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The Innate Immune Protein S100A9 Protects from T-Helper Cell Type 2-mediated Allergic Airway Inflammation.
Palmer LD, Maloney KN, Boyd KL, Goleniewska AK, Toki S, Maxwell CN, Chazin WJ, Peebles RS, Newcomb DC, Skaar EP
(2019) Am J Respir Cell Mol Biol 61: 459-468
MeSH Terms: Adaptive Immunity, Allergens, Alternaria, Alveolitis, Extrinsic Allergic, Animals, Bronchial Hyperreactivity, Bronchoalveolar Lavage Fluid, Calgranulin A, Calgranulin B, Cytokines, Forkhead Transcription Factors, Immunoglobulin E, Inflammation, Leukocyte L1 Antigen Complex, Lung, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pulmonary Eosinophilia, Specific Pathogen-Free Organisms, T-Lymphocytes, Regulatory, Th2 Cells
Show Abstract · Added April 7, 2019
Calprotectin is a heterodimer of the proteins S100A8 and S100A9, and it is an abundant innate immune protein associated with inflammation. In humans, calprotectin transcription and protein abundance are associated with asthma and disease severity. However, mechanistic studies in experimental asthma models have been inconclusive, identifying both protective and pathogenic effects of calprotectin. To clarify the role of calprotectin in asthma, calprotectin-deficient and wild-type (WT) C57BL/6 mice were compared in a murine model of allergic airway inflammation. Mice were intranasally challenged with extracts of the clinically relevant allergen, (Alt Ext), or PBS every third day over 9 days. On Day 10, BAL fluid and lung tissue homogenates were harvested and allergic airway inflammation was assessed. Alt Ext challenge induced release of S100A8/S100A9 to the alveolar space and increased protein expression in the alveolar epithelium of WT mice. Compared with WT mice, mice displayed significantly enhanced allergic airway inflammation, including production of IL-13, CCL11, CCL24, serum IgE, eosinophil recruitment, and airway resistance and elastance. In response to Alt Ext, mice accumulated significantly more IL-13IL-5CD4 T-helper type 2 cells. mice also accumulated a significantly lower proportion of CD4 T regulatory (Treg) cells in the lung that had significantly lower expression of CD25. Calprotectin enhanced WT Treg cell suppressive activity . Therefore, this study identifies a role for the innate immune protein, S100A9, in protection from CD4 T-helper type 2 cell hyperinflammation in response to Alt Ext. This protection is mediated, at least in part, by CD4 Treg cell function.
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23 MeSH Terms
Mucus T helper 2 biomarkers predict chronic rhinosinusitis disease severity and prior surgical intervention.
Turner JH, Li P, Chandra RK
(2018) Int Forum Allergy Rhinol 8: 1175-1183
MeSH Terms: Biomarkers, Chronic Disease, Female, Humans, Interleukin-13, Interleukin-5, Male, Middle Aged, Mucus, Nasal Mucosa, Nasal Polyps, Prospective Studies, Rhinitis, Sinusitis, Th2 Cells
Show Abstract · Added July 23, 2020
BACKGROUND - Chronic rhinosinusitis (CRS) is a diverse clinical syndrome with a heterogeneous pathophysiology. Early attempts to identify CRS endotypes and biomarkers have largely relied on analysis of surgically obtained tissue, thus limiting their practical utility. This study examined the ability of mucus T helper 2 (Th2) biomarkers to predict CRS disease severity and clinical characteristics.
METHODS - CRS (n = 90) and healthy control subjects (n = 17) were prospectively enrolled prior to surgical intervention and mucus levels of interleukin (IL)-4, IL-5, and IL-13 were determined using a multiplex cytometric bead assay. Data for relevant cytokines was then scaled, normalized, and later combined to develop standardized metrics indicative of Th2-associated inflammation. Th2-high and Th2-low subgroups were consequently identified and validated against factors associated with disease severity and clinical outcomes.
