellence for Influenza Research and Response (75N93019R00028).
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Walzer, P. D., and M. J. Linke. "A comparison of the antigenic characteristics of rat and human Pneumocystis carinii by immunoblotting." Journal of Immunology 138, no. 7 (April 1, 1987): 2257–65. http://dx.doi.org/10.4049/jimmunol.138.7.2257.
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Abstract The antigenic characteristics of rat Pneumocystis carinii obtained from infected lungs and grown in tissue culture were compared with the properties of human P. carinii obtained from the lungs of AIDS and non-AIDS patients by the immunoblotting technique, using different sources of antibody. Major immunoreactive bands of 45, 50, and 116 kd were found in both lung and tissue culture-derived rat P. carinii, suggesting the organism retains its antigenic characteristics in short-term culture. The principal immunoreactive bands in human P. carinii included a band of 40 kd, and to a lesser extent, a band of 66 kd; these antigens were found in the lungs of six and seven AIDS patients but in only one of eight non-AIDS patients with pneumocystosis. The rat and human P. carinii antigens reacted with sera from immunized rabbits, from rats with pneumocystosis and prolonged environmental exposure to the organism, from AIDS and non-AIDS P. carinii patients, and from healthy blood donors. Reactivity of these antigens could be removed by adsorption of antisera with P. carinii-infected lungs but not with normal lungs or lungs infected with bacteria and fungi. We conclude that rat and human P. carinii have shared, as well as species-specific, antigenic determinants, which should be useful for a variety of studies with this organism.
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McGill, Jodi, Nico Van Rooijen, and Kevin L. Legge. "Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs." Journal of Experimental Medicine 205, no. 7 (June 30, 2008): 1635–46. http://dx.doi.org/10.1084/jem.20080314.
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Influenza infections induce a rapid, but transient, dendritic cell (DC) migration from the lungs to the lymph nodes (LNs) that is followed by substantial recruitment of DCs into the lungs without subsequent migration to the LNs. Given that peripheral DCs are primarily thought to be involved in the initiation of adaptive immunity after migration into lymphoid tissues, what role these newly lung-recruited DCs play in influenza virus immunity is unclear. In this study, we demonstrate that loss of non-LN migratory pulmonary DC subsets increases mortality, sustains higher viral titers, and impairs pulmonary CD8 T cell responses. Reconstitution of the lungs with pulmonary plasmacytoid DCs, CD8α+ DCs, or interstitial DCs restores CD8 T cell responses in a cell contact–, major histocompatability complex I–, and influenza peptide–dependent manner. Thus, after their initial activation in the LN, protective influenza-specific CD8 T cell responses require additional antigen-dependent interactions, specifically with DCs in the lungs.
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Jung, Bock-Gie, Biodun A. Adeniyi, and Buka Samten. "Mycobacterium tuberculosis stimulates neutrophil infiltration into the lungs through activation of S100A proteins in an early secreted antigenic target of 6-kDa dependent manner." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 52.17. http://dx.doi.org/10.4049/jimmunol.200.supp.52.17.
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Abstract Health Science Center at Tyler Neutrophils infiltrate the lungs in active tuberculosis (TB) and contribute to the exacerbation of TB pathology. However, the contributing factors and the mechanisms of neutrophil infiltration in TB are unclear. As secretion of early secreted antigenic target of 6 kDa (ESAT-6) and its molecular partner culture filtrate protein 10 kD (CFP10) by ESX-1 secretion system is essential for pathogenesis of Mycobacterium tuberculosis (Mtb), we infected C57BL/6 mice intranasally with Mtb strains H37Rv, its esat-6 deletion mutant, and esat-6 complemented strain and evaluated lung neutrophil infiltration. H37Rv and esat-6 complemented strain induced neutrophil infiltration at day 7 and peaked at day 14 post infection. Whereas esat-6 deletion mutant induced significantly less neutrophil infiltration at both time points. In line with this, intranasal delivery of recombinant ESAT-6 but not CFP10 or Hank’s balanced salt solution (vehicle) induced neutrophil infiltration of the lungs as early as 2 hours, peaked at 24 hours, and started to decline at 72 hours post treatment. RNA-sequencing analysis of total lung RNA from ESAT-6 or CFP10 treated mice identified S100A9 as one of the most significantly upregulated genes by ESAT-6. Real-time PCR and ELISA validated that ESAT-6 stimulated increased gene expression and protein secretion of S100A9 in mouse lungs. Immunohistochemistry analysis revealed that ESAT-6 induced neutrophilic lung inflammation. Consistent with this, H37Rv and esat-6 complemented strain induced significantly higher levels of S100A9 compared to their esat-6 deletion mutant in mouse lungs after intranasal infection. We conclude that ESAT-6-induced S100A9 plays a critical role in lung neutrophil infiltrations in TB infection.
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Yuan, Xiaoyi, Ming Shan, Ran You, Rick Wetsel, Scott Drouin, Alexander Seryshev, Li-zhen Song, David Corry, and Farrah Kheradmand. "Differential requirement of C3a receptor in APC-driven emphysema in response to cigarette smoke (P6225)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 115.8. http://dx.doi.org/10.4049/jimmunol.190.supp.115.8.
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Abstract Pathogenic lung antigen presenting cells (APCs) are abundant in the lungs of smokers with emphysema and are capable of inducing T helper type 1 (Th1) and Th17 cell differentiation. Mice exposed to chronic cigarette smoke develop emphysema and harbor CD11b+CD11c+ APCs that can transfer the disease to naïve mice. Proteolytic products from activated innate immune cells cleave complement proteins but the contribution of their downstream signaling in APC-driven lung parenchyma destruction is less clear. We show here that relative to control smokers, complement 3 (C3) is increased in the plasma and its cleaved products are deposited on the lung tissue of smokers with advanced lung disease. Matrix metalloproteinase 12 and neutrophils elastase directly cleave human C3, and generate multiple activated signaling products. Compared to wild type, C3 deficient mice exposed to chronic smoke showed reduced CD11b+CD11c+ cells in the lungs and were protected against emphysema development. C3a and C5a, two of the major anaphylatoxin and chemoattractant mediators downstream of C3 activation, are present in the lungs of mice exposed to smoke, but only C3a signaling was critical in emphysema development because deficiency in C3a receptor (C3aR) but not C5aR phenocopied C3-/- mice in this model. These findings suggest a critical role for C3aR in the pathogenesis of smoke induced lung disease, and could be explored to develop specific new therapeutic targets for emphysema treatment.
