Journal articles: 'CELLULAR AND SYSTEMIC RESPONSES'

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Galluzzi, Lorenzo, Takahiro Yamazaki, and Guido Kroemer. "Linking cellular stress responses to systemic homeostasis." Nature Reviews Molecular Cell Biology 19, no. 11 (October 10, 2018): 731–45. http://dx.doi.org/10.1038/s41580-018-0068-0.

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da Silva, Paulo F. L., and Björn Schumacher. "DNA damage responses in ageing." Open Biology 9, no. 11 (November 2019): 190168. http://dx.doi.org/10.1098/rsob.190168.

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Ageing appears to be a nearly universal feature of life, ranging from unicellular microorganisms to humans. Longevity depends on the maintenance of cellular functionality, and an organism's ability to respond to stress has been linked to functional maintenance and longevity. Stress response pathways might indeed become therapeutic targets of therapies aimed at extending the healthy lifespan. Various progeroid syndromes have been linked to genome instability, indicating an important causal role of DNA damage accumulation in the ageing process and the development of age-related pathologies. Recently, non-cell-autonomous mechanisms including the systemic consequences of cellular senescence have been implicated in regulating organismal ageing. We discuss here the role of cellular and systemic mechanisms of ageing and their role in ageing-associated diseases.

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Ermolaeva, Maria A., Alexander Dakhovnik, and Björn Schumacher. "Quality control mechanisms in cellular and systemic DNA damage responses." Ageing Research Reviews 23 (September 2015): 3–11. http://dx.doi.org/10.1016/j.arr.2014.12.009.

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Qiu, Jin, Lin Yan, Jianbo Chen, Crystal Y. Chen, Ling Shen, Norman L. Letvin, Barton F. Haynes, et al. "Intranasal Vaccination with the Recombinant Listeria monocytogenes ΔactA prfA*Mutant Elicits Robust Systemic and Pulmonary Cellular Responses and Secretory Mucosal IgA." Clinical and Vaccine Immunology 18, no. 4 (January 26, 2011): 640–46. http://dx.doi.org/10.1128/cvi.00254-10.

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ABSTRACTWe previously showed that recombinant (r)Listeria monocytogenescarrying ΔactAand a selectedprfA*mutation (r-ListeriaΔactA prfA*) secreted >100-fold more immunogen in broth culture than wild-type r-Listeriaor r-ListeriaΔactAand elicited much greater cellular and humoral immune responses than r-ListeriaΔactAafter intravenous vaccination of mice. Here, we conducted comparative studies evaluating vaccine-elicited immune responses in systemic and mucosal sites after intranasal, intravenous, intraperitoneal, or subcutaneous immunization of mice with r-ListeriaΔactA prfA*vaccine candidates. Intranasal vaccination of mice with r-ListeriaΔactA prfA* vaccine candidates elicited a robust gamma interferon-positive (IFN-γ+) cellular response in systemic sites, although intravenous or intraperitoneal immunization was more efficient. Surprisingly, intranasal vaccination elicited an appreciable pulmonary IFN-γ+cellular response that was nonstatistically higher than the magnitude induced by the intravenous route but was significantly greater than that elicited by subcutaneous immunization. Furthermore, although intranasal r-ListeriaΔactA prfA*delivery induced poor systemic IgG responses, intranasal vaccination elicited appreciable secretory immunogen-specific IgA titers that were similar to or higher in mucosal fluid than those induced by subcutaneous and intravenous immunizations. Thus, intranasal vaccination with r-ListeriaΔactA prfA*appears to be a useful approach for eliciting robust systemic and pulmonary cellular responses and measurable secretory mucosal IgA titers.

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Donina, S. A., A. N. Naikhin, G. D. Petukhova, I. B. Barantseva, T. V. Chirkova, Е. P. Grigor’eva, А. R. Rekstin, and L. G. Rudenko. "SYSTEMIC ANTIBODY AND CELLULAR IMMUNE RESPONSES IN INFLUENZA INFECTION AND POSTSVACCINATION." Medical Immunology (Russia) 8, no. 1 (July 21, 2014): 31. http://dx.doi.org/10.15789/1563-0625-2006-1-31-36.

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Prabhakar, Nanduri R., Ganesh K. Kumar, Jayasri Nanduri, and Gregg L. Semenza. "ROS Signaling in Systemic and Cellular Responses to Chronic Intermittent Hypoxia." Antioxidants & Redox Signaling 9, no. 9 (September 2007): 1397–404. http://dx.doi.org/10.1089/ars.2007.1732.

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Littauer, Elizabeth Q., E. Stein Esser, Olivia Q. Antao, Dahnide T. Williams, Richard W. Compans, and Ioanna Skountzou. "Systemic dysregulation of cellular immune responses to H1N1 infection during pregnancy." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 208.20. http://dx.doi.org/10.4049/jimmunol.196.supp.208.20.

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Abstract The 2009 H1N1 flu pandemic demonstrated that pregnant women infected with influenza were at risk for severe respiratory distress and premature-rupture-of-membranes (PROM), leading to high incidence of hospitalization, preterm births and small for gestation age (SGA) neonates. We utilize a syngeneic BALB/c pregnant mouse model which recapitulates clinical phenotypes shown during influenza infection of pregnant women. Pregnant mice sublethally infected (0.5xLD50) with pandemic H1N1 A/California/07/09 showed higher viral titers and delayed viral clearance relative to non-pregnant mice, and increased incidence of stillbirths and SGA offspring. Lymphocytes isolated at days 7 and 14 from lungs and spleens of infected pregnant and non-pregnant female mice were analyzed for H1N1 A/Ca/07/09 specific IL-4 and IFN-γ responses. Pregnancy delayed influenza-specific cytokine secretion at the site of infection, indicating systemic dysregulation of anti-viral responses. Lymphocytes from draining mediastinal lymph nodes, spleens and lungs were used to quantify activation of B cells in germinal centers (GC), maturation into antibody secreting cells and memory B cells, and mucosal homing to lung tissue following infection. Pregnancy decreased maturation of GC+ B cells in the spleen and migration of plasma cells from the spleen to the lungs. Infected pregnant mice generated equivalent serum influenza-specific neutralizing antibody titers and increased IgA antibody secreting cells (ASC) in the lungs 6 weeks post-infection relative to infected non-pregnant mice, indicating a potential role in pregnancy favoring the development of mucosal immunity in response to prolonged viral exposure.

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Waickman, Adam T., Joseph Lu, Corey Chase, Hengsheng Fang, Erinn McDowell, Erin Bingham, Jeffrey Bogart, Stephen Graziano, Stephen J. Thomas, and Teresa Gentile. "Systemic Cancer Therapy Does Not Significantly Impact Early Vaccine-Elicited SARS-CoV-2 Immunity in Patients with Solid Tumors." Vaccines 10, no. 5 (May 9, 2022): 738. http://dx.doi.org/10.3390/vaccines10050738.

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mRNA vaccines have been shown to be safe and effective in individuals with cancer. It is unclear, however, if systemic anti-cancer therapy impacts the coordinated cellular and humoral immune responses elicited by SARS-CoV-2 mRNA vaccines. To fill this knowledge gap, we assessed SARS-CoV-2 mRNA vaccine-elicited immunity in a cohort of patients with advanced solid tumors either under observation or receiving systemic anti-cancer therapy. This analysis revealed that SARS-CoV-2 mRNA vaccine-elicited cellular and humoral immunity was not significantly different in individuals with cancer receiving systemic anti-cancer therapy relative to individuals under observation. Furthermore, even though some patients exhibited suboptimal antibody titers after vaccination, SARS-CoV-2 specific cellular immune responses were still detected. These data suggest that antibody titers offer an incomplete picture of vaccine-elicited SARS-CoV-2 immunity in cancer patients undergoing active systemic anti-cancer therapy, and that vaccine-elicited cellular immunity exists even in the absence of significant quantities of SARS-CoV-2 specific antibodies.

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Lillard, James W., Udai P. Singh, Prosper N. Boyaka, Shailesh Singh, Dennis D. Taub, and Jerry R. McGhee. "MIP-1α and MIP-1β differentially mediate mucosal and systemic adaptive immunity." Blood 101, no. 3 (February 1, 2003): 807–14. http://dx.doi.org/10.1182/blood-2002-07-2305.

