53 results on '"Anne I. Sperling"'
Search Results
2. Hypersensitivity pneumonitis: Current concepts in pathogenesis, diagnosis, and treatment
- Author
-
Ian Glaspole, Mary E. Strek, Anne I. Sperling, Lauren K. Troy, Cathryn Lee, and Hayley Barnes
- Subjects
Inflammation ,Lung Diseases ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Immunology ,Interstitial lung disease ,Extrinsic Allergic Alveolitis ,Lung biopsy ,respiratory system ,medicine.disease ,Bronchoalveolar Lavage ,Fibrosis ,Bronchoalveolar lavage ,medicine ,Humans ,Immunology and Allergy ,Honeycombing ,Occupational lung disease ,business ,Hypersensitivity pneumonitis ,Alveolitis, Extrinsic Allergic - Abstract
Hypersensitivity pneumonitis is an immune-mediated interstitial lung disease caused by an aberrant response to an inhaled exposure, which results in mostly T cell-mediated inflammation, granuloma formation, and fibrosis in some cases. HP is diagnosed by exposure identification, HRCT findings of ground-glass opacities, centrilobular nodules, and mosaic attenuation, with traction bronchiectasis and honeycombing in fibrotic cases. Additional testing including serum IgG testing for the presence of antigen exposure, bronchoalveolar lavage lymphocytosis, and lung biopsy demonstrating granulomas, inflammation, and fibrosis, increases the diagnostic confidence. Treatment for HP includes avoidance of the implicated exposure, immunosuppression, and anti-fibrotic therapy in select cases. This narrative review presents the recent literature in the understanding of the immunopathological mechanisms, diagnosis, and treatment of HP.
- Published
- 2021
3. A series of <scp>COVID</scp> ‐19 autopsies with clinical and pathologic comparisons to both seasonal and pandemic influenza
- Author
-
Lindsay Alpert, Alexis Snyder, David Wu, James Brainer, Thomas Krausz, Aliya N. Husain, Peter Pytel, Heather L. Smith, Nathan Schoettler, Anne I. Sperling, Jeffrey Mueller, Anthony Chang, Ayodeji Adegunsoye, John Hart, Jasmine Vickery, Robert D. Guzy, Phillip McMullen, and Sandeep Gurbuxani
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,viral pneumonia ,Autopsy ,Lung injury ,Pathology and Forensic Medicine ,autopsy ,COVID‐19 ,Influenza, Human ,RB1-214 ,Humans ,Medicine ,Diffuse alveolar damage ,Lung ,Pandemics ,In Situ Hybridization ,Aged ,SARS-CoV-2 ,business.industry ,Pandemic influenza ,COVID-19 ,Histology ,Original Articles ,medicine.disease ,Immunohistochemistry ,diffuse alveolar damage ,viral sepsis ,Viral pneumonia ,Original Article ,Female ,Seasons ,influenza ,business - Abstract
Autopsies of patients who have died from COVID‐19 have been crucial in delineating patterns of injury associated with SARS‐CoV‐2 infection. Despite their utility, comprehensive autopsy studies are somewhat lacking relative to the global burden of disease, and very few comprehensive studies contextualize the findings to other fatal viral infections. We developed a novel autopsy protocol in order to perform postmortem examinations on victims of COVID‐19 and herein describe detailed clinical information, gross findings, and histologic features observed in the first 16 complete COVID‐19 autopsies. We also critically evaluated the role of ancillary studies used to establish a diagnosis of COVID‐19 at autopsy, including immunohistochemistry (IHC), in situ hybridization (ISH), and electron microscopy (EM). IHC and ISH targeting SARS‐CoV‐2 were comparable in terms of the location and number of infected cells in lung tissue; however, nonspecific staining of bacteria was seen occasionally with IHC. EM was unrevealing in blindly sampled tissues. We then compared the clinical and histologic features present in this series to six archival cases of fatal seasonal influenza and six archival cases of pandemic influenza from the fourth wave of the ‘Spanish Flu’ in the winter of 1920. In addition to routine histology, the inflammatory infiltrates in the lungs of COVID‐19 and seasonal influenza victims were compared using quantitative IHC. Our results demonstrate that the clinical and histologic features of COVID‐19 are similar to those seen in fatal cases of influenza, and the two diseases tend to overlap histologically. There was no significant difference in the composition of the inflammatory infiltrate in COVID‐19 and influenza at sites of acute lung injury at the time of autopsy. Our study underscores the relatively nonspecific clinical features and pathologic changes shared between severe cases of COVID‐19 and influenza, while also providing important caveats to ancillary methods of viral detection.