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Naura, Amarjit, Kunal Kapoor, Esha Singla, and Bijayani Sahu. "PARP inhibitor, olaparib ameliorates acute lung injury by modulating oxidative stress and NF-κB mediated inflammatory response in mice (HUM1P.265)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 52.14. http://dx.doi.org/10.4049/jimmunol.194.supp.52.14.
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Abstract We have previously shown that poly (ADP-ribose) polymerase (PARP)-1 gene deletion in mice provide robust protection against lung inflammation in the context of asthma and acute lung injury. Olaparib is a potent new generation PARP inhibitor that has been approved for human testing in cancer patients. The present work was designed to evaluate its beneficial potential against LPS-induced acute lung injury upon intra-tracheal administration of the endotoxin in mice. Administration of olaparib at different doses, 30 min after LPS treatment showed that single injection of the drug effectively reduced the total number of inflammatory cells particularly neutrophils in the lungs. This was associated with reduced pulmonary edema as the total protein content in bronchoalveolar fluid was found to be decreased substantially. The drug restored the LPS mediated oxidative stress toward normal in lungs as assessed by measuring malondialdehyde and GSH levels. Finally, RT-PCR data revealed that olaparib downregulates the LPS induced expression of NF-κB dependent genes namely TNF-α, IL-1β and VCAM-1 in the lungs without altering the expression of total p65NF-κB. Overall, the data suggests that olaparib possesses a strong therapeutic potential against LPS induced lung injury in mice. Given the fact that olaparib is approved by FDA for human testing, our findings can pave the way for testing of the drug on humans inflicted with acute lung injury.
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Shenkar, Robert, and Edward Abraham. "Mechanisms of Lung Neutrophil Activation After Hemorrhage or Endotoxemia: Roles of Reactive Oxygen Intermediates, NF-κB, and Cyclic AMP Response Element Binding Protein." Journal of Immunology 163, no. 2 (July 15, 1999): 954–62. http://dx.doi.org/10.4049/jimmunol.163.2.954.
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Abstract Acute inflammatory lung injury occurs frequently in the setting of severe infection or blood loss. Accumulation of activated neutrophils in the lungs and increased pulmonary proinflammatory cytokine levels are major characteristics of acute lung injury. In the present experiments, we examined mechanisms leading to neutrophil accumulation and activation in the lungs after endotoxemia or hemorrhage. Levels of IL-1β, TNF-α, and macrophage inflammatory protein-2 mRNA were increased in lung neutrophils from endotoxemic or hemorrhaged mice compared with those present in lung neutrophils from control mice or in peripheral blood neutrophils from endotoxemic, hemorrhaged, or control mice. The transcriptional regulatory factors NF-κB and cAMP response element binding protein were activated in lung but not blood neutrophils after hemorrhage or endotoxemia. Xanthine oxidase inhibition, achieved by feeding allopurinol or tungsten-containing diets, did not affect neutrophil trafficking to the lungs after hemorrhage or endotoxemia. Xanthine oxidase inhibition did prevent hemorrhage- but not endotoxemia- induced increases in proinflammatory cytokine expression among lung neutrophils. Hemorrhage- or endotoxemia-associated activation of NF-κB in lung neutrophils was not affected by inhibition of xanthine oxidase. cAMP response element binding protein activation was increased after hemorrhage, but not endotoxemia, in mice fed xanthine oxidase-inhibiting diets. Our results indicate that xanthine oxidase modulates cAMP response element binding protein activation and proinflammatory cytokine expression in lung neutrophils after hemorrhage, but not endotoxemia. These findings suggest that the mechanisms leading to acute inflammatory lung injury after hemorrhage differ from those associated with endotoxemia.
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Alharris, Esraah Sattar, Hasan F. Alghetaa, Philip Brandon Busbee, Mitzi Nagarkatti, and Prakash Nagarkatti. "Resveratrol treatment alters lung microbiome in the murine ovalbumin-induced asthma model by increasing mucus-degrading Akkermansia muciniphila." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 44.31. http://dx.doi.org/10.4049/jimmunol.200.supp.44.31.
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Abstract Asthma is a chronic inflammatory disease that involves the narrowing of the lung airways and excessive mucus production. Resveratrol (RES), a polyphenolic stilbene, is known to control asthmatic attacks via different molecular mechanisms. However, no studies have examined the effect of resveratrol on the microbiome in the ovalbumin (OVA)-induced asthma mouse model. In this study, we induced asthma in BALB/c mice by injecting OVA followed by 7 days treatment with RES. Plethysmography showed that the expiratory resistance in the lung tissue was significantly reduced in the RES treated group, while mean volume, peak expiratory flow, and frequency of respiration was increased. Histopathological examination of the lungs of the RES-treated group showed significant reduction in inflammatory cell infiltration and led to restoration of normal lung tissue architecture. In addition, there were significant increases in the expression of the genes encoding tight-junction molecules (claudin-1 and cadherin-18) in the RES-treated group. We performed 16S rRNA microbial analysis of cecal flushes and pulmonary tissues, which showed that RES treatment alters the gut microbiome by significantly increasing the level of Bacteroides acidifaciens spp. compared to disease controls. In addition, there was a significant increase in Akkermansia muciniphila (AM) species within the lungs after RES treatment. AM is a gram-negative, non-spore-forming bacterium known to induce mucus degradation. Since asthma is characterized by an increase in mucus in the lungs, we concluded that RES improves asthma in OVA-induced mouse model by significantly increasing AM and preventing mucus build-up in the lungs.
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Mehta, Simren, Jiayong Xu, Yanhua Wang, and John Chan. "Role of secreted IgM in regulating the host response to Mycobacterium tuberculosis." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 65.19. http://dx.doi.org/10.4049/jimmunol.196.supp.65.19.