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AbstractMacrophage inflammatory protein-1α (MIP-1α) and MIP-1β are distinct but highly homologous CC chemokines produced by a variety of host cells in response to various external stimuli and share affinity for CCR5. To better elucidate the role of these CC chemokines in adaptive immunity, we have characterized the affects of MIP-1α and MIP-1β on cellular and humoral immune responses. MIP-1α stimulated strong antigen (Ag)–specific serum immunoglobulin G (IgG) and IgM responses, while MIP-1β promoted lower IgG and IgM but higher serum IgA and IgE antibody (Ab) responses. MIP-1α elevated Ag-specific IgG1 and IgG2b followed by IgG2a and IgG3 subclass responses, while MIP-1β only stimulated IgG1 and IgG2b subclasses. Correspondingly, MIP-1β produced higher titers of Ag-specific mucosal secretory IgA Ab levels when compared with MIP-1α. Splenic T cells from MIP-1α– or MIP-1β–treated mice displayed higher Ag-specific Th1 (interferon-γ [IFN-γ]) as well as selective Th2 (interleukin-5 [IL-5] and IL-6) cytokine responses than did T cells from control groups. Interestingly, mucosally derived T cells from MIP-1β–treated mice displayed higher levels of IL-4 and IL-6 compared with MIP-1α–treated mice. However, MIP-1α effectively enhanced Ag-specific cell-mediated immune responses. In correlation with their selective effects on humoral and cellular immune responses, these chemokines also differentially attract CD4+ versus CD8+ T cells and modulate CD40, CD80, and CD86 expressed by B220+ cells as well as CD28, 4-1BB, and gp39 expression by CD4+ and CD8+ T cells in a dose-dependent fashion. Taken together, these studies suggest that these CC chemokines differentially enhance mucosal and serum humoral as well as cellular immune responses.

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Mineo, Tiago Wilson Patriarca, and Rosangela Zacarias Machado. "Neospora caninum modulates canine systemic cellular immune responses during acute oral infection." Veterinary Immunology and Immunopathology 128, no. 1-3 (March 2009): 300–301. http://dx.doi.org/10.1016/j.vetimm.2008.10.192.

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Yousif, Ashraf S., Tatsushi Omatsu, Grant Weaver, Pankaj Shah, Hans-Christian Reinnecker, and Daniel Lingwood. "Cellular gatekeepers of the humoral immune response." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 211.12. http://dx.doi.org/10.4049/jimmunol.198.supp.211.12.

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Abstract The spleen is critical for eliminating bloodborne pathogens and preventing systemic infection. In the marginal zone (MZ), the site in which splenic antibody responses are first initiated, we have discovered a dendritic cell (DC) ‘hairnet’ architecture that is responsible for extracting two unrelated viral antigens from the perfusing blood and importing them into B cell follicle to initiate IgM and IgG responses. The IgM response was independent of T-cell help, and proceeded via DC display of conformationally intact antigen in the absence of MHC proteins. Interestingly the DC-antigen captures and importing mechanism are solely governed by the glycan of the antigens. Taking all together, we propose that DC hairnet architecture, inshealthing the MZ, constitutes a filtering device that capture and concentrates protein antigens in a glycan-dependent manner from solution and catalyzes their delivery to B cells follicle to initiate humoral immune responses.

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Raeven, R. HM, J. Brummelman, J. LA Pennings, L. van der Maas, K. Helm, W. Tilstra, A. van der Ark, et al. "Molecular and cellular signatures underlying superior immunity against Bordetella pertussis upon pulmonary vaccination." Mucosal Immunology 11, no. 3 (September 20, 2017): 979–93. http://dx.doi.org/10.1038/mi.2017.81.

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Abstract Mucosal immunity is often required for protection against respiratory pathogens but the underlying cellular and molecular mechanisms of induction remain poorly understood. Here, systems vaccinology was used to identify immune signatures after pulmonary or subcutaneous immunization of mice with pertussis outer membrane vesicles. Pulmonary immunization led to improved protection, exclusively induced mucosal immunoglobulin A (IgA) and T helper type 17 (Th17) responses, and in addition evoked elevated systemic immunoglobulin G (IgG) antibody levels, IgG-producing plasma cells, memory B cells, and Th17 cells. These adaptive responses were preceded by unique local expression of genes of the innate immune response related to Th17 (e.g., Rorc) and IgA responses (e.g., Pigr) in addition to local and systemic secretion of Th1/Th17-promoting cytokines. This comprehensive systems approach identifies the effect of the administration route on the development of mucosal immunity, its importance in protection against Bordetella pertussis, and reveals potential molecular correlates of vaccine immunity to this reemerging pathogen.

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Niewold, Timothy B., Daniel N. Clark, Rafah Salloum, and Brian D. Poole. "Interferon Alpha in Systemic Lupus Erythematosus." Journal of Biomedicine and Biotechnology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/948364.

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The pleiotropic cytokine interferon alpha is involved in multiple aspects of lupus etiology and pathogenesis. Interferon alpha is important under normal circumstances for antiviral responses and immune activation. However, heightened levels of serum interferon alpha and expression of interferon response genes are common in lupus patients. Lupus-associated autoantibodies can drive the production of interferon alpha and heightened levels of interferon interfere with immune regulation. Several genes in the pathways leading to interferon production or signaling are associated with risk for lupus. Clinical and cellular manifestations of excess interferon alpha in lupus combined with the genetic risk factors associated with interferon make this cytokine a rare bridge between genetic risk and phenotypic effects. Interferon alpha influences the clinical picture of lupus and may represent a therapeutic target. This paper provides an overview of the cellular, genetic, and clinical aspects of interferon alpha in lupus.

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Reinhardt, H. Christian, and Björn Schumacher. "The p53 network: cellular and systemic DNA damage responses in aging and cancer." Trends in Genetics 28, no. 3 (March 2012): 128–36. http://dx.doi.org/10.1016/j.tig.2011.12.002.

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Cloquell, Ana, Isidro Mateo, Stefano Gambera, Martí Pumarola, Ramon Alemany, Javier García-Castro, and Ana Judith Perisé-Barrios. "Systemic cellular viroimmunotherapy for canine high-grade gliomas." Journal for ImmunoTherapy of Cancer 10, no. 12 (December 2022): e005669. http://dx.doi.org/10.1136/jitc-2022-005669.

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BackgroundOncolytic viruses constitute a growing field of interest, both in human and veterinary oncology, given that they are particularly helpful for treating non-surgical tumors and disseminated cancer, such as high-grade gliomas. Companion dogs present malignant gliomas with biological, genetic, phenotypic, immunological, and clinical similarities to human gliomas. These features favor comparative approaches, leading to the treatment of canine oncological patients to achieve translational applications to the human clinic. The systemic administration of oncolytic viruses presents a challenge due to their limitations in effectively targeting tumors and metastases. Therefore, the aim of this study is to evaluate the safety and antitumor activity of a virotherapy used in spontaneous canine tumors.MethodsTen dogs with high-grade rostrotentorial gliomas underwent weekly systemic endovenous cellular virotherapy with dCelyvir (canine mesenchymal stem cells infected with the canine oncolytic adenovirus ICOCAV17) for 8 weeks. Efficacy was determined in seven dogs according to the Response Assessment in Veterinary Neuro-Oncology criteria considering clinical status and MRI measurements. Medical history, physical and neurological examinations, and vaccination status were evaluated prior to and during follow-up. Safety was evaluated by physical examinations and hematological and biochemical changes in peripheral blood. Immune populations were analyzed by flow cytometry in peripheral blood and by gene expression and immunohistochemistry in the tumor microenvironment.ResultsThe treatment was well tolerated and major adverse effects were not observed. Two dogs had partial responses (76% and 86% reduction in tumor size), and 3/7 showed stable disease. ICOCAV17 was detected in peripheral blood in nine dogs, and a correlation between the ICOCAV17 particles and anti-canine adenovirus (CAV) antibodies was observed. ICOCAV17 was detected in 3/9 tumor tissues after necropsies. Regarding tumor-infiltrating lymphocytes, the dogs with disease stabilization and partial response tended to have reduced memory B-cell infiltration and increased monocyte/macrophage lineage cells.ConclusionsThese findings indicate that dCelyvir is safe and presents efficacy in canine rostrotentorial high-grade gliomas. These data are relevant to the ongoing phase Ib regulated human clinical trial that is administering this virotherapy to children, adolescents, and young adults with diffuse pontine glioma. Celyvir should be further explored as a treatment in veterinary and human neuro-oncology.