- Published
- 2021
4. Temperature Trajectory Subphenotypes Correlate With Immune Responses in Patients With Sepsis
- Author
-
Bhakti K. Patel, Philip A. Verhoef, Craig M. Coopersmith, Julie Lin, John P. Kress, Cara L. Hrusch, Jared A. Greenberg, K. S. Wolfe, Sivasubramanium V. Bhavani, Paulette A. Krishack, P. Lecompte-Osorio, Kyle A Carey, Matthew M. Churpek, and Anne I. Sperling
- Subjects
Male ,medicine.medical_specialty ,Fever ,medicine.medical_treatment ,Bacteremia ,Critical Care and Intensive Care Medicine ,Article ,Body Temperature ,Sepsis ,03 medical and health sciences ,0302 clinical medicine ,Immunophenotyping ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Aged ,Cytokine Measurement ,Septic shock ,business.industry ,Immunity ,030208 emergency & critical care medicine ,Middle Aged ,Staphylococcal Infections ,medicine.disease ,Shock, Septic ,Cytokine ,030228 respiratory system ,Cohort ,Cytokines ,Female ,business - Abstract
OBJECTIVES We recently found that distinct body temperature trajectories of infected patients correlated with survival. Understanding the relationship between the temperature trajectories and the host immune response to infection could allow us to immunophenotype patients at the bedside using temperature. The objective was to identify whether temperature trajectories have consistent associations with specific cytokine responses in two distinct cohorts of infected patients. DESIGN Prospective observational study. SETTING Large academic medical center between 2013 and 2019. SUBJECTS Two cohorts of infected patients: 1) patients in the ICU with septic shock and 2) hospitalized patients with Staphylococcus aureus bacteremia. INTERVENTIONS Clinical data (including body temperature) and plasma cytokine concentrations were measured. Patients were classified into four temperature trajectory subphenotypes using their temperature measurements in the first 72 hours from the onset of infection. Log-transformed cytokine levels were standardized to the mean and compared with the subphenotypes in both cohorts. MEASUREMENTS AND MAIN RESULTS The cohorts consisted of 120 patients with septic shock (cohort 1) and 88 patients with S. aureus bacteremia (cohort 2). Patients from both cohorts were classified into one of four previously validated temperature subphenotypes: "hyperthermic, slow resolvers" (n = 19 cohort 1; n = 13 cohort 2), "hyperthermic, fast resolvers" (n = 18 C1; n = 24 C2), "normothermic" (n = 54 C1; n = 31 C2), and "hypothermic" (n = 29 C1; n = 20 C2). Both "hyperthermic, slow resolvers" and "hyperthermic, fast resolvers" had high levels of G-CSF, CCL2, and interleukin-10 compared with the "hypothermic" group when controlling for cohort and timing of cytokine measurement (p < 0.05). In contrast to the "hyperthermic, slow resolvers," the "hyperthermic, fast resolvers" showed significant decreases in the levels of several cytokines over a 24-hour period, including interleukin-1RA, interleukin-6, interleukin-8, G-CSF, and M-CSF (p < 0.001). CONCLUSIONS Temperature trajectory subphenotypes are associated with consistent cytokine profiles in two distinct cohorts of infected patients. These subphenotypes could play a role in the bedside identification of cytokine profiles in patients with sepsis.