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Abstract B cell aggregates, which display characteristics of germinal center reactions, are a prominent feature in the lungs of Mycobacterium tuberculosis (Mtb)-infected hosts. Using the B cell-deficient mouse strain μMT, we have previously shown that B cells are required for optimal protection against aerosol Mtb infection. μMT mice display exacerbated lung granulomatous inflammation during acute tuberculosis (TB), and this can be ameliorated by adoptive transfer of B cells or treatment with immune serum, suggesting a role for immunoglobulin in modulating the local lung response to Mtb. To investigate the role of antibody in a protective host response to Mtb, we utilized mice deficient in various immunoglobulins. Mice unable to secrete IgM (μS−/−) were more susceptible to aerosol Mtb infection than those lacking all other immunoglobulin isotypes, and displayed increased mortality during chronic TB. Relative to wild-type (WT) mice, Mtb-infected μS−/− mice had fewer lymphoid aggregates and a delayed granulomatous response in the lungs, despite having greater numbers of activated pulmonary CD4+ T cells. Treatment of μS−/− mice with immune serum (derived from Mtb-infected WT mice) during acute infection, led to increased lymphoid aggregates and plasma cells in the lungs, more pulmonary infiltrate, a concomitant decrease in the lung bacterial burden, and ultimately delayed the onset of death of μS−/− mice during chronic TB. These data suggest IgM plays an important role in controlling Mtb infection by orchestrating local granulomatous responses in the lungs, which leads to improved host survival during the chronic phase of infection.
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McGill, Jodi, and Kevin Legge. "Influenza specific CD8 T cells require interactions with pulmonary DC in the lungs in order to mount an effective immune response (42.8)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S34. http://dx.doi.org/10.4049/jimmunol.178.supp.42.8.
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Abstract Our studies show that respiratory dendritic cells (rDC) transiently migrate (i.e. within the first 48 hours post infection) from the lungs to the lymph nodes (LN) following influenza virus infections. However, DC are continually recruited into the lungs even after DC migration to the LN has ceased. Since CD8 T cell activation and programming occurs in the LN, the role of these lung-recruited DC in influenza immunity was unclear. To better understand their role, we depleted rDC after the conclusion of normal rDC trafficking to the LN and assessed the immune response. Our results show decreased CD8 T cell responses, resulting in increased viral titers, morbidity and mortality. Initial T cell expansion and activation in the LN, and migration to the lungs appears equivalent in both wildtype and rAPC depleted mice (rAPCneg). However, in rAPCneg mice, these activated T cells fail to continue their expansion once arriving in the lungs. Examination of the DC subtypes present in the lungs revealed decreased numbers of both pulmonary pDC and CD8+ DC in rAPCneg mice through 6 days p.i. Reconstitution of rAPCneg mice with purified pulmonary pDC or CD8+ DC restores influenza-specific CD8 T cell immunity in a MHC I dependent manner. These results suggest that activated influenza-specific CD8 T cells may require additional antigen-specific interactions with recruited DC in the lungs in order to protect against influenza virus infections.
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Naik, Shibani, Jack Gallup, Shan Yu, Young-Je Sim, Kyoung-Jin Yoon, Daniel Nettleton, and Marian Kohut. "Exercise modulates the immune response to influenza infection in aged mice. (170.28)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 170.28. http://dx.doi.org/10.4049/jimmunol.188.supp.170.28.
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Abstract Exercise training prior to influenza virus infection in aged mice decreases illness severity, reduces lung viral load, and decreases inflammatory cytokine/chemokine levels in bronchoalveolar lavage (BAL) fluid. We hypothesized that an exercise-associated increase in anti-viral responses (Type I IFN and related genes, pentraxins) may contribute to reduced viral load. Exercise may also increase the rate of cell turnover in the lungs to limit the spread of virus. METHODS: Old mice (18mos) were exercised moderately 5d/wk for 10 wks, rested for 24h, and then infected with influenza A/PR/8/34 H1N1. Non-exercised old mice and young mice (2mos) were controls. Lungs were collected several times post-infection (p.i.); mRNA was detected in lungs using RT qPCR. Cytokines in BAL were measured by ELISA. Formalin Fixed Paraffin Embedded (FFPE) lungs were used to detect the presence of virus and Caspase 3 by IHC. RESULTS: After exercise training, interferon-inducible antiviral gene expression (Oas1b, B2m, BST2 & GBP1) was increased, but at 12-24 hr p.i., exercise was associated with decreased BAL IFNα & IFNβ, and reduced lung mRNA of IFNα4 and Oas1a. Exercise did not alter viral attachment or apoptosis 6hr p.i. The results suggest that exercised basal level expression of several interferon-related genes which may contribute to the early reduction in viral load.
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Tjota, Melissa, and Anne Sperling. "Activation of monocytes through FcRγ-signaling promotes IL-33-dependent migration into the lung interstitium (HYP7P.270)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 191.18. http://dx.doi.org/10.4049/jimmunol.194.supp.191.18.
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Abstract The development of Type 2 responses, such as those seen in asthma, has been significantly associated with IL-33. Previously, we demonstrated that allergen-specific IgG immune complex (IC) signaling through FcγRIII on IL-33 sufficient DCs induced Type 2 allergic airway inflammation. These data suggested that IL-33-/- mice, which had diminished Type 2 responses in the lungs, had a defect in APC function. For this study, we focused on monocytes and CD11b+ monocyte-derived DCs (moDCs) as they were shown to have the highest levels of FcγRIII expression, antigen uptake, and IL-33 upregulation. Notably, there was a significant reduction in the numbers of monocytes and CD11b+ moDCs in the lungs of IL-33-/- mice compared to WT mice after IC sensitization, although no defect was observed at baseline. Using intravascular staining to identify cell localization, we demonstrated that antigen uptake of ICs promoted migration of monocytes from the lung vasculature to the lung interstitium in an FcγRIII- and IL-33-dependent manner. Functionally, failure of monocyte migration during IC-mediated Type 2 inflammation led to reduced eosinophilia in the lungs. Overall, our findings suggest that during sensitization, activation of FcγRIII in monocytes promotes migration into the interstitium in an IL-33 dependent manner, and that this migration is essential for the development of Type 2 responses in the lungs during allergic airway inflammation.
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Gimenes-Junior, Joao, Luana Vitoretti, Beatriz Accetturi, Adriana Lino-dos-Santos-Franco, Ana Ligeiro-de-Oliveira, Jean Peron, Thiago Aloia, Joao Palermo-Neto, Ricardo Oliveira-Filho, and Wothan Tavares-de-Lima. "Influence of ovariectomy on the cytokine release in acute lung injury induced by LPS in mice (P5052)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 180.9. http://dx.doi.org/10.4049/jimmunol.190.supp.180.9.