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Li, Yi-jing, Guang-peng Ma, Gui-wei Li, Xin-yuan Qiao, Jun-wei Ge, Li-jie Tang, Min Liu, and Li-wei Liu. "Oral Vaccination with the Porcine Rotavirus VP4 Outer Capsid Protein Expressed byLactococcus lactisInduces Specific Antibody Production." Journal of Biomedicine and Biotechnology 2010 (2010): 1–9. http://dx.doi.org/10.1155/2010/708460.

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The objective of this study to design a delivery system resistant to the gastrointestinal environment for oral vaccine against porcine rotavirus.Lactococcus lactisNZ9000 was transformed with segments ofvP4of the porcine rotavirus inserted into the pNZ8112 surface-expression vector, and a recombinantL. lactisexpressing VP4 protein was constructed. An approximately 27 kDa VP4 protein was confirmed by SDS-PAGE , Western blot and immunostaining analysis. BALB/c mice were immunized orally with VP4-expression recombinantL. lactisand cellular, mucosal and systemic humoral immune responses were examined. Specific anti-VP4 secretory IgA and IgG were found in feces, ophthalmic and vaginal washes and in serum. The induced antibodies demonstrated neutralizing effects on porcine rotavirus infection on MA104 cells. Our findings suggest that oral immunization with VP4-expressingL. lactisinduced both specific local and systemic humoral and cellular immune responses in mice.

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Giles, Thomas D., Gary E. Sander, Janet C. Rice, and Antonio C. Quiroz. "Systemic methionine-enkephalin evokes cardiostimulatory responses in the human." Peptides 8, no. 4 (July 1987): 609–12. http://dx.doi.org/10.1016/0196-9781(87)90033-7.

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J. Heath, John, and Michael D. Grant. "The Immune Response Against Human Cytomegalovirus Links Cellular to Systemic Senescence." Cells 9, no. 3 (March 20, 2020): 766. http://dx.doi.org/10.3390/cells9030766.

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Aging reflects long-term decline in physiological function and integrity. Changes arise at a variable pace governed by time-dependent and -independent mechanisms that are themselves complex, interdependent and variable. Molecular decay produces inferior cells that eventually dominate over healthy counterparts in tissues they comprise. In a form of biological entropy, progression from molecular through cellular to tissue level degeneration culminates in organ disease or dysfunction, affecting systemic health. To better understand time-independent contributors and their potential modulation, common biophysical bases for key molecular and cellular changes underlying age-related physiological deterioration must be delineated. This review addresses the potential contribution of cytomegalovirus (CMV)-driven T cell proliferation to cellular senescence and immunosenescence. We first describe molecular processes imposing cell cycle arrest, the foundation of cellular senescence, then focus on the unique distribution, phenotype and function of CMV-specific CD8+ T cells in the context of cellular senescence and “inflammaging”. Their features position CMV infection as a pathogenic accelerant of immune cell proliferation underlying immune senescence. In human immunodeficiency virus (HIV) infection, where increased inflammation and exaggerated anti-CMV immune responses accelerate immune senescence, CMV infection has emerged as a major factor in unhealthy aging. Thus, we speculate on mechanistic links between CMV-specific CD8+ T-cell expansion, immune senescence and prevalence of age-related disorders in HIV infection.

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Wang, Lingshu, Cheng Cheng, Sung-Youl Ko, Wing-Pui Kong, Masaru Kanekiyo, David Einfeld, Richard M. Schwartz, C. Richter King, Jason G. D. Gall, and Gary J. Nabel. "Delivery of Human Immunodeficiency Virus Vaccine Vectors to the Intestine Induces Enhanced Mucosal Cellular Immunity." Journal of Virology 83, no. 14 (May 6, 2009): 7166–75. http://dx.doi.org/10.1128/jvi.00374-09.

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ABSTRACT Effective vaccines for human immunodeficiency virus type 1 (HIV-1) will likely need to stimulate protective immunity in the intestinal mucosa, where HIV-1 infection causes severe CD4+ T-cell depletion. While replication-competent recombinant adenovirus (rAd) vectors can stimulate adenovirus-specific mucosal immunity after replication, oral delivery of replication-defective rAd vectors encoding specific immunogens has proven challenging. In this study, we have systematically identified barriers to effective gut delivery of rAd vectors and identified sites and strategies to induce potent cellular and humoral immunity. Vector-mediated gene transfer by rAd5 was susceptible to low-pH buffer, gastric and pancreatic proteases, and extracellular mucins. Using ex vivo organ explants, we found that transduction with rAd5 was highest in the ileum and colon among all intestinal segments. Transgene expression was 100-fold higher after direct surgical introduction into the ileum than after oral gavage, with rAd5 showing greater potency than the rAd35 or the rAd41 vector. A single immunization of rAd5 encoding HIV-1 gp140B to the ileum stimulated potent CD8+ T-cell responses in the intestinal and systemic compartments, and these responses were further enhanced by intramuscular rAd5 boosting. These studies suggest that induction of primary immune responses by rAd5 gut immunization and subsequent systemic boosting elicits potent antigen-specific gut mucosal responses.

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Drake, Wonder P., Mary S. Dhason, Michele Nadaf, Bryan E. Shepherd, Sangeetha Vadivelu, Rana Hajizadeh, Lee S. Newman, and Spyros A. Kalams. "Cellular Recognition of Mycobacterium tuberculosis ESAT-6 and KatG Peptides in Systemic Sarcoidosis." Infection and Immunity 75, no. 1 (November 6, 2006): 527–30. http://dx.doi.org/10.1128/iai.00732-06.

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ABSTRACT Sarcoidosis is an enigmatic disease with a pathology similar to that of tuberculosis. We detected Th-1 immune responses to Mycobacterium tuberculosis ESAT-6 and KatG peptides from peripheral blood mononuclear cells from 15/26 sarcoidosis, 1/24 purified-protein-derivative-negative (PPD−) (P < 0.0001, Fisher's exact test), and 7/8 PPD-positive (PPD+) subjects (P = 0.21). This finding provides immunologic links between mycobacteria and systemic sarcoidosis.

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Nanduri, Jayasri, Ning Wang, Benjamin L. Wang, and Nanduri R. Prabhakar. "Lysine demethylase KDM6B regulates HIF-1α-mediated systemic and cellular responses to intermittent hypoxia." Physiological Genomics 53, no. 9 (September 1, 2021): 385–94. http://dx.doi.org/10.1152/physiolgenomics.00045.2021.

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Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA). Rodents treated with IH exhibit hypertension. Hypoxia-inducible factor (HIF)-1-dependent transcriptional activation of NADPH oxidases ( Nox) and the resulting increase in reactive oxygen species (ROS) levels is a major molecular mechanism underlying IH/OSA-induced hypertension. Jumanji C (JmjC)-containing histone lysine demethylases (JmjC-KDMs) are coactivators of HIF-1-dependent transcriptional activation. In the present study, we tested the hypothesis that JmjC-KDMs are required for IH-evoked HIF-1 transcriptional activation of Nox4 and the ensuing hypertension. Studies were performed on pheochromocytoma (PC)12 cells and rats. IH increased KDM6B protein and enzyme activity in PC12 cells in an HIF-1-independent manner as evidenced by unaltered KDM6B activation by IH in HIF-1α shRNA-treated cells. Cells treated with IH showed increased HIF-1-dependent Nox4 transcription as indicated by increased HIF-1α binding to hypoxia-responsive element (HRE) sequence of the Nox4 gene promoter demonstrated by chromatin immunoprecipitation (ChiP) assay. Pharmacological blockade of KDM6B with GSKJ4, a specific KDM6 inhibitor, or genetic silencing of KDM6B with shRNA abolished IH-induced Nox4 transcriptional activation by blocking HIF-1α binding to the promoter of the Nox4 gene. Treating IH-exposed rats with GSKJ4 showed: 1) absence of KDM6B activation and HIF-1-dependent Nox4 transcription in the adrenal medullae, and 2) absence of elevated plasma catecholamines and hypertension. Collectively, these findings indicate that KDM6B functions as a coactivator of HIF-1-mediated Nox4 transactivation and demonstrates a hitherto uncharacterized role for KDMs in IH-induced hypertension by HIF-1.