- Published
- 2020
5. Circulating Plasma Biomarkers of Progressive Interstitial Lung Disease
- Author
-
Claire Cutting, Mary E. Strek, Angela L. Linderholm, Cara L. Hrusch, Anne I. Sperling, Shwu Fan Ma, Justin M. Oldham, Ayodeji Adegunsoye, Shehabaldin Alqalyoobi, and Imre Noth
- Subjects
Male ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Vital Capacity ,Vascular Cell Adhesion Molecule-1 ,Critical Care and Intensive Care Medicine ,Plasma biomarkers ,Idiopathic pulmonary fibrosis ,Correspondence ,Humans ,Medicine ,Lung transplantation ,Chitinase-3-Like Protein 1 ,Progression-free survival ,Connective Tissue Diseases ,Aged ,Proportional Hazards Models ,business.industry ,Interstitial lung disease ,Middle Aged ,Prognosis ,Pulmonary Surfactant-Associated Protein D ,medicine.disease ,Chemokine CXCL13 ,Connective tissue disease ,Progression-Free Survival ,Biomarker (cell) ,CA-125 Antigen ,Matrix Metalloproteinase 7 ,Disease Progression ,Female ,Lung Diseases, Interstitial ,business ,Biomarkers ,Hypersensitivity pneumonitis ,Alveolitis, Extrinsic Allergic ,Lung Transplantation - Published
- 2020
6. Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis
- Author
-
Monique Hinchcliff, Monica Chi, Manu Jain, Anna P. Lam, Vince K. Morgan, Gökhan M. Mutlu, Ali Shilatifard, Luís A. Nunes Amaral, A. Christine Argento, Satoshi Watanabe, Robert D. Guzy, SeungHye Han, Ankit Bharat, Colin T. Gillespie, Stacy A. Marshall, Kishore R. Anekalla, Ching I. Chen, Kiwon Nam, Alexandra C. McQuattie-Pimentel, Alexander V. Misharin, Remzi Bag, Annette S. Flozak, Harris Perlman, Karen M. Ridge, Rohan Verma, Benjamin D. Singer, James M. Walter, Jane Dematte, Catherine A. Bonham, Stephen Chiu, Ramiro Fernandez, Ziyou Ren, Cara L. Hrusch, Saul Soberanes, Anjana Yeldandi, Francisco J. Gonzalez-Gonzalez, Nikita Joshi, Hiam Abdala-Valencia, Trevor T. Nicholson, G. R. Scott Budinger, Sangeeta Bhorade, Anne I. Sperling, Paul A. Reyfman, Mahzad Akbarpour, Jacob I. Sznajder, Deborah R. Winter, Robert B. Hamanaka, Kinola J.N. Williams, and Cara J. Gottardi
- Subjects
Male ,Pulmonary and Respiratory Medicine ,Cell type ,Pathology ,medicine.medical_specialty ,Population ,Cell ,Critical Care and Intensive Care Medicine ,Transcriptome ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Fibrosis ,Pulmonary fibrosis ,medicine ,Animals ,Humans ,030212 general & internal medicine ,education ,Cells, Cultured ,education.field_of_study ,Sequence Analysis, RNA ,business.industry ,Stem Cells ,Editorials ,Epithelial Cells ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,3. Good health ,Disease Models, Animal ,medicine.anatomical_structure ,030228 respiratory system ,Female ,Stem cell ,business - Abstract
Rationale: The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. Objectives: To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects. Methods: We performed single-cell RNA sequencing on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and on one bronchoscopic cryobiospy sample from a patient with idiopathic pulmonary fibrosis. We validated these data using in situ RNA hybridization, immunohistochemistry, and bulk RNA-sequencing on flow-sorted cells from 22 additional subjects. Measurements and Main Results: We identified a distinct, novel population of profibrotic alveolar macrophages exclusively in patients with fibrosis. Within epithelial cells, the expression of genes involved in Wnt secretion and response was restricted to nonoverlapping cells. We identified rare cell populations including airway stem cells and senescent cells emerging during pulmonary fibrosis. We developed a web-based tool to explore these data. Conclusions: We generated a single-cell atlas of pulmonary fibrosis. Using this atlas, we demonstrated heterogeneity within alveolar macrophages and epithelial cells from subjects with pulmonary fibrosis. These results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.