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Abstract Acute respiratory distress syndrome is a multifactorial disease characterized by acute lung injury, hypoxemia and polymorphonuclear cells infiltration. Clinical and experimental evidences indicate that female sex hormones may greatly influence lung inflammation. Previous data from our group revealed that ovariectomy (OVx) blunted LPS-induced lung inflammation in mice after 24 h. Here, we expanded the study and assessed the influence of OVx on the release of cytokines by lung cells after LPS. 7 day-OVx female C57BL/6 mice were subjected to intranasal instillation of LPS or saline. Non-manipulated animals were subjected to the same procedures and served as controls (Sham-OVx). 24 h thereafter, animals were euthanized and lungs removed. The levels of IL-1β, IL-17, IFN-γ and IL-10 were measured. Ovaries removal per se did not alter the cytokines levels in the lung compared with the control group. Moreover, intranasal instillation of LPS increased the cytokines released in the lungs from both OVx and Sham-OVx groups compared to controls. On the other hand, LPS challenged animals had more IL-1β, IL-17 and IFN-γ within the OVx group. This was associated with significantly higher levels of IL-10 in the same group. Lack of female sex hormones led to an increased release of pro-inflammatory cytokines by the lungs, demonstrating its role in modulating the development of acute lung injury induced by LPS in mice.
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McKallip, Robert, Christy Bridges, Gabriela Law, and Jingping Sun. "Targeting CD44 in SEB-induced acute respiratory distress syndrome (54.13)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 54.13. http://dx.doi.org/10.4049/jimmunol.188.supp.54.13.
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Abstract Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). In the current study we investigated the role of CD44 in ALI/ARDS. Intranasal exposure of CD44 wild type (CD44 WT) mice to SEB led to a significant increase in the expression of CD44 on lung mononuclear cells. CD44 knockout (CD44 KO) mice developed significantly reduced SEB-induced ALI/ARDS, compared to similarly treated CD44 WT mice. Deletion of CD44 did not have a significant effect on lymphocyte activation, apoptosis or inflammatory cytokine production. However, mononuclear cell migration to the lungs of SEB-exposed CD44 KO mice was significantly reduced when compared to mononuclear infiltration in the lungs of SEB-exposed CD44 WT mice. Mechanistically, deletion of CD44 led to reduced ability of SEB-exposed spleen cells to bind to lung epithelial cells. Finally, treatment of SEB-exposed mice with anti-CD44 mAbs led to a significant reduction in vascular permeability, prevented inflammatory cells infiltration in the lungs and reduced the ability of SEB-exposed splenocytes to adhere to epithelial cells. Together, these results demonstrate an important role of CD44 in SEB-induced lung injury and suggest the possibility of targeting CD44 for the treatment of SEB-induced ALI/ARDS.
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Turner, Damian L., Jacob Verter, Ronak Turner, and Minwei Cao. "Tissue resident memory B cells established in lungs in allergic asthma." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 71.3. http://dx.doi.org/10.4049/jimmunol.198.supp.71.3.
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Abstract Allergic asthma is a disease driven by the adaptive immune system in the lungs. B cells play a critical role during the allergen sensitization process by producing IgE and possibly through antigen presentation. While most current research has focused on the role of CD4+ tissue resident memory (TRM) cells, it is not known whether TRM B cells exist within the lungs and what role they might play. To investigate this question, we sensitized mice to house dust mite (HDM) intranasally for three weeks to induce asthmatic symptoms. We in vivo labeled mice with circulating fluorescent anti CD45 mAb and assessed the lung B cells’ susceptibility to labeling. We found that B cells, that are resistant to in vivo labeling, are a major population of lung lymphocytes following HDM sensitization. We were further able to detect these non-circulating B cells in the lungs as late as 10 weeks after treatment in sensitized mice. Furthermore, these cells were found in the same anatomic locations as CD4+ TRM cells and underwent expansion during HDM challenge. These data suggest that B cells do form a tissue resident population in the lungs and that these cells are involved in allergic asthmatic responses. This resident memory population of B cells are also locally activated upon allergen rechallenge. Whether these B cells are reactivated by HDM-derived antigens or by T cell-derived cytokines is yet to be determined.
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Boulares, Hamid A., Amarjit S. Naura, Chetan P. Hans, Mourad Zerfaoui, Youssef Errami, Jihang Ju, Hogyoung Kim, and Jong Kim. "High Fat Diet Induces Lung Remodeling in Apoe Deficient Mice: An Association with an Increase In Circulatory and Lung Inflammatory Factors (94.31)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 94.31. http://dx.doi.org/10.4049/jimmunol.182.supp.94.31.
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Abstract Hypercholesterolemia is increasingly considered the basis for not only cardiovascular pathologies but also several complications affecting other organs including lungs. Here, we examined the effect of hypercholesterolemia on lung integrity using a mouse model (ApoE−/−) of high fat (HF) diet-induced atherosclerosis. A twelve-week HF diet regimen induced systemic production of TNF-α, IFN-γ, GMC-SF, RANTES, IL-1α, IL-2, and IL-12 with TNF-α as the predominant cytokine in ApoE−/− mice. Concomitantly, TNF-α, IFN-γ, and MIP-1α were detected in brochoalveolar lavage fluids of these mice, coinciding with lung inflammation consisting primarily of monocytes/macrophages. Such lung inflammation correlated with marked collagen deposition and an increase in matrix metalloproteinase-9 activity in ApoE−/− mice without mucus production or the mucus-promoting IL-13. Although TGF-β was undetectable in brochoalveolar lavage fluid of ApoE−/− mice on HF diet, it displayed a much wider tissue distribution compared to that of control animals. Direct intratracheal TNF-α-administration induced a lung inflammation pattern in wild-type mice that was strikingly similar to that induced by HF diet in ApoE−/− mice. TNF-α administration induced expression of several factors known to be critically involved in lung remodeling including MCP-1, IL-1β, TGF-β1, adhesion molecules, collagen type-1, and TNF-α itself in the lungs of treated mice. These results suggest that hypercholesterolemia may promote chronic inflammatory conditions in lungs that are conducive to lung remodeling potentially through TNF-α-mediated processes.
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Werner, Jessica, Melissa Gessner, Lauren Lilly, Michael Nelson, Allison Metz, Dawn Horn, Jessy Deshane, et al. "Mechanisms of Dectin-1 dependent IL-17A production during invasive fungal infection. (56.14)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 56.14. http://dx.doi.org/10.4049/jimmunol.186.supp.56.14.