RESULTS - Mucus levels of IL-5 and IL-13 were elevated in CRS subjects compared to controls, while no significant difference was noted for IL-4. IL-5 and IL-13 high CRS were associated with worse objective measures of disease severity and greater rates of revision surgery. Similar relationships were noted for both cytokines when CRS with nasal polyps (CRSwNP) patients were analyzed separately. Th2-high CRS and Th2-low CRS were then categorized using a scaled IL-5/IL-13 metric. Th2-high CRS was characterized by an increased number of subjects with nasal polyps and comorbid asthma, and worse symptom and computed tomography (CT) scores.
CONCLUSION - The Th2-associated cytokines, IL-5 and IL-13, are detectable in sinonasal mucus and their levels can be used to define Th2-high and Th2-low CRS. Identification of Th2-high and Th2-low endotypes using mucus-based biomarkers could facilitate stratification of CRS subgroups and guide personalized therapies.
© 2018 ARS-AAOA, LLC.
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Definition of Human Epitopes Recognized in Tetanus Toxoid and Development of an Assay Strategy to Detect Ex Vivo Tetanus CD4+ T Cell Responses.
da Silva Antunes R, Paul S, Sidney J, Weiskopf D, Dan JM, Phillips E, Mallal S, Crotty S, Sette A, Lindestam Arlehamn CS
(2017) PLoS One 12: e0169086
MeSH Terms: Adult, Epitope Mapping, Epitopes, T-Lymphocyte, Female, Humans, Immunoassay, Immunologic Memory, Male, Tetanus Toxoid, Th1 Cells, Th2 Cells
Show Abstract · Added March 30, 2020
Despite widespread uses of tetanus toxoid (TT) as a vaccine, model antigen and protein carrier, TT epitopes have been poorly characterized. Herein we defined the human CD4+ T cell epitope repertoire by reevaluation of previously described epitopes and evaluation of those derived from prediction of HLA Class II binding. Forty-seven epitopes were identified following in vitro TT stimulation, with 28 epitopes accounting for 90% of the total response. Despite this diverse range of epitopes, individual responses were associated with only a few immunodominant epitopes, with each donor responding on average to 3 epitopes. For the top 14 epitopes, HLA restriction could be inferred based on HLA typing of the responding donors. HLA binding predictions re-identified the vast majority of known epitopes, and identified 24 additional novel epitopes. With these epitopes, we created a TT epitope pool, which allowed us to characterize TT responses directly ex vivo using a cytokine-independent Activation Induced Marker (AIM) assay. These TT responses were highly Th1 or Th2 polarized, which was dependent upon the original priming vaccine, either the cellular DTwP or acellular DTaP formulation. This polarization remained despite the original priming having occurred decades past and a recent booster immunization with a reduced acellular vaccine formulation. While TT responses following booster vaccination were not durably increased in magnitude, they were associated with a relative expansion of CD4+ effector memory T cells.
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Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation.
Zhou W, Zhang J, Goleniewska K, Dulek DE, Toki S, Newcomb DC, Cephus JY, Collins RD, Wu P, Boothby MR, Peebles RS
(2016) J Immunol 197: 1577-86
MeSH Terms: Allergens, Animals, Antihypertensive Agents, Asthma, CD4-Positive T-Lymphocytes, Cell Proliferation, Chemokines, Epoprostenol, Hypersensitivity, Indomethacin, Inflammation, Interleukin-13, Interleukin-5, Lung, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Knockout, Ovalbumin, Receptors, Epoprostenol, STAT6 Transcription Factor, Signal Transduction, Th2 Cells
Show Abstract · Added March 14, 2018
Allergic airway diseases are immune disorders associated with heightened type 2 immune responses and IL-5 and IL-13 production at the site of inflammation. We have previously reported that cyclooxygenase (COX) inhibition by indomethacin augmented allergic airway inflammation in a STAT6-independent manner. However, the key COX product(s) responsible for restraining indomethacin-mediated STAT6-independent allergic inflammation is unknown. In this study, using the mouse model of OVA-induced allergic airway inflammation, we identified that PGI2 receptor (IP) signaling was critical for indomethacin-induced, STAT6-independent proallergic effects. We demonstrated that IP deficiency increased inflammatory cell infiltration, eosinophilia, and IL-5 and IL-13 expression in the lung in a STAT6-independent manner. The augmented STAT6-independent allergic inflammation correlated with enhanced primary immune responses to allergic sensitization and elevated production of multiple inflammatory chemokines (CCL11, CCL17, CCL22, and CXCL12) in the lung after allergen challenge. We also showed that the PGI2 analogue cicaprost inhibited CD4 T cell proliferation and IL-5 and IL-13 expression in vitro, and IP deficiency diminished the stimulatory effect of indomethacin on STAT6-independent IL-5 and IL-13 responses in vivo. The inhibitory effects of PGI2 and the IP signaling pathway on CD4 T cell activation, inflammatory chemokine production, and allergic sensitization and airway inflammation suggest that PGI2 and its analogue iloprost, both Food and Drug Administration-approved drugs, may be useful in treating allergic diseases and asthma. In addition, inhibiting PGI2 signaling by drugs that either block PGI2 production or restrain IP signaling may augment STAT6-independent pathways of allergic inflammation.