- Published
- 2019
7. Prognosticating Outcomes in Interstitial Lung Disease by Mediastinal Lymph Node Assessment. An Observational Cohort Study with Independent Validation
- Author
-
Imre Noth, Kiran H. Thakrar, Aliya N. Husain, Ayodeji Adegunsoye, Jonathan H. Chung, Steven M. Montner, Justin M. Oldham, Uday K. Mehta, Shashi Bellam, Wesley Klejch, Anne I. Sperling, Rekha Vij, Mary E. Strek, Paul Nolan, Janelle Vu Pugashetti, Catherine A. Bonham, Cara L. Hrusch, and Christopher M. Straus
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Lymphadenopathy ,Computed tomography ,Critical Care and Intensive Care Medicine ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Pulmonary fibrosis ,Mediastinal Diseases ,medicine ,Humans ,In patient ,030212 general & internal medicine ,medicine.diagnostic_test ,business.industry ,Interstitial lung disease ,Original Articles ,respiratory system ,medicine.disease ,respiratory tract diseases ,body regions ,030228 respiratory system ,Mediastinal lymph node ,Lymph Nodes ,Radiology ,Lung Diseases, Interstitial ,business ,Cohort study - Abstract
Rationale: Mediastinal lymph node (MLN) enlargement on chest computed tomography (CT) is prevalent in patients with interstitial lung disease (ILD) and may reflect immunologic activation and subsequent cytokine-mediated immune cell trafficking. Objectives: We aimed to determine whether MLN enlargement on chest CT predicts clinical outcomes and circulating cytokine levels in ILD. Methods: MLN measurements were obtained from chest CT scans of patients with ILD at baseline evaluation over a 10-year period. Patients with sarcoidosis and drug toxicity–related ILD were excluded. MLN diameter and location were assessed. Plasma cytokine levels were analyzed in a subset of patients. The primary outcome was transplant-free survival (TFS). Secondary outcomes included all-cause and respiratory hospitalizations, lung function, and plasma cytokine concentrations. Cox regression was used to assess mortality risk. Outcomes were assessed in three independent ILD cohorts. Measurements and Main Results: Chest CT scans were assessed in 1,094 patients (mean age, 64 yr; 52% male). MLN enlargement (≥10 mm) was present in 66% (n = 726) and strongly predicted TFS (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.12–2.10; P = 0.008) and risk of all-cause and respiratory hospitalizations (internal rate of return [IRR], 1.52; 95% CI, 1.17–1.98; P = 0.002; and IRR, 1.71; 95% CI, 1.15–2.53; P = 0.008, respectively) when compared with subjects with MLN 45 pg/ml predicted mortality (HR, 4.21; 95% CI, 1.21–14.68; P = 0.024). Independent analysis of external datasets confirmed these findings. Conclusions: MLN enlargement predicts TFS and hospitalization risk in ILD and is associated with decreased levels of a key circulating cytokine, soluble CD40L. Incorporating MLN and cytokine findings into current prediction models might improve ILD prognostication.