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Abstract In the current work, we show that mice deficient in the beta-glucan receptor Dectin-1 demonstrate significantly reduced levels of IL-17A in the lungs 48 h after Aspergillus fumigatus (AF) challenge. Culturing cells from enzymatic lung digests ex vivo further demonstrated Dectin-1 dependent IL-17A production, providing a sensitive method to identify mechanisms associated with lung IL-17A production after AF challenge. Neutralization of IL-23, but not IL-1β or IL-6, in WT lung digest cell cultures reduced IL-17A production by 60%. Lung digest cells from AF-challenged Rorc-/- deficient mice had attenuated IL-17A production, however, Rorc and Rora mRNA, and RORγt protein, expression was not impaired in lung digest cells from Dectin-1 KO mice. Ahr, Irf4 and Card9 mRNA expression was also unchanged. Intracellular cytokine staining revealed that CD11b+ and CD11b+ Ly-6G+ cells were sources of IL-17A, although only CD11b+ Ly-6G+ cells produced IL-17A in a Dectin-1 dependent manner. In turn, Ly-6G+ cells purified from the lungs of AF-challenged Dectin-1 KO mice displayed a 2-fold reduction in Il17a mRNA expression, yet increased Rorc and Rora mRNA expression. IL-23R+ cells in lung digest were predominantly CD11b+ Ly-6G+ cells. In summary, Dectin-1 dependent innate IL-17A production in the lungs during invasive fungal infection is mediated in part by CD11b+ Ly-6G+ neutrophils, which is partially dependent on IL-23. Dectin-1 deficiency does not, however, compromise induction of Rorc.
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Vijay, Rahul, Xiaoyang Hua, David K. Meyerholz, Yoshimi Miki, Kei Yamamoto, Michael Gelb, Makoto Murakami, and Stanley Perlman. "Critical role of phospholipase A2 group IID in age-related susceptibility to severe acute respiratory syndrome–CoV infection." Journal of Experimental Medicine 212, no. 11 (September 21, 2015): 1851–68. http://dx.doi.org/10.1084/jem.20150632.
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Oxidative stress and chronic low-grade inflammation in the lungs are associated with aging and may contribute to age-related immune dysfunction. To maintain lung homeostasis, chronic inflammation is countered by enhanced expression of proresolving/antiinflammatory factors. Here, we show that age-dependent increases of one such factor in the lungs, a phospholipase A2 (PLA2) group IID (PLA2G2D) with antiinflammatory properties, contributed to worse outcomes in mice infected with severe acute respiratory syndrome-coronavirus (SARS-CoV). Strikingly, infection of mice lacking PLA2G2D expression (Pla2g2d−/− mice) converted a uniformly lethal infection to a nonlethal one (>80% survival), subsequent to development of enhanced respiratory DC migration to the draining lymph nodes, augmented antivirus T cell responses, and diminished lung damage. We also observed similar effects in influenza A virus–infected middle-aged Pla2g2d−/− mice. Furthermore, oxidative stress, probably via lipid peroxidation, was found to induce PLA2G2D expression in mice and in human monocyte–derived macrophages. Thus, our results suggest that directed inhibition of a single inducible phospholipase, PLA2G2D, in the lungs of older patients with severe respiratory infections is potentially an attractive therapeutic intervention to restore immune function.
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Wolf, Andrea J., Ludovic Desvignes, Beth Linas, Niaz Banaiee, Toshiki Tamura, Kiyoshi Takatsu, and Joel D. Ernst. "Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs." Journal of Experimental Medicine 205, no. 1 (December 24, 2007): 105–15. http://dx.doi.org/10.1084/jem.20071367.
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The onset of the adaptive immune response to Mycobacterium tuberculosis is delayed compared with that of other infections or immunization, and allows the bacterial population in the lungs to expand markedly during the preimmune phase of infection. We used adoptive transfer of M. tuberculosis Ag85B-specific CD4+ T cells to determine that the delayed adaptive response is caused by a delay in initial activation of CD4+ T cells, which occurs earliest in the local lung-draining mediastinal lymph node. We also found that initial activation of Ag85B-specific T cells depends on production of antigen by bacteria in the lymph node, despite the presence of 100-fold more bacteria in the lungs. Although dendritic cells have been found to transport M. tuberculosis from the lungs to the local lymph node, airway administration of LPS did not accelerate transport of bacteria to the lymph node and did not accelerate activation of Ag85B-specific T cells. These results indicate that delayed initial activation of CD4+ T cells in tuberculosis is caused by the presence of the bacteria in a compartment that cannot be mobilized from the lungs to the lymph node, where initial T cell activation occurs.
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Shea, L. M., C. Beehler, M. Schwartz, R. Shenkar, R. Tuder, and E. Abraham. "Hyperoxia activates NF-kappaB and increases TNF-alpha and IFN-gamma gene expression in mouse pulmonary lymphocytes." Journal of Immunology 157, no. 9 (November 1, 1996): 3902–8. http://dx.doi.org/10.4049/jimmunol.157.9.3902.
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Abstract Hyperoxia-associated production of reactive oxygen species leads to neutrophil infiltration into the lungs and increased pulmonary proinflammatory cytokine expression. However, the initial events induced by hyperoxia, and leading to acute inflammatory lung injury, remain incompletely characterized. To explore this issue, we examined nuclear transcriptional regulatory factor (NF-kappaB and NF-IL-6) activation and cytokine expression in the lungs following 12 to 48 h of hyperoxia exposure. No increases in cytokine (IL-1beta, IL-6, IL-10, TGF-beta, TNF-alpha, IFN-gamma) expression nor in NF-kappaB activation were found after 12 h of hyperoxia. Following 24 h of hyperoxia, NF-kappaB activation and increased levels of TNF-alpha mRNA were present in pulmonary lymphocytes. By 48 h of hyperoxia, amounts of IFN-gamma and TNF-alpha protein as well as mRNA were increased in the lungs, and NF-kappaB continued to show activation, even though no histologic abnormalities were present. These results show that hyperoxia activates NF-kappaB in the lungs before any increase in proinflammatory cytokine protein occurs, and suggest that NF-kappaB activation may represent an initial event in the proinflammatory sequence induced by hyperoxia.
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Khare, Anupriya, Zengbiao Qi, Mingjian Fei, Prabir Ray, and Anuradha Ray. "Role of specific dendritic cells in inducing Tregs in response to inhaled allergen. (103.5)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 103.5. http://dx.doi.org/10.4049/jimmunol.186.supp.103.5.