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Shen-Orr, Shai, David Furman, Brian Kidd, Holden Maecker, Cornelia Dekker, Atul Butte, and Mark Davis. "A Systemic age dependent defect in immune-cell signaling response induced by inflammation (138.2)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 138.2. http://dx.doi.org/10.4049/jimmunol.184.supp.138.2.

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Abstract Immune system function generally degrades with age and is associated with increased risk of infection and disease. Though differences between young and old have been noted in many immune system components, no system wide understanding of how these disparate observation act together exists to date, nor how they relate to genes found to associated with increased longevity, many of which are immune related. Here we characterize the immune system of 29 young and old individuals by concurrently measuring from peripheral blood, immune cell subset frequency, serum cytokines, gene expression and individual cellular responses to cytokine stimuli by pathway specific phospho-protein abundance. We identify age-dependent changes in STAT signaling baseline and in response to stimulation by a panel of 7 different cytokines, particularly prominent in CD8 and CD4 T cells, but also in monocytes and B-cells. The observed differences in cellular responses are not due to adaptation to higher level of cytokine stimuli but rather to an inert inability to mount a full response, many times augmented by a higher base line phosphorylation level in the elderly. We construct an immune network spanning multiple biological layers and identify co-occurring modules which link longevity associated genes with these cellular immune phenotypes. We quantify the contributions of these modules to the observed reduction in cellular response to stimuli in the elderly and suggest a common responsible mechanism.

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Nossaman, Bobby D., Syed R. Baber, Mohammed M. Nazim, John D. Detrolio, and Philip J. Kadowitz. "Differential effects of losartan and candesartan on vasoconstrictor responses in the ratThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute." Canadian Journal of Physiology and Pharmacology 85, no. 3-4 (March 2007): 360–71. http://dx.doi.org/10.1139/y06-087.

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Losartan has been reported to have inhibitory effects on thromboxane (TP) receptor-mediated responses. In the present study, the effects of 2 nonpeptide angiotensin II (AT1) receptor antagonists, losartan and candesartan, on responses to angiotensin II, the thromboxane A2 mimic, U46619, and norepinephrine were investigated and compared in the pulmonary and systemic vascular beds of the intact-chest rat. In this study, intravenous injections of angiotensin II, U46619, and norepinephrine produced dose-related increases in pulmonary and systemic arterial pressure. Losartan and candesartan, in the doses studied, decreased or abolished responses to angiotensin II. Losartan, but not candesartan, and only in a higher dose, produced small, but statistically significant, reductions in pressor responses to U46619 and to norepinephrine in the pulmonary and systemic vascular beds. Furthermore, losartan significantly reduced arachidonic acid-induced platelet aggregation, whereas candesartan had no effect. Pressor responses to angiotensin II were not changed by thromboxane and alpha-adrenergic receptor antagonists, or by cyclooxygenase and NO synthase inhibitors. These results show that losartan and candesartan are potent selective AT1 receptor antagonists in the pulmonary and systemic vascular beds and that losartan can attenuate thromboxane and alpha-adrenergic responses when administered at a high dose, whereas candesartan in the highest dose studied had no effect on responses to U46619 or to norepinephrine. The present data show that the effects of losartan and candesartan on vasoconstrictor responses are different and that pulmonary and systemic pressor responses to angiotensin II are not modulated or mediated by the release of cyclooxygenase products, activation of TP receptors, or the release of NO in the anesthetized rat.

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Becker, Pablo D., Miriam Nörder, Carlos A. Guzmán, and Saul Grinstein. "Immune Modulator Adamantylamide Dipeptide Stimulates Efficient Major Histocompatibility Complex Class I-Restricted Responses in Mice." Clinical and Vaccine Immunology 14, no. 5 (March 7, 2007): 538–43. http://dx.doi.org/10.1128/cvi.00316-06.

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ABSTRACT Adamantylamide l-alanyl-d-isoglutamine (AdDP) is a synthetic adjuvant which belongs to the family of the desmuramyl peptides. AdDP exerts its adjuvant properties when it is administered either by the parenteral or by the mucosal route, leading to the elicitation of strong humoral responses at both the systemic and the mucosal levels. However, very little is known about the effect of AdDP on cellular immunity. Here we demonstrate that AdDP is able to stimulate cellular responses, which are characterized by the release of gamma interferon by CD8+ T cells when they are restimulated with a major histocompatibility complex class I-restricted peptide and strong in vivo lymphocyte-mediated cytotoxic activity. The capacity of AdDP to stimulate the elicitation of both cellular and humoral adaptive responses makes this adjuvant a promising tool for the development of mucosal vaccine formulations.

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Neupane, Sabita, Sunil Srivastav, Sunil Bhurtel, Nikita Katila, Sina Shadfar, Pil-Hoon Park, Jin Tae Hong, and Dong-Young Choi. "Enhanced neuroinflammatory responses after systemic LPS injection in IL-32β transgenic mice." Journal of Chemical Neuroanatomy 94 (December 2018): 173–82. http://dx.doi.org/10.1016/j.jchemneu.2018.07.002.

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MOURA, VANIA B. L., SARAH B. LIMA, HIDELBERTO MATOS-SILVA, MARINA C. VINAUD, PATRICIA R. A. N. LOYOLA, and RUY S. LINO. "Cellular immune response in intraventricular experimental neurocysticercosis." Parasitology 143, no. 3 (December 2, 2015): 334–42. http://dx.doi.org/10.1017/s0031182015001572.

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SUMMARYNeurocysticercosis (NCC) is considered a neglected parasitic infection of the human central nervous system. Its pathogenesis is due to the host immune response, stage of evolution and location of the parasite. The aim of this study was to evaluate thein situand systemic immune response through cytokines dosage (IL-4, IL-10, IL-17 and IFN-γ) as well as the local inflammatory response of the experimental NCC withTaenia crassiceps. Thein situand systemic cellular and inflammatory immune response were evaluated through the cytokines quantification at 7, 30, 60 and 90 days after inoculation and histopathological analysis. All cysticerci were found within the cerebral ventricles. There was a discrete intensity of inflammatory cells of mixed immune profile, polymorphonuclear and mononuclear cells, at the beginning of the infection and predominance of mononuclear cells at the end. The systemic immune response showed a significant increase in all the analysed cytokines and predominance of the Th2 immune profile cytokines at the end of the infection. These results indicate that the location of the cysticerci may lead to ventriculomegaly. The acute phase of the infection showed a mixed Th1/Th17 profile accompanied by high levels of IL-10 while the late phase showed a Th2 immune profile.

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Kubrak, Olga I., Oleh V. Lushchak, Meet Zandawala, and Dick R. Nässel. "Systemic corazonin signalling modulates stress responses and metabolism in Drosophila." Open Biology 6, no. 11 (November 2016): 160152. http://dx.doi.org/10.1098/rsob.160152.

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Stress triggers cellular and systemic reactions in organisms to restore homeostasis. For instance, metabolic stress, experienced during starvation, elicits a hormonal response that reallocates resources to enable food search and readjustment of physiology. Mammalian gonadotropin-releasing hormone (GnRH) and its insect orthologue, adipokinetic hormone (AKH), are known for their roles in modulating stress-related behaviour. Here we show that corazonin (Crz), a peptide homologous to AKH/GnRH, also alters stress physiology in Drosophila . The Crz receptor (CrzR) is expressed in salivary glands and adipocytes of the liver-like fat body, and CrzR knockdown targeted simultaneously to both these tissues increases the fly's resistance to starvation, desiccation and oxidative stress, reduces feeding, alters expression of transcripts of Drosophila insulin-like peptides (DILPs), and affects gene expression in the fat body. Furthermore, in starved flies, CrzR-knockdown increases circulating and stored carbohydrates. Thus, our findings indicate that elevated systemic Crz signalling during stress coordinates increased food intake and diminished energy stores to regain metabolic homeostasis. Our study suggests that an ancient stress-peptide in Urbilateria evolved to give rise to present-day GnRH, AKH and Crz signalling systems.

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Mohammadi, M., S. Czinn, R. Redline, and J. Nedrud. "Helicobacter-specific cell-mediated immune responses display a predominant Th1 phenotype and promote a delayed-type hypersensitivity response in the stomachs of mice." Journal of Immunology 156, no. 12 (June 15, 1996): 4729–38. http://dx.doi.org/10.4049/jimmunol.156.12.4729.