Copyright © 2016 by The American Association of Immunologists, Inc.
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23 MeSH Terms
TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization.
Caballero MT, Serra ME, Acosta PL, Marzec J, Gibbons L, Salim M, Rodriguez A, Reynaldi A, Garcia A, Bado D, Buchholz UJ, Hijano DR, Coviello S, Newcomb D, Bellabarba M, Ferolla FM, Libster R, Berenstein A, Siniawaski S, Blumetti V, Echavarria M, Pinto L, Lawrence A, Ossorio MF, Grosman A, Mateu CG, Bayle C, Dericco A, Pellegrini M, Igarza I, Repetto HA, Grimaldi LA, Gudapati P, Polack NR, Althabe F, Shi M, Ferrero F, Bergel E, Stein RT, Peebles RS, Boothby M, Kleeberger SR, Polack FP
(2015) J Clin Invest 125: 571-82
MeSH Terms: Animals, Bronchiolitis, Viral, Disease Models, Animal, Environmental Exposure, Female, GATA3 Transcription Factor, Genotype, Humans, Infant, Infant, Newborn, Interferon-gamma, Interleukin-4, Lipopolysaccharides, Male, Mice, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, T-Box Domain Proteins, Th2 Cells, Toll-Like Receptor 4
Show Abstract · Added January 20, 2015
While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.
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20 MeSH Terms
Simultaneous inhibition of T helper 2 and T regulatory cell differentiation by small molecules enhances Bacillus Calmette-Guerin vaccine efficacy against tuberculosis.
Bhattacharya D, Dwivedi VP, Kumar S, Reddy MC, Van Kaer L, Moodley P, Das G
(2014) J Biol Chem 289: 33404-11
MeSH Terms: Animals, Anti-Allergic Agents, Arylsulfonates, Benzamides, Cell Differentiation, Imidazoles, Mice, Mice, Inbred BALB C, Mycobacterium bovis, Mycobacterium tuberculosis, Sulfonium Compounds, T-Lymphocytes, Regulatory, Th2 Cells, Tuberculosis Vaccines, Tuberculosis, Pulmonary
Show Abstract · Added January 20, 2015
Tuberculosis affects nine million individuals and kills almost two million people every year. The only vaccine available, Bacillus Calmette-Guerin (BCG), has been used since its inception in 1921. Although BCG induces host-protective T helper 1 (Th1) cell immune responses, which play a central role in host protection, its efficacy is unsatisfactory, suggesting that additional methods to enhance protective immune responses are needed. Recently we have shown that simultaneous inhibition of Th2 cells and Tregs by using the pharmacological inhibitors suplatast tosylate and D4476, respectively, dramatically enhances Mycobacterium tuberculosis clearance and induces superior Th1 responses. Here we show that treatment with these two drugs during BCG vaccination dramatically improves vaccine efficacy. Furthermore, we demonstrate that these drugs induce a shift in the development of T cell memory, favoring central memory T (Tcm) cell responses over effector memory T (Tem) cell responses. Collectively, our findings provide evidence that simultaneous inhibition of Th2 cells and Tregs during BCG vaccination promotes vaccine efficacy.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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15 MeSH Terms
STAT4 deficiency fails to induce lung Th2 or Th17 immunity following primary or secondary respiratory syncytial virus (RSV) challenge but enhances the lung RSV-specific CD8+ T cell immune response to secondary challenge.