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Abstract Foxp3+ Regulatory T cells (Treg), both naturally occurring thymus-derived nTregs and peripherally induced Foxp3+ induced Tregs (iTreg), play a critical role in suppressing immune responses to self as well as external antigens, ensuring protection from autoimmune and allergic diseases such as asthma. Recent investigations have established a role for iTregs in the regulation of chronic allergic lung inflammation. However, the cellular and molecular mechanisms mediating induction of Tregs in the lungs are still unclear. In this study, we explored the role of dendritic cells (DCs) in Treg induction in response to inhaled allergen. Using an adoptive transfer model we demonstrate that exposure to low doses of allergen results in the induction of Foxp3+ Tregs (tolerance) in the lungs which requires the presence of CD11c+ DCs. Amongst the various resident DC subsets in the lungs, CD103+ lung DCs were the most potent inducers of iTregs. The tolerogenic property of the CD103+ DCs was compromised under inflammatory conditions and the DCs did not induce Tregs as efficiently. Finally, the induction of Tregs by CD103+ DCs was dependent on retinoic acid and TGF-β and was promoted in the absence of IL-4 signaling. Taken together, we show that despite the presence of multiple DC subsets in the lung, CD103+ DCs selectively mediate airway tolerance to inhaled allergens. Thus, strategies to improve the function of CD103+ DCs in the lung would help ameliorate allergic airways disease.
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Silva-Sanchez, Aaron, Selene Meza-Perez, Sara L. Stone, and Troy Randall. "Sterile-activated cDC1 cells in neonatal lung induce T cell IL-4 production and lymph node maturation." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 153.16. http://dx.doi.org/10.4049/jimmunol.198.supp.153.16.
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Abstract Neonates are susceptible to respiratory tract infections, possibly due to immature pulmonary dendritic cells (cDCs). Here we assessed the development and function of conventional DCs in the lung and the lung-draining mediastinal lymph node (MedLN). We found that neonatal lungs, from days 3 to 10 of life, contained a higher proportion of CD103+ cDC1 cells than adult lungs and that these cells could be divided into a small population of CD103hi cDC1 and a larger population of CD103int cDC1, which were not found in adult lungs. A similar expansion of cDC1 cells was observed in the MedLN migratory cDCs during the first 2 weeks after birth. Transcriptional and functional assays showed that neonatal CD103int cDC1 cells had an activated phenotype and efficiently migrated to the MedLN, their formation was dependent on the transcription factor Batf3 but CD103int cDC1 cells developed independently of the microbiota or MyD88 signaling. Neonatal cDC1 cells express high levels of OX-40L and produce IL-12p40, but not IL-12p70, and stimulated the differentiation of IL-4-producing OT-II cells. Importantly, the MedLNs of neonatal Batf3−/− had poorly developed HEVs and FRCs, which were restored by transfer of neonatal lung CD103int into Batf3−/− mice. These changes were not observed following transfer of CD103hi or CCR7−/− CD103int DCs. Overall our results indicate that neonatal lung CD103int cDCs are activated as part of a developmental program that promotes MedLN maturation and biases CD4 T cell activation towards IL-4 production.
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Li, Hong, J. Alyce Bradbury, XiaoJan Xu, Matthew L. Edin, Jianliang Li, Kevin Katen, Artiom Gruzdev, Joan P. Graves, Caroline N. Duval, and Darryl C. Zeldin. "Single-Cell RNA Sequencing Identifies a Novel Population of CD4+CD8+ T Cells that are Regulated by COX-2 During Allergic Lung Inflammation." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 65.17. http://dx.doi.org/10.4049/jimmunol.204.supp.65.17.
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Abstract To better understand the relative contributions of different cell types during allergic lung inflammation and the role of cyclooxygenase (COX)-derived eicosanoids in this process, we compared vehicle (control) and ovalbumin (OVA)-exposed lungs from wild type (WT) and COX-2−/− mice by single-cell RNA sequencing (scRNA-Seq). Twenty-two unique cell clusters were identified in allergic lungs based on cell signature markers. In addition to known cell types, we identified 2 clusters of CD4+CD8+. Both populations were mitotically active (high % in S/G2/M phases) and exhibited a unique molecular identifier (UMI) index. FACS analysis confirmed the presence of these two distinct cell populations (CD4+HCD8+H and CD4+LCD8+H) that were increased after OVA-induced allergic lung inflammation. Interestingly, isolated CD4+HCD8+H T cells stimulated with phorbol ester expressed IL-4, IL-5 and IL-13, but not IFNγ. In contrast, isolated and stimulated CD4+LCD8+H T cells primarily expressed IL-5. Mass cytometry (CyTOF) using a 37-antibody panel confirmed the increase in CD4+CD8+ T cells after OVA sensitization/exposure, as well as the induction of IL-4, IL-5 and IL-13. Importantly, CD4+CD8+-1 and CD4+CD8+-2 cell populations identified by scRNA-Seq were increased in lungs from OVA-treated COX-2−/− mice compared to lungs from OVA-treated WT mice. Furthermore, COX-2−/− CD4+CD8+ T cells preferentially produced more IL-4 and IL-5 than WT CD4+CD8+ T cells. Thus, using scRNA-Seq, CyTOF and FACS analyses, we identified two populations of CD4+CD8+ T cells that produce immunoregulatory cytokines and are regulated by COX-2. These cells may play an important, previously unappreciated role in the pathogenesis of allergic lung disease.
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Salgar, Shashikumar, Eddie Manning, Phillip Ruiz, and Si Pham. "Mesenchymal Stem Cell (MSC) Therapy To Prevent Ischemia-Reperfusion Injury in Lung Transplantation (145.24)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 145.24. http://dx.doi.org/10.4049/jimmunol.184.supp.145.24.