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Abstract Studies regarding the nature of cell-mediated immunity in Helicobacter pylori infection and its role in pathogenesis have yielded controversial results. To address this issue in a controlled manner, we have employed the well-characterized Helicobacter felis-mouse model. Immunized/challenged and nonimmunized/infected mice were evaluated for cellular proliferation, gastric inflammation, and cytokine and Ab production at various times after infection. We observed two types of cell-mediated immune responses depending on the nature of the Ag preparation. The first response is a Helicobacter-independent response, present in all experimental groups, which is directed toward Ags such as urease and heat shock proteins. The second is a Helicobacter-dependent cellular response restricted to mice previously exposed to Helicobacter Ags either by immunization or infection. This response was not seen in noninfected controls. The Helicobacter-dependent cellular response had a Th1 phenotype, as either infected or immunized/challenged mice demonstrated local and systemic production of IFN-gamma and undetectable levels of IL-4 or IL-5. Cellular proliferation correlated with the severity of gastric inflammation in both immunized/challenged (protected) and nonimmunized/infected mice. Finally, in vivo neutralization of IFN-gamma resulted in a significant reduction of gastric inflammation in H. felis-infected, as well as immunized/challenged, mice. This treatment also revealed the presence of Th2 cells, restricted to immunized/challenged mice, as demonstrated by local and systemic production of IL-4 in these mice. These data demonstrate that Helicobacter infection and/or immunization stimulate a predominantly Th1-type, Ag-specific response and promote a local delayed-type hypersensitivity response in the stomach that may be inhibited by depletion of IFN-gamma.

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Ahn, Il-Pyung, Sang-Woo Lee, and Seok-Cheol Suh. "Rhizobacteria-Induced Priming in Arabidopsis Is Dependent on Ethylene, Jasmonic Acid, and NPR1." Molecular Plant-Microbe Interactions® 20, no. 7 (July 2007): 759–68. http://dx.doi.org/10.1094/mpmi-20-7-0759.

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A nonpathogenic rhizobacterium, Pseudomonas putida LSW17S, elicited systemic protection against Fusarium wilt and pith necrosis caused by Fusarium oxysporum f. sp. lycopersici and P. corrugata in tomato (Lycopersicon esculentum L.). LSW17S also confers disease resistance against P. syringae pv. tomato DC3000 (DC3000) on Arabidopsis ecotype Col-0. To investigate mechanisms underlying disease protection, expression patterns of defense-related genes PR1, PR2, PR5, and PDF1.2 and cellular defense responses such as hydrogen peroxide accumulation and callose deposition were investigated. LSW17S treatment exhibited the typical phenomena of priming. Strong and faster transcription of defense-related genes was induced and hydrogen peroxide or callose were accumulated in Arabidopsis treated with LSW17S and infected with DC3000. In contrast, individual actions of LSW17S and DC3000 did not elicit rapid molecular and cellular defense responses. Priming by LSW17S was translocated systemically and retained for more than 10 days. Treatment with LSW17S reduced pathogen proliferation in Arabidopsis ecotype Col-0 expressing bacterial NahG; however, npr1, etr1, and jar1 mutations impaired inhibition of pathogen growth. Cellular and molecular priming responses support these results. In sum, LSW17S primes Arabidopsis for NPR1-, ethylene-, and jasmonic acid-dependent disease resistance, and efficient molecular and cellular defense responses.

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Ryan Kuhlman, Kate, Steven W. Cole, Michael R. Irwin, Andrew J. Fuligni, Michelle G. Craske, and Julienne E. Bower. "Early life adversity and systemic, cellular, and genomic responses to acute psychosocial stress among adolescents." Brain, Behavior, and Immunity 98 (November 2021): 27. http://dx.doi.org/10.1016/j.bbi.2021.08.105.

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Johnston, Carolyn M., and Stephen J. Brown. "Cutaneous and systemic cellular responses induced by the feeding of the argasid tick Ornithodoros parkeri." International Journal for Parasitology 15, no. 6 (December 1985): 621–28. http://dx.doi.org/10.1016/0020-7519(85)90007-4.

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Cuesta, Alberto, Irene Salinas, Alejandro Rodríguez, M. Ángeles Esteban, and José Meseguer. "Injection of xenogeneic cells into teleost fish elicits systemic and local cellular innate immune responses." Cell and Tissue Research 326, no. 1 (May 31, 2006): 93–99. http://dx.doi.org/10.1007/s00441-006-0209-1.

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Lauwerys, Bernard R., Nathalie Garot, Jean‐Christophe Renauld, and Frédéric A. Houssiau. "Interleukin‐10 blockade corrects impaired in vitro cellular immune responses of systemic lupus erythematosus patients." Arthritis & Rheumatism 43, no. 9 (September 2000): 1976–81. http://dx.doi.org/10.1002/1529-0131(200009)43:9<1976::aid-anr8>3.0.co;2-v.

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Wormley, Floyd L., Joseph Chaiban, and Paul L. Fidel. "Cell Adhesion Molecule and Lymphocyte Activation Marker Expression during Experimental Vaginal Candidiasis." Infection and Immunity 69, no. 8 (August 1, 2001): 5072–79. http://dx.doi.org/10.1128/iai.69.8.5072-5079.2001.

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ABSTRACT Cell-mediated immunity by Th1-type CD4+ T cells is the predominant host defense mechanism against mucosal candidiasis. However, studies using an estrogen-dependent murine model of vaginal candidiasis have demonstrated little to no change in resident vaginal T cells during infection and no systemic T-cell infiltration despite the presence of Candida-specific systemic Th1-type responses in infected mice. The present study was designed to further investigate these observations by characterizing T-cell activation and cell adhesion molecule expression during primary and secondary C. albicans vaginal infections. While flow cytometry analysis of activation markers showed some evidence for activation of CD3+ draining lymph node and/or vaginal lymphocytes during both primary and secondary vaginal Candida infection, CD3+ cells expressing the homing receptors and integrins α4β7, αM290β7, and α4β1 in draining lymph nodes of mice with primary and secondary infections were reduced compared to results for uninfected mice. At the local level, few vaginal lymphocytes expressed integrins, with only minor changes observed during both primary and secondary infections. On the other hand, immunohistochemical analysis of vaginal cell adhesion molecule expression showed increases in mucosal addressin cell adhesion molecule 1 and vascular cell adhesion molecule 1 expression during both primary and secondary infections. Altogether, these data suggest that although the vaginal tissue is permissive to cellular infiltration during a vaginal Candida infection, the reduced numbers of systemic cells expressing the reciprocal cellular adhesion molecules may preempt cellular infiltration, thereby limitingCandida-specific T-cell responses against infection.

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Moyon, Quentin, Delphine Sterlin, Makoto Miyara, François Anna, Alexis Mathian, Raphael Lhote, Pascale Ghillani-Dalbin, et al. "BNT162b2 vaccine-induced humoral and cellular responses against SARS-CoV-2 variants in systemic lupus erythematosus." Annals of the Rheumatic Diseases 81, no. 4 (October 4, 2021): 575–83. http://dx.doi.org/10.1136/annrheumdis-2021-221097.

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ObjectivesOur aim was to evaluate systemic lupus erythematosus (SLE) disease activity and SARS-CoV-2-specific immune responses after BNT162b2 vaccination.MethodsIn this prospective study, disease activity and clinical assessments were recorded from the first dose of vaccine until day 15 after the second dose in 126 patients with SLE. SARS-CoV-2 antibody responses were measured against wild-type spike antigen, while serum-neutralising activity was assessed against the SARS-CoV-2 historical strain and variants of concerns (VOCs). Vaccine-specific T cell responses were quantified by interferon-γ release assay after the second dose.ResultsBNT162b2 was well tolerated and no statistically significant variations of BILAG (British Isles Lupus Assessment Group) and SLEDAI (SLE Disease Activity Index) scores were observed throughout the study in patients with SLE with active and inactive disease at baseline. Mycophenolate mofetil (MMF) and methotrexate (MTX) treatments were associated with drastically reduced BNT162b2 antibody response (β=−78, p=0.007; β=−122, p<0.001, respectively). Anti-spike antibody response was positively associated with baseline total immunoglobulin G serum levels, naïve B cell frequencies (β=2, p=0.018; β=2.5, p=0.003) and SARS-CoV-2-specific T cell response (r=0.462, p=0.003). In responders, serum neutralisation activity decreased against VOCs bearing the E484K mutation but remained detectable in a majority of patients.ConclusionMMF, MTX and poor baseline humoral immune status, particularly low naïve B cell frequencies, are independently associated with impaired BNT162b2 mRNA antibody response, delineating patients with SLE who might need adapted vaccine regimens and follow-up.