- Published
- 2019
8. Improving the Quality and Reproducibility of Flow Cytometry in the Lung. An Official American Thoracic Society Workshop Report
- Author
-
Hideki Nakano, Alexander V. Misharin, William J. Zacharias, Susanne Herold, Suchitra Swaminathan, Benjamin D. Singer, Elizabeth F. Redente, Claudia Jakubzick, Ryan Duggan, William J. Janssen, Anne I. Sperling, Christine M. Freeman, Jeffrey L. Curtis, Ryan R. Brinkman, Robert M. Tighe, and Yen-Rei A. Yu
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Lung Diseases ,medicine.medical_specialty ,media_common.quotation_subject ,Clinical Biochemistry ,Apoptosis ,Cell Separation ,lung biology ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Quality (business) ,Myeloid Cells ,Intensive care medicine ,Molecular Biology ,Pulmonary flow ,reproducibility ,Lung ,Organ system ,Societies, Medical ,media_common ,American Thoracic Society Documents ,Reproducibility ,medicine.diagnostic_test ,business.industry ,flow cytometry ,Reproducibility of Results ,Cell Biology ,Limiting ,Congresses as Topic ,United States ,030104 developmental biology ,medicine.anatomical_structure ,Phenotype ,030228 respiratory system ,Practice Guidelines as Topic ,cells ,business ,Cytometry - Abstract
Defining responses of the structural and immune cells in biologic systems is critically important to understanding disease states and responses to injury. This requires accurate and sensitive methods to define cell types in organ systems. The principal method to delineate the cell populations involved in these processes is flow cytometry. Although researchers increasingly use flow cytometry, technical challenges can affect its accuracy and reproducibility, thus significantly limiting scientific advancements. This challenge is particularly critical to lung immunology, as the lung is readily accessible and therefore used in preclinical and clinical studies to define potential therapeutics. Given the importance of flow cytometry in pulmonary research, the American Thoracic Society convened a working group to highlight issues and technical challenges to the performance of high-quality pulmonary flow cytometry, with a goal of improving its quality and reproducibility.
- Published
- 2019
9. SARS-CoV-2 infection reduces Krüppel-Like Factor 2 in human lung autopsy
- Author
-
Ayodeji Adegunsoye, Yun Fang, Nathan Schoettler, Robert D. Guzy, Gökhan M. Mutlu, Aliya Hussein, David Wu, Anne I. Sperling, Tzu-Han Lee, and Jeffrey Mueller
- Subjects
Male ,ARDS ,Kruppel-Like Transcription Factors ,Inflammation ,Respiratory Mucosa ,Lung injury ,Article ,Correspondence ,medicine ,Humans ,Endothelial dysfunction ,Lung ,SARS-CoV-2 ,business.industry ,COVID-19 ,Pulmonary edema ,medicine.disease ,medicine.anatomical_structure ,Immunology ,KLF2 ,Female ,Autopsy ,medicine.symptom ,business ,Cytokine storm - Abstract
Acute respiratory distress syndrome (ARDS) occurred in ~12% of hospitalized COVID-19 patients in a recent New York City cohort. Pulmonary endothelial dysfunction, characterized by increased expression of inflammatory genes and increased monolayer permeability, is a major component of ARDS. Vascular leak results in parenchymal accumulation of leukocytes, protein, and extravascular water, leading to pulmonary edema, ischemia, and activation of coagulation associated with COVID-19. Endothelial inflammation further contributes to uncontrolled cytokine storm in ARDS. We have recently demonstrated that Krüppel-like factor 2 (KLF2), a transcription factor which promotes endothelial quiescence and monolayer integrity, is significantly reduced in experimental models of ARDS. Lung inflammation and high-tidal volume ventilation result in reduced KLF2, leading to pulmonary endothelial dysfunction and acute lung injury. Mechanistically, we found that KLF2 is a potent transcriptional activator of Rap guanine nucleotide exchange factor 3 (RAPGEF3) which orchestrates and maintains vascular integrity. Moreover, KLF2 regulates multiple genome-wide association study (GWAS)-implicated ARDS genes. Whether lung KLF2 is regulated by SARS-CoV-2 infection is unknown. Here we report that endothelial KLF2 is significantly reduced in human lung autopsies from COVID-19 patients, which supports that ARDS due to SARS-CoV-2 is a vascular phenotype possibly attributed to KLF2 down-regulation. We provide additional data demonstrating that KLF2 is down-regulated in SARS-CoV infection in mice.