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Abstract Ischemia-reperfusion (IR) injury is an important cause for lung graft loss (~25%). In this study MSC were tested for their ability to prevent lung IR injury. MSC derived from bone marrow and fibroblasts from skin of Lewis rat were expanded ex vivo. Following 120 minutes of left lung ischemia induction, rats received autologous MSC or fibroblasts ( ~2 x 106; i.v.; passage ≤6) or saline. Significant (P<0.01) improvement in lung function as determined by blood oxygenation (PaO2/FiO2 ratio, mmHg) with MSC therapy was observed as early as 4h IR (305 ± 31; n =6) compared to untreated (63 ± 19; n=6) or fibroblast treated (142 ± 96; n=5) controls. By 24h IR blood oxygenation values reached normal (454 ± 59; n=5) in MSC treated group but not in fibroblast or saline treated controls. Histopathology demonstrated reduced (P<0.05) injury score (Grade 1.1 ± 1; n=7) with MSC therapy compared to untreated controls (Grade 2.5 ± 1.4; n=6). ISOL (in situ oligo ligation for DNA fragmentation) & Caspase-3 staining demonstrated reduced (p<0.05) apoptotic cells in MSC treated lungs. Inflammatory mediators (MCP-1, TNF-α, and IL-6) and cells, and wet to dry ratio/microvascular permiability index in the IR injured lungs were reduced (P<0.05) in MSC treated lungs. Long-term MSC (passage >25) improved blood oxygenation marginally by 72h (320±158; n= 6) compared to untreated controls (198±141; n= 6). In conclusion MSC therapy to prevent IR injury and improve lung transplant function seems promising.
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Coomes, Stephanie M., Carol A. Wilke, Thomas A. Moore, and Bethany B. Moore. "Impaired Anti-viral Immunity Following Syngeneic Bone Marrow Transplant (45.7)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 45.7. http://dx.doi.org/10.4049/jimmunol.182.supp.45.7.
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Abstract Patients receiving autologous hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT) as therapy for various malignancies or autoimmune diseases have an increased risk for infectious complications post-transplant, especially in the lung. We have used syngeneic BMT in mice and the murine gammaherpesvirus, MHV-68, to study the efficacy of adaptive immune responses post-BMT. Using this model, we have shown that mice 5 weeks post-transplant have fully reconstituted their hematopoeitic lineages in both the lung and periphery. However, the BMT mice have a reduced ability to clear lytic virus from the lung, despite increased expression of interferon gamma, interleukin-2, and TNF-alpha in the lungs of BMT mice. Recruitment of immune cells to the lungs after MHV-68 infection is similar in BMT mice and untransplanted controls, suggesting functional defects. While bone-marrow derived dendritic cells from transplanted mice are able to stimulate allogeneic T cell proliferation in mixed leukocyte reactions (MLRs), CD4+ T cells from BMT mice show reduced proliferative responses in MLRs. These results suggest defects in CD4+ T cell responses post-BMT may contribute to enhanced susceptibility to viral infections. Additionally, levels of TGF beta are significantly increased in the lungs of BMT mice before infection, and numbers of CD4+Foxp3+ regulatory CD4+ T cells are increased in the BMT lung (but not spleen) both before and at day 7 after viral infection. We speculate that TGF beta-induced expansion of Tregs in the lung limits anti-viral host defense post-bone marrow transplantation.
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Onami, Thandi M., and John R. Harp. "Unexpected role of selectin ligands in T cell trafficking to the lung (95.6)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 95.6. http://dx.doi.org/10.4049/jimmunol.182.supp.95.6.
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Abstract Selectin mediated tethering represents one of the earliest steps in T cell extravasation into lymph nodes via HEVs. Fucosyltransferases (FucT) -IV and -VII are required for production of the sialyl Lewis X moiety, which is essential for selectin mediated T cell entry into LNs. We examined T cell trafficking to lymphoid and non-lymphoid compartments such as the lung using FucT -IV and -VII double knockout (FucT DKO) mice. Examination of uninfected FucT DKO mice revealed significantly increased numbers of T cells localized in lungs, with no evidence of induced bronchial associated lymphoid tissue (iBALT). Following LCMV viral infection, we noted similar numbers of antigen specific CD8 T cells, but reduced numbers of total activated CD8 T cells in the lungs compared to wildtype mice. Finally, we transferred bona fide naïve or memory CD8 T cells into recipient mice and show increased trafficking of T cells into lungs of uninfected FucT DKO mice. We conclude from these studies that while selectin mediated entry may play an important role in T cell trafficking to the inflamed lung, in the absence of selectin ligand expression, T cells preferentially migrate to and are retained in the lung under non-pathological conditions. In situations where normal trafficking of T cells to LNs are compromised, tissues such as the lung may become sites for T cell accumulation, and this may play a role in the initiation of T cell mediated lung diseases. This work was supported by NIH grants AI057719, GM62116 (CFG), and University of Tennessee start up funds
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Papinska, Joanna Aleksandra, Grzegorz Gmyrek, R. Sathish Srinivasan, Umesh Deshmukh, and Harini Bagavant. "Pulmonary involvement in a mouse model of Sjögren’s syndrome induced by activation of the STING pathway." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 180.16. http://dx.doi.org/10.4049/jimmunol.202.supp.180.16.
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Abstract Sjögren’s Syndrome (SS) is a chronic autoimmune disorder characterized by an increased type 1 interferon gene signature, autoantibody production, and salivary gland inflammation. Engagement of Stimulator of interferon genes (STING) induces type 1 interferon production. Gain of function mutations in TMEM173, encoding STING, results in a severe vasculopathy affecting the skin and lungs. We have previously reported that activation of the STING pathway in mice, using a STING agonist DMXAA, causes an SS-like disease characterized by sialoadenitis and salivary gland dysfunction. Considering that lungs are affected in 9–20% of SS patients, this study was undertaken to investigate lung involvement in DMXAA treated mice. Female C57BL/6 mice injected with DMXAA rapidly upregulated expression of IFNβ, IFNγ, and Mx1 in the lungs at 4 hours. This was followed by an increase in type 1 innate lymphoid cells on day 8. Histopathologic analysis showed the presence of peri-bronchial inflammatory infiltrates on day 35, which persisted until day 57. The lung inflammation was associated with an increased expression of multiple pro-inflammatory genes including CCl20, CXCl10, CXCl9, and IL17α. In addition, there was an increased frequency of lymphatic endothelial cells, suggestive of lymphangiogenesis. Although STING expression was seen in bronchial epithelium and alveolar cells in the lung, bone marrow chimeras between STING KO and wild type mice suggest that STING expression in myeloid cells was critical for lung inflammation. Our results show that systemic activation of the STING pathway might play an essential role in lung inflammation in SS patients.
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Walsh, Kevin Barry, David Marsolais, Dorian McGavern, Yasuko Hatta, Yoshihiro Kawaoka, Hugh Rosen, and Michael B. A. Oldstone. "TREATMENT WITH A SPHINGOSINE ANALOG DIMINSHES IMMUNOPATHOLOGY FOLLOWING INFLUENZA VIRUS INFECTION (45.2)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 45.2. http://dx.doi.org/10.4049/jimmunol.182.supp.45.2.