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Moyon, Quentin, Delphine Sterlin, Makoto Miyara, François Anna, Alexis Mathian, Raphael Lhote, Pascale Ghillani-Dalbin, et al. "BNT162b2 vaccine-induced humoral and cellular responses against SARS-CoV-2 variants in systemic lupus erythematosus." Annals of the Rheumatic Diseases 81, no. 4 (October 4, 2021): 575–83. http://dx.doi.org/10.1136/annrheumdis-2021-221097.

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ObjectivesOur aim was to evaluate systemic lupus erythematosus (SLE) disease activity and SARS-CoV-2-specific immune responses after BNT162b2 vaccination.MethodsIn this prospective study, disease activity and clinical assessments were recorded from the first dose of vaccine until day 15 after the second dose in 126 patients with SLE. SARS-CoV-2 antibody responses were measured against wild-type spike antigen, while serum-neutralising activity was assessed against the SARS-CoV-2 historical strain and variants of concerns (VOCs). Vaccine-specific T cell responses were quantified by interferon-γ release assay after the second dose.ResultsBNT162b2 was well tolerated and no statistically significant variations of BILAG (British Isles Lupus Assessment Group) and SLEDAI (SLE Disease Activity Index) scores were observed throughout the study in patients with SLE with active and inactive disease at baseline. Mycophenolate mofetil (MMF) and methotrexate (MTX) treatments were associated with drastically reduced BNT162b2 antibody response (β=−78, p=0.007; β=−122, p<0.001, respectively). Anti-spike antibody response was positively associated with baseline total immunoglobulin G serum levels, naïve B cell frequencies (β=2, p=0.018; β=2.5, p=0.003) and SARS-CoV-2-specific T cell response (r=0.462, p=0.003). In responders, serum neutralisation activity decreased against VOCs bearing the E484K mutation but remained detectable in a majority of patients.ConclusionMMF, MTX and poor baseline humoral immune status, particularly low naïve B cell frequencies, are independently associated with impaired BNT162b2 mRNA antibody response, delineating patients with SLE who might need adapted vaccine regimens and follow-up.

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Fike, Adam J., Sathi Babu Chodisetti, Phillip P. Domeier, Harinder Singh, Stephanie L. Schell, Taryn E. Mockus, Nicholas M. Choi, et al. "Serine phosphorylation of the STAT1 transactivation domain promotes autoreactive B cell and systemic autoimmunity development." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 218.10. http://dx.doi.org/10.4049/jimmunol.204.supp.218.10.

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Abstract Although STAT1 tyrosine-701 phosphorylation (STAT1-pY701) is indispensable for STAT1 function, the requirement for STAT1 serine-727 phosphorylation (STAT1-pS727) during autoimmune and anti-pathogen responses remains unclear. Here we report that STAT1-pS727 promotes autoimmune antibody-forming cell (AFC) and germinal center (GC) responses, driving systemic lupus erythematosus (SLE) development. STAT1-pS727, however, is not required for GC and antibody responses to foreign-antigens including pathogens or gut microbiota. STAT1-pS727 plays an important B cell-intrinsic role in driving autoimmunity. Transcriptomic analysis of B cells from TLR7-accelerated SLE-prone mice reveals STAT1-pS727-mediated gene regulation of cellular pathways known to be involved in autoimmune GC and AFC responses. Mechanistically, TLR7 activation in B cells induces STAT1-pS727 and during autoimmune responses TLR7 signaling converges with IFNγ-STAT1 signaling in B cells by recruiting STAT1 into the MyD88 signaling complex. Together, we identify previously unappreciated differential regulation of autoimmune and anti-pathogen responses by STAT1-pS727, and implicate STAT1-pS727 as a therapeutic target for SLE.

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Noble, Alistair, Lydia Durant, Lesley Hoyles, Anne L. Mccartney, Ripple Man, Jonathan Segal, Samuel P. Costello, et al. "Deficient Resident Memory T Cell and CD8 T Cell Response to Commensals in Inflammatory Bowel Disease." Journal of Crohn's and Colitis 14, no. 4 (October 26, 2019): 525–37. http://dx.doi.org/10.1093/ecco-jcc/jjz175.

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Abstract Background and Aims The intestinal microbiota is closely associated with resident memory lymphocytes in mucosal tissue. We sought to understand how acquired cellular and humoral immunity to the microbiota differ in health versus inflammatory bowel disease [IBD]. Methods Resident memory T cells [Trm] in colonic biopsies and local antibody responses to intraepithelial microbes were analysed. Systemic antigen-specific immune T and B cell memory to a panel of commensal microbes was assessed. Results Systemically, healthy blood showed CD4 and occasional CD8 memory T cell responses to selected intestinal bacteria, but few memory B cell responses. In IBD, CD8 memory T cell responses decreased although B cell responses and circulating plasmablasts increased. Possibly secondary to loss of systemic CD8 T cell responses in IBD, dramatically reduced numbers of mucosal CD8+ Trm and γδ T cells were observed. IgA responses to intraepithelial bacteria were increased. Colonic Trm expressed CD39 and CD73 ectonucleotidases, characteristic of regulatory T cells. Cytokines/factors required for Trm differentiation were identified, and in vitro-generated Trm expressed regulatory T cell function via CD39. Cognate interaction between T cells and dendritic cells induced T-bet expression in dendritic cells, a key mechanism in regulating cell-mediated mucosal responses. Conclusions A previously unrecognised imbalance exists between cellular and humoral immunity to the microbiota in IBD, with loss of mucosal T cell-mediated barrier immunity and uncontrolled antibody responses. Regulatory function of Trm may explain their association with intestinal health. Promoting Trm and their interaction with dendritic cells, rather than immunosuppression, may reinforce tissue immunity, improve barrier function, and prevent B cell dysfunction in microbiota-associated disease and IBD aetiology.

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Paffett, Michael L., and Benjimen R. Walker. "Vascular adaptations to hypoxia: molecular and cellular mechanisms regulating vascular tone." Essays in Biochemistry 43 (August 10, 2007): 105–20. http://dx.doi.org/10.1042/bse0430105.

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Several molecular and cellular adaptive mechanisms to hypoxia exist within the vasculature. Many of these processes involve oxygen sensing which is transduced into mediators of vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation. A variety of oxygen-responsive pathways, such as HIF (hypoxia-inducible factor)-1 and HOs (haem oxygenases), contribute to the overall adaptive process during hypoxia and are currently an area of intense research. Generation of ROS (reactive oxygen species) may also differentially regulate vascular tone in these circulations. Potential candidates underlying the divergent responses between the systemic and pulmonary circulations may include Nox (NADPH oxidase)-derived ROS and mitochondrial-derived ROS. In addition to alterations in ROS production governing vascular tone in the hypoxic setting, other vascular adaptations are likely to be involved. HPV (hypoxic pulmonary vasoconstriction) and CH (chronic hypoxia)-induced alterations in cellular proliferation, ionic conductances and changes in the contractile apparatus sensitivity to calcium, all occur as adaptive processes within the vasculature.

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Ma, Zhong-Min, Kristina Abel, Tracy Rourke, Yichuan Wang, and Christopher J. Miller. "A Period of Transient Viremia and Occult Infection Precedes Persistent Viremia and Antiviral Immune Responses during Multiple Low-Dose Intravaginal Simian Immunodeficiency Virus Inoculations." Journal of Virology 78, no. 24 (December 15, 2004): 14048–52. http://dx.doi.org/10.1128/jvi.78.24.14048-14052.2004.

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ABSTRACT In rhesus macaques, classic systemic infection, characterized by persistent viremia and seroconversion, occurred after multiple low-dose (103 50% tissue culture infective doses) intravaginal (IVAG) inoculations with simian immunodeficiency virus (SIV) strain SIVmac251. Monkeys developed classic SIV infections after a variable number of low-dose IVAG exposures to SIVmac251. Once established, the systemic infection was identical to SIV infection following high-dose IVAG SIV inoculation. However, occult systemic infection characterized by transient cell-associated or cell-free viremia consistently occurred early in the series of multiple vaginal SIV exposures. Further, antiviral cellular immune responses were present prior to the establishment of a classic systemic infection in the low-dose vaginal SIV transmission model.