Dulek DE, Newcomb DC, Toki S, Goliniewska K, Cephus J, Reiss S, Bates JT, Crowe JE, Boyd KL, Moore ML, Zhou W, Peebles RS
(2014) J Virol 88: 9655-72
MeSH Terms: Animals, CD8-Positive T-Lymphocytes, Disease Models, Animal, Female, Lung, Mice, Inbred BALB C, Mice, Knockout, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, STAT4 Transcription Factor, Th17 Cells, Th2 Cells
Show Abstract · Added January 20, 2015
UNLABELLED - Immune-mediated lung injury is a hallmark of lower respiratory tract illness caused by respiratory syncytial virus (RSV). STAT4 plays a critical role in CD4+ Th1 lineage differentiation and gamma interferon (IFN-γ) protein expression by CD4+ T cells. As CD4+ Th1 differentiation is associated with negative regulation of CD4+ Th2 and Th17 differentiation, we hypothesized that RSV infection of STAT4-/- mice would result in enhanced lung Th2 and Th17 inflammation and impaired lung Th1 inflammation compared to wild-type (WT) mice. We performed primary and secondary RSV challenges in WT and STAT4-/- mice and used STAT1-/- mice as a positive control for the development of RSV-specific lung Th2 and Th17 inflammation during primary challenge. Primary RSV challenge of STAT4-/- mice resulted in decreased T-bet and IFN-γ expression levels in CD4+ T cells compared to those of WT mice. Lung Th2 and Th17 inflammation did not develop in primary RSV-challenged STAT4-/- mice. Decreased IFN-γ expression by NK cells, CD4+ T cells, and CD8+ T cells was associated with attenuated weight loss and enhanced viral clearance with primary challenge in STAT4-/- mice compared to WT mice. Following secondary challenge, WT and STAT4-/- mice also did not develop lung Th2 or Th17 inflammation. In contrast to primary challenge, secondary RSV challenge of STAT4-/- mice resulted in enhanced weight loss, an increased lung IFN-γ expression level, and an increased lung RSV-specific CD8+ T cell response compared to those of WT mice. These data demonstrate that STAT4 regulates the RSV-specific CD8+ T cell response to secondary infection but does not independently regulate lung Th2 or Th17 immune responses to RSV challenge.
IMPORTANCE - STAT4 is a protein critical for both innate and adaptive immune responses to viral infection. Our results show that STAT4 regulates the immune response to primary and secondary challenge with RSV but does not restrain RSV-induced lung Th2 or Th17 immune responses. These findings suggest that STAT4 expression may influence lung immunity and severity of illness following primary and secondary RSV infections.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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12 MeSH Terms
Small molecule-directed immunotherapy against recurrent infection by Mycobacterium tuberculosis.
Bhattacharya D, Dwivedi VP, Maiga M, Maiga M, Van Kaer L, Bishai WR, Das G
(2014) J Biol Chem 289: 16508-15
MeSH Terms: Animals, Flow Cytometry, Immunotherapy, Mice, Mice, Inbred BALB C, Mycobacterium tuberculosis, Th1 Cells, Th2 Cells, Tuberculosis
Show Abstract · Added January 20, 2015
Tuberculosis remains the biggest infectious threat to humanity with one-third of the population infected and 1.4 million deaths and 8.7 million new cases annually. Current tuberculosis therapy is lengthy and consists of multiple antimicrobials, which causes poor compliance and high treatment dropout, resulting in the development of drug-resistant variants of tuberculosis. Therefore, alternate methods to treat tuberculosis are urgently needed. Mycobacterium tuberculosis evades host immune responses by inducing T helper (Th)2 and regulatory T (Treg) cell responses, which diminish protective Th1 responses. Here, we show that animals (Stat-6(-/-)CD4-TGFβRIIDN mice) that are unable to generate both Th2 cells and Tregs are highly resistant to M. tuberculosis infection. Furthermore, simultaneous inhibition of these two subsets of Th cells by therapeutic compounds dramatically reduced bacterial burden in different organs. This treatment was associated with the generation of protective Th1 immune responses. As these therapeutic agents are not directed to the harbored organisms, they should avoid the risk of promoting the development of drug-resistant M. tuberculosis variants.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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9 MeSH Terms
STAT4 and T-bet are required for the plasticity of IFN-γ expression across Th2 ontogeny and influence changes in Ifng promoter DNA methylation.