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Abstract Highly pathogenic strains of influenza virus can result in high mortality rates due to severe tissue damage caused by direct injury induced by the virus or by the immune response against the virus (immunopathology). Immune-mediated pulmonary tissue damage is a result of cytokine/chemokine release and the antiviral activity by cells of the innate and adaptive immune responses. Here we report that intratracheal treatment with a sphingosine analog, AAL-R, results in the inhibition of dendritic cell (DC) activation and antigen presentation to T cells in the mediastinal lymph nodes and the lung. Diminished DC function restricts virus-specific T cell proliferation causing a subsequent reduction in the accumulation of T cells in the lungs. The immunosuppressive effect involves signaling through S1P receptors on DC, but is independent of S1P1, S1P2 and S1P3. Inhibition of the accumulation of virus-specific T cells in the lungs occurs without impinging the production of anti-viral neutralizing antibodies. AAL-R treatment hinders cytokine/chemokine production which leads to a reduction in polymorphonuclear leukocyte and macrophage infiltration resulting in reduced lung injury. Importantly, local AAL-R administration into the lung was effective in controlling CD8+ T cell accumulation in the lungs when given four days following influenza virus infection. Administration of sphingosine analogs during influenza virus infection offers a potentially powerful therapeutic for alleviating pulmonary immunopathology.
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Fulton, S. A., S. M. Reba, T. D. Martin, and W. H. Boom. "Neutrophil-Mediated Mycobacteriocidal Immunity in the Lung during Mycobacterium bovis BCG Infection in C57BL/6 Mice." Infection and Immunity 70, no. 9 (September 2002): 5322–27. http://dx.doi.org/10.1128/iai.70.9.5322-5327.2002.
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ABSTRACT Although neutrophils have been identified as sources of inflammatory cytokines and chemokines, little is known about their immunologic function during mycobacterial infection in the lungs. In this study, we examined the growth of Mycobacterium bovis BCG in the lungs under experimental conditions that altered neutrophil recruitment to the lungs. Depletion and recruitment of neutrophils was associated with respective increases and decreases in M. bovis BCG growth. Thus, neutrophils may enhance mycobacteriocidal immunity in the lungs.
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Huffnagle, Gary B., Michael B. Boyd, Nancy E. Street, and Mary F. Lipscomb. "IL-5 Is Required for Eosinophil Recruitment, Crystal Deposition, and Mononuclear Cell Recruitment During a Pulmonary Cryptococcus neoformans Infection in Genetically Susceptible Mice (C57BL/6)." Journal of Immunology 160, no. 5 (March 1, 1998): 2393–400. http://dx.doi.org/10.4049/jimmunol.160.5.2393.
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Abstract CBA/J (highly resistant), BALB/c (moderately resistant), and C57BL/6 (susceptible) mice displayed three resistance patterns following intratracheal inoculation of Cryptococcus neoformans 52. The inability to clear the infection correlated with the duration of the eosinophil infiltrate in the lungs. The role of IL-5 in promoting the pulmonary eosinophilia and subsequent inflammatory damage in susceptible C57BL/6 mice was investigated. C57BL/6 mice developed a chronic alveolar, peribronchiolar, and perivascular eosinophilia following C. neoformans infection. This resulted in the accumulation of intracellular Charcot-Leyden-like crystals in alveolar macrophages by wk 4 and the extracellular deposition of these crystals in the bronchioles with associated destruction of airway epithelium by wk 6. IL-5 mRNA was expressed in the lungs, and injections of anti-IL-5 mAb prevented eosinophil recruitment and crystal deposition but did not alter cryptococcal clearance. Depletion of CD4+ T cells (but not CD8+) ablated IL-5 production by lung leukocytes in vitro and eosinophil recruitment in vivo. Neutralization of IL-5 also inhibited the recruitment of macrophages, CD8+ T lymphocytes, and B lymphocytes by 47 to 57%. Anti-IL-5 mAb inhibited CD4+ T lymphocyte recruitment by 30% but did not affect neutrophil recruitment. Thus, the development of a chronic eosinophil infiltrate in the lungs of C. neoformans-infected C57BL/6 mice is a nonprotective immune response that causes significant lung pathology. Furthermore, IL-5 promotes the recruitment and activation of eosinophils, resulting in the recruitment of additional macrophages and lymphocytes into the lungs.
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Walmrath, D., H. A. Ghofrani, S. Rosseau, H. Schütte, A. Cramer, W. Kaddus, F. Grimminger, S. Bhakdi, and W. Seeger. "Endotoxin "priming" potentiates lung vascular abnormalities in response to Escherichia coli hemolysin: an example of synergism between endo- and exotoxin." Journal of Experimental Medicine 180, no. 4 (October 1, 1994): 1437–43. http://dx.doi.org/10.1084/jem.180.4.1437.
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The pore-forming hemolysin of Escherichia coli (HlyA), an important virulence factor in extraintestinal E. coli infections, causes thromboxane generation and related vasoconstriction in perfused rabbit lungs (Seeger, W., H. Walter, N. Suttorp, M. Muhly, and S. Bhakdi. 1989. J. Clin. Invest. 84:220). We investigated the influence of pulmonary vascular "priming" with endotoxin on the responsiveness of the lung to a low-dose HlyA challenge. Rabbit lungs were perfused with Krebs Henseleit buffer containing 0.1-100 ng/ml Salmonella abortus equii lipopolysaccharide (LPS) for 60-180 min. This treatment caused protracted release of tumor necrosis factor into the recirculating medium, but did not induce significant alterations of pulmonary hemodynamics and fluid balance. At a dose of 1 ng/ml, HlyA elicited only moderate thromboxane release (< 200 pg/ml) and pulmonary artery pressure increase (< or = 6 mmHg) in control lungs. Acceleration and potentiation of both the metabolic and vasoconstrictor response occurred in lungs primed with LPS. This priming effect displayed dose (threshold integral of 0.1-1 ng/ml LPS) and time dependencies (threshold integral of 60-90 min LPS incubation). Maximum thromboxane release and pulmonary artery pressure increase surpassed the responses to HlyA in nonprimed lungs by more than 15-fold. Cyclooxygenase inhibition and thromboxane-receptor antagonism blocked these effects. These data demonstrate that LPS priming synergizes with HlyA challenge to provoke vascular abnormalities that are possibly relevant to the pathogenesis of organ failure in severe local and systemic infections.