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Baig, Jamal, Daniel B. Levy, Paul F. McKay, Joern E. Schmitz, Sampa Santra, Ramu A. Subbramanian, Marcelo J. Kuroda, et al. "Elicitation of Simian Immunodeficiency Virus-Specific Cytotoxic T Lymphocytes in Mucosal Compartments of Rhesus Monkeys by Systemic Vaccination." Journal of Virology 76, no. 22 (November 15, 2002): 11484–90. http://dx.doi.org/10.1128/jvi.76.22.11484-11490.2002.

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ABSTRACT Since most human immunodeficiency virus (HIV) infections are initiated following mucosal exposure to the virus, the anatomic containment or abortion of an HIV infection is likely to require vaccine-elicited cellular immune responses in those mucosal sites. Studying vaccine-elicited mucosal immune responses has been problematic because of the difficulties associated with sampling T lymphocytes from those anatomic compartments. In the present study, we demonstrate that mucosal cytotoxic T lymphocytes (CTL) specific for simian immunodeficiency virus (SIV) and simian HIV can be reproducibly sampled from intestinal mucosal tissue of rhesus monkeys obtained under endoscopic guidance. These lymphocytes recognize peptide-major histocompatibility complex class I complexes and express gamma interferon on exposure to peptide antigen. Interestingly, systemic immunization of monkeys with plasmid DNA immunogens followed by live recombinant attenuated poxviruses or adenoviruses with genes deleted elicits high-frequency SIV-specific CTL responses in these mucosal tissues. These studies therefore suggest that systemic delivery of potent HIV immunogens may suffice to elicit substantial mucosal CTL responses.

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Hidajat, Rachmat, Peng Xiao, Qifeng Zhou, David Venzon, L. Ebonita Summers, Vaniambadi S. Kalyanaraman, David C. Montefiori, and Marjorie Robert-Guroff. "Correlation of Vaccine-Elicited Systemic and Mucosal Nonneutralizing Antibody Activities with Reduced Acute Viremia following Intrarectal Simian Immunodeficiency Virus SIVmac251 Challenge of Rhesus Macaques." Journal of Virology 83, no. 2 (October 29, 2008): 791–801. http://dx.doi.org/10.1128/jvi.01672-08.

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ABSTRACT Cell-mediated immunity and neutralizing antibodies contribute to control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infection, but the role of nonneutralizing antibodies is not defined. Previously, we reported that sequential oral/oral or intranasal/oral (I/O) priming with replication-competent adenovirus type 5 host range mutant (Ad5hr)-SIV recombinants, followed by intramuscular envelope protein boosting, elicited systemic and mucosal cellular immunity and exhibited equivalent, significant reductions of chronic viremia after rectal SIVmac251 challenge. However, I/O priming gave significantly better control of acute viremia. Here, systemic and mucosal humoral immunity were investigated for potential correlates with the acute challenge outcome. Strong serum binding but nonneutralizing antibody responses against SIVmac251 were induced in both groups. Antibody responses appeared earlier and overall were higher in the I/O group. Reduced acute viremia was significantly correlated with higher serum binding titer, stronger antibody-dependent cellular cytotoxicity activity, and peak prechallenge and 2-week-postchallenge antibody-dependent cell-mediated viral inhibition (ADCVI). The I/O group consistently displayed greater anti-envelope immunoglobulin A (IgA) antibody responses in bronchoalveolar lavage and a stronger rectal anti-envelope IgA anamnestic response 2 weeks postchallenge. Pre- and postchallenge rectal secretions inhibited SIV transcytosis across epithelial cells. The inhibition was significantly higher in the I/O group, although a significant correlation with reduced acute viremia was not reached. Overall, the replicating Ad5hr-SIV priming/envelope boosting approach elicited strong systemic and mucosal antibodies with multiple functional activities. The pattern of elevated immune responses in the I/O group is consistent with its better control of acute viremia mediated, at least in part, by ADCVI activity and transcytosis inhibition.

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Ko, Sung-Youl, Cheng Cheng, Wing-Pui Kong, Lingshu Wang, Masaru Kanekiyo, David Einfeld, C. Richter King, Jason G. D. Gall, and Gary J. Nabel. "Enhanced Induction of Intestinal Cellular Immunity by Oral Priming with Enteric Adenovirus 41 Vectors." Journal of Virology 83, no. 2 (November 5, 2008): 748–56. http://dx.doi.org/10.1128/jvi.01811-08.

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection is characterized by the rapid onset of intestinal T-cell depletion that initiates the progression to AIDS. The induction of protective immunity in the intestinal mucosa therefore represents a potentially desirable feature of a preventive AIDS vaccine. In this study, we have evaluated the ability of an enteric adenovirus, recombinant adenovirus 41 (rAd41), to elicit intestinal and systemic immune responses by different immunization routes, alone or in combination with rAd5. rAd41 expressing HIV envelope (Env) protein induced cellular immune responses comparable to those of rAd5-based vectors after either a single intramuscular injection or a DNA prime/rAd boost. Oral priming with rAd41-Env followed by intramuscular boosting with rAd5-Env stimulated a more potent CD8+ T-cell response in the small intestine than the other immunization regimens. Furthermore, the direct injection of rAd41-Env into ileum together with intramuscular rAd5-Env boosting increased Env-specific cellular immunity markedly in mucosal as well as systemic compartments. These data demonstrate that heterologous rAd41 oral or ileal priming with rAd5 intramuscular boosting elicits enhanced intestinal mucosal cellular immunity and that oral or ileal vector delivery for primary immunization facilitates the generation of mucosal immunity.

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Strange, Kevin, Jerod Denton, and Keith Nehrke. "Ste20-Type Kinases: Evolutionarily Conserved Regulators of Ion Transport and Cell Volume." Physiology 21, no. 1 (February 2006): 61–68. http://dx.doi.org/10.1152/physiol.00139.2005.

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Ste20 serine/threonine kinases regulate fundamental cellular processes including the cell cycle, apoptosis, and stress responses. Recent studies in Caenorhabditis elegans and mammals demonstrate that Ste20 kinases also function in cell volume sensing and Cl− transport regulation. Yeast Ste20 initiates a shrinkage activated MAPK cascade that regulates organic osmolyte accumulation. Ste20 kinases thus play evolutionarily conserved roles in cellular volume sensing and regulation. They may also function in systemic osmotic homeostasis and to link cell-cycle events with cell volume.

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Rosseto-Welter, Eliane Aparecida, Silvia Sanches Rodrigues, Amanda Braga de Figueiredo, Carolina Nunes França, Danielle Bruna Leal Oliveira, André Luis Lacerda Bachi, Jônatas Bussador do Amaral, et al. "Cellular and Humoral Immune Responses to Vaccination for COVID-19 Are Negatively Impacted by Senescent T Cells: A Case Report." Vaccines 11, no. 4 (April 14, 2023): 840. http://dx.doi.org/10.3390/vaccines11040840.

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Background: Herein, we aimed to follow up on the cellular and humoral immune responses of a group of individuals who initially received the CoronaVac vaccine, followed by a booster with the Pfizer vaccine. Methods: Blood samples were collected: before and 30 days after the first CoronaVac dose; 30, 90, and 180 days after the second CoronaVac dose, and also 20 days after the booster with the Pfizer vaccine. Results: Whilst the positivity to gamma interferon-type cellular response increased after the first CoronaVac dose, neutralizing and IgG antibody levels only raised 30 days after the second dose, followed by a drop in these responses after 90 and 180 days. The booster with the Pfizer vaccine elicited a robust cellular and humoral response. A higher number of double-negative and senescent T cells, as well as increased pro-inflammatory cytokines levels were found in the participants with lower humoral immune responses. Conclusion: CoronaVac elicited an early cellular response, followed by a humoral response, which dropped 90 days after the second dose. The booster with the Pfizer vaccine significantly enhanced these responses. Furthermore, a pro-inflammatory systemic status was found in volunteers who presented senescent T cells, which could putatively impair the immune response to vaccination.

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Jneid, Bakhos, Aurore Bochnakian, Fabien Delisle, Emeline Djacoto, Jordan Denizeau, Christine Sedlik, Frédéric Fiore, et al. "Abstract LB198: Cellular selectivity of STING stimulation determines priming of anti-tumor T cell responses." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB198. http://dx.doi.org/10.1158/1538-7445.am2022-lb198.