Williams CL, Schilling MM, Cho SH, Lee K, Wei M, Aditi , Boothby M
(2013) J Immunol 191: 678-87
MeSH Terms: Animals, Cell Differentiation, Cells, Cultured, CpG Islands, DNA Methylation, Immunologic Memory, Interferon-gamma, Interleukin-4, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Nude, Promoter Regions, Genetic, STAT4 Transcription Factor, T-Box Domain Proteins, Th1 Cells, Th2 Cells
Show Abstract · Added March 7, 2014
CD4(+) T cells developing toward a Th2 fate express IL-4, IL-5, and IL-13 while inhibiting production of cytokines associated with other Th types, such as the Th1 cytokine IFN- γ. IL-4-producing Th2 effector cells give rise to a long-lived memory population committed to reactivation of the Th2 cytokine gene expression program. However, reactivation of these effector-derived cells under Th1-skewing conditions leads to production of IFN-γ along with IL-4 in the same cell. We now show that this flexibility ("plasticity") of cytokine expression is preceded by a loss of the repressive DNA methylation of the Ifng promoter acquired during Th2 polarization yet requires STAT4 along with T-box expressed in T cells. Surprisingly, loss of either STAT4 or T-box expressed in T cells increased Ifng promoter CpG methylation in both effector and memory Th2 cells. Taken together, our data suggest a model in which the expression of IFN-γ by Th2-derived memory cells involves attenuation of epigenetic repression in memory Th2 cells, combined with Th1-polarizing signals after their recall activation.
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18 MeSH Terms
Deficiency of gp91phox inhibits allergic airway inflammation.
Sevin CM, Newcomb DC, Toki S, Han W, Sherrill TP, Boswell MG, Zhu Z, Collins RD, Boyd KL, Goleniewska K, Huckabee MM, Blackwell TS, Peebles RS
(2013) Am J Respir Cell Mol Biol 49: 396-402
MeSH Terms: Animals, Asthma, Bronchoalveolar Lavage Fluid, Cells, Cultured, Dendritic Cells, Female, Gene Deletion, Interleukin-12, Interleukin-13, Lipopolysaccharides, Lung, Membrane Glycoproteins, Mice, Mice, Knockout, NADPH Oxidase 2, NADPH Oxidases, Ovalbumin, Reactive Oxygen Species, Th1 Cells, Th1-Th2 Balance, Th17 Cells, Th2 Cells
Show Abstract · Added March 7, 2014
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a multienzyme complex, is the major source for production of reactive oxygen species (ROS). ROS are increased in allergic diseases, such as asthma, but the role of ROS in disease pathogenesis remains uncertain. We hypothesized that mice unable to generate ROS via the NADPH oxidase pathway would have decreased allergic airway inflammation. To test this hypothesis, we studied gp91phox(-/-) mice in a model of allergic airway inflammation after sensitization and challenge with ovalbumin. Serum, bronchoalveolar lavage fluid, and lungs were then examined for evidence of allergic inflammation. We found that mice lacking a functional NADPH oxidase complex had significantly decreased ROS production and allergic airway inflammation, compared with wild-type (WT) control animals. To determine the mechanism by which allergic inflammation was inhibited by gp91phox deficiency, we cultured bone marrow-derived dendritic cells from WT and gp91phox(-/-) mice and activated them with LPS. IL-12 expression was significantly increased in the gp91phox(-/-) bone marrow-derived dendritic cells, suggesting that the cytokine profile produced in the absence of gp91phox enhanced the conditions leading to T helper (Th) type 1 differentiation, while inhibiting Th2 polarization. Splenocytes from sensitized gp91phox(-/-) animals produced significantly less IL-13 in response to ovalbumin challenge in vitro compared with splenocytes from sensitized WT mice, suggesting that NADPH oxidase promotes allergic sensitization. In contrast, inflammatory cytokines produced by T cells cultured from WT and gp91phox(-/-) mice under Th0, Th1, Th2, and Th17 conditions were not significantly different. This study demonstrates the importance of NADPH oxidase activity and ROS production in a murine model of asthma.
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22 MeSH Terms