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Abstract T cells that recognize tumor antigens are crucial for anti-tumor immune responses. Induction of anti-tumor T cells in immunogenic tumors depends on STING, the intracellular innate immune receptor for cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) and related cyclic dinucleotides (CDN). However, the optimal way to leverage STING activation in non-immunogenic tumors is still unclear. Here, we show that cGAMP delivery by intra-tumoral injection of virus-like particles (cGAMP-VLP) leads to differentiation of tumor-specific T cells, decrease in tumor regulatory T cells (Tregs) and anti-tumoral responses that synergize with PD1 blockade. By contrast, intra-tumoral injection of synthetic CDN leads to tumor necrosis and systemic T cell activation but no differentiation of tumor-specific T cells, and a demise of immune cells in injected tumors. Analyses of cytokine responses and genetic models revealed that cGAMP-VLP preferentially targets STING in dendritic cells at a 1000-fold less dose than synthetic CDN. Sub-cutaneous administration of cGAMP-VLP showed synergy when combined with a tumor Treg-depleting antibody to elicit systemic tumor-specific T cells, leading to complete and lasting tumor eradication. These findings show that cell targeting of STING stimulation shapes the anti-tumor T cell response and reveal a therapeutic strategy with T cell modulators, which may address the current limitations of STING-based approaches in patients. Citation Format: Bakhos Jneid, Aurore Bochnakian, Fabien Delisle, Emeline Djacoto, Jordan Denizeau, Christine Sedlik, Frédéric Fiore, Robert Kramer, Ian Walters, Sylvain Carlioz, Bernard Malissen, Eliane Piaggio, Nicolas Manel. Cellular selectivity of STING stimulation determines priming of anti-tumor T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB198.

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Chen, William A., Yuetan Dou, Hansel M. Fletcher, and Danilo S. Boskovic. "Local and Systemic Effects of Porphyromonas gingivalis Infection." Microorganisms 11, no. 2 (February 13, 2023): 470. http://dx.doi.org/10.3390/microorganisms11020470.

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Porphyromonas gingivalis, a gram-negative anaerobe, is a leading etiological agent in periodontitis. This infectious pathogen can induce a dysbiotic, proinflammatory state within the oral cavity by disrupting commensal interactions between the host and oral microbiota. It is advantageous for P. gingivalis to avoid complete host immunosuppression, as inflammation-induced tissue damage provides essential nutrients necessary for robust bacterial proliferation. In this context, P. gingivalis can gain access to the systemic circulation, where it can promote a prothrombotic state. P. gingivalis expresses a number of virulence factors, which aid this pathogen toward infection of a variety of host cells, evasion of detection by the host immune system, subversion of the host immune responses, and activation of several humoral and cellular hemostatic factors.

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Nozaki, Yuji, A. Richard Kitching, Hisaya Akiba, Hideo Yagita, Koji Kinoshita, Masanori Funauchi, and Itaru Matsumura. "Endogenous Tim-1 promotes severe systemic autoimmunity and renal disease MRL-Faslpr mice." American Journal of Physiology-Renal Physiology 306, no. 10 (May 15, 2014): F1210—F1221. http://dx.doi.org/10.1152/ajprenal.00570.2013.

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The T-cell immunoglobulin mucin 1, also known as kidney injury molecule-1, modulates CD4+ T-cell responses and is also expressed by damaged proximal tubules within the kidney. Both Th subset imbalance (Th1/Th2/Th17) and regulatory T-cell and B-cell alterations contribute to the pathogenesis of autoimmune disease. This study investigated the effects of an inhibitory anti-T-cell immunoglobulin mucin 1 antibody (RMT1–10) in lupus-prone MRL- Fas lpr mice. MRL- Fas lpr mice were treated with RMT1–10 or a control antibody intraperitoneally twice weekly from 3 mo of age for 16 wk. RMT1–10 treatment significantly improved survival, limited the development of lymphadenopathy and skin lesions, preserved renal function and decreased proteinuria, reduced serum anti-DNA antibody levels, and attenuated renal leukocyte accumulation. Th1 and Th17 cellular responses systemically and intrarenally were reduced, but regulatory T and B cells were increased. RMT1–10 treatment also reduced glomerular immunoglobulin and C3 deposition and suppressed cellular proliferation and apoptosis. Urinary excretion and renal expression of kidney injury molecule-1 was reduced, reflecting diminished interstitial injury. As RMT1–10 attenuated established lupus nephritis, manipulating immune system T-cell immunoglobulin mucin 1 may represent a therapeutic strategy in autoimmune diseases affecting the kidney.

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Slofstra, Sjoukje H., Maarten F. Bijlsma, Angelique P. Groot, Pieter H. Reitsma, Theo Lindhout, Hugo ten Cate, and C. Arnold Spek. "Protease-activated receptor-4 inhibition protects from multiorgan failure in a murine model of systemic inflammation." Blood 110, no. 9 (November 1, 2007): 3176–82. http://dx.doi.org/10.1182/blood-2007-02-075440.

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AbstractCoagulation proteases may act as cell signaling molecules via protease-activated receptor (PAR) cleavage, subsequently affecting cellular and inflammatory responses. Activation of PARs in the setting of systemic inflammation and disseminated intravascular coagulation (DIC) might thus exacerbate the inflammatory response contributing to tissue and organ damage. To investigate the role of PAR-4 in these processes, we subjected mice to a model of systemic inflammation and DIC (Shwartzman reaction) in the absence or presence of a cell-penetrating pepducin antagonist of PAR-4 (P4pal-10). P4pal-10 dose-dependently diminished the severity of endotoxemia and preserved liver, kidney, as well as lung function. Moreover, systemic inflammation and local (neutrophilic) inflammatory responses were attenuated. In vitro migration assays and P4pal-10 treatment in neutropenic mice suggest an essential role for neutrophils in PAR-4–mediated pathology. P4pal-10 treatment of thrombocytopenic mice excluded the involvement of platelets in this phenomenon. These results uncover an important role for PAR-4 in the Shwartzman reaction and suggest that inhibition of PAR-4 signaling in neutrophils could be protective in systemic inflammation and DIC.

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Bricker, Kristen N., Adam J. Fike, Sara A. Luckenbill, Julia L. Weber, Jasmine S. Jackson, Nancy J. Olsen, and Ziaur Rahman. "miR-21 promotes B cell autoreactivity, inflammatory signaling, and metabolism in TLR7-driven systemic autoimmunity." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 77.02. http://dx.doi.org/10.4049/jimmunol.210.supp.77.02.

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Abstract MicroRNA-21 (miR-21) is upregulated in SLE patients and promotes disease in multiple autoimmune mouse models; however, mechanisms by which miR-21 promote autoimmunity are unknown. Here we show that TLR7 overexpressing SLE-prone B6.Sle1b Yaamice deficient in miR-21 (Sle1b YaamiR-21 −/−) resisted autoimmunity development through reduced germinal center (GC) B cell, T follicular helper cell, and plasma cell responses. Sle1b YaamiR-21 −/−mice had reduced serum autoantibody titers and numbers of autoantibody-producing antibody forming cells (AFCs) in the spleen and bone marrow. Downstream of TLR7 signaling, PELI1, a negative regulator of the NF-κB family member c-Rel and a direct target of miR-21, was increased in Sle1b YaamiR-21 −/−B cells. Consequently, Sle1b YaamiR-21 −/−B cells had reduced c-Rel expression and proinflammatory cytokines IL-6 and IL-1β. Additionally, Sle1b YaamiR-21 −/−B cells had reduced oxidative phosphorylation, glycolysis, and mitochondrial membrane potential compared to Sle1b YaaB cells. To define the cell-intrinsic mechanisms, we generated B cell-, T cell- and DC-specific miR-21 conditional knockout (cKO) mice on the Sle1b Yaabackground. Reduced B cell autoreactivity, inflammatory signaling, and metabolism in Sle1b YaamiR-21 −/−mice were recapitulated in B cell-specific miR-21 cKO mice. T cell-specific miR-21 cKO mice had a moderate reduction in cellular responses due to reduced co-stimulatory molecules and glycolysis; however, autoimmune responses remained intact. miR-21 deficiency in DCs had no deficit in cellular or autoimmune responses. Our data substantiate a B cell-intrinsic role for miR-21 in promoting inflammatory signaling and metabolic activity in B cells, leading to autoimmunity.

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Journal articles on the topic 'CELLULAR AND SYSTEMIC RESPONSES'

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