- Published
- 2021
10. Circulating Plasma Biomarkers of Survival in Antifibrotic-Treated Patients With Idiopathic Pulmonary Fibrosis
- Author
-
Mary E. Strek, Janelle Vu Pugashetti, Imre Noth, Angela L. Linderholm, Ayodeji Adegunsoye, Anne I. Sperling, Willis S. Bowman, Justin M. Oldham, Cathryn Lee, Nandini Sarma, Shwu Fan Ma, Angela Franciska Haczku, and Shehabaldin Alqalyoobi
- Subjects
Oncology ,Male ,Indoles ,Respiratory System ,Critical Care and Intensive Care Medicine ,Cohort Studies ,Idiopathic pulmonary fibrosis ,chemistry.chemical_compound ,0302 clinical medicine ,80 and over ,030212 general & internal medicine ,Lung ,Aged, 80 and over ,interstitial lung disease ,education.field_of_study ,screening and diagnosis ,Hazard ratio ,Interstitial lung disease ,Pirfenidone ,idiopathic pulmonary fibrosis ,Survival Rate ,Detection ,Biomarker (medicine) ,biomarker ,Nintedanib ,Female ,Cardiology and Cardiovascular Medicine ,medicine.drug ,4.2 Evaluation of markers and technologies ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Pyridones ,Population ,Clinical Sciences ,survival ,Autoimmune Disease ,03 medical and health sciences ,Rare Diseases ,Clinical Research ,Internal medicine ,medicine ,Humans ,education ,Aged ,business.industry ,Proportional hazards model ,antifibrotic ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,4.1 Discovery and preclinical testing of markers and technologies ,030228 respiratory system ,chemistry ,business ,Biomarkers - Abstract
BackgroundA number of circulating plasma biomarkers have been shown to predict survival in patients with idiopathic pulmonary fibrosis (IPF), but most were identified before the use of antifibrotic (AF) therapy in this population. Because pirfenidone and nintedanib have been shown to slow IPF progression and may prolong survival, the role of such biomarkers in AF-treated patients is unclear.Research questionTo determine whether plasma concentration of cancer antigen 125 (CA-125), C-X-C motif chemokine 13 (CXCL13), matrix metalloproteinase 7 (MMP7), surfactant protein D (SP-D), chitinase-3-like protein-1 (YKL-40), vascular cell adhesion protein-1 (VCAM-1), and osteopontin (OPN) is associated with differential transplant-free survival (TFS) in AF-exposed and nonexposed patients with IPF.Study design and methodsA pooled, multicenter, propensity-matched analysis of IPF patients with and without AF exposure was performed. Optimal thresholds for biomarker dichotomization were identified in each group using iterative Cox regression. Longitudinal biomarker change was assessed in a subset of patients using linear mixed regression modeling. A clinical-molecular signature of IPF TFS was then derived and validated in an independent IPF cohort.ResultsThree hundred twenty-five patients were assessed, of which 68 AF-exposed and 172 nonexposed patients were included after propensity matching. CA-125, CXCL13, MMP7, YKL-40, and OPN predicted differential TFS in AF-exposed patients but at higher thresholds than in AF-nonexposed individuals. Plasma biomarker level generally increased over time in nonexposed patients but remained unchanged in AF-exposed patients. A clinical-molecular signature predicted decreased TFS in AF-exposed patients (hazard ratio [HR], 5.91; 95%CI, 2.25-15.5; P< .001) and maintained this association in an independent AF-exposed cohort (HR, 3.97; 95%CI, 1.62-9.72; P= .003).InterpretationMost plasma biomarkers assessed predicted differential TFS in AF-exposed patients with IPF, but at higher thresholds than in nonexposed patients. A clinical-molecular signature of IPF TFS may provide a reliable predictor of outcome risk in AF-treated patients but requires additional research for optimization and validation.
- Published
- 2020
11. Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization
- Author
-
Shuei-Liong Lin, Shen-Chuan Lo, Yu-Shan Lin, Y.-H. Lee, Frank-Leigh Lu, Kai-Chien Yang, Sung-Jan Lin, Tzu-Pin Shentu, Pei-Chen Wu, Chen-Ting Hung, Ying-Chun Shih, Robert D. Guzy, Chau-Chung Wu, Wan-Lin Wu, Yen-Ting Chen, Tzu-Han Lee, Anne I. Sperling, Ru-Ting Huang, Ming-Yi You, Yueh-Feng Wu, Chiung-Nien Chen, Yun Fang, Po-Nien Tsao, Chih-Fan Yeh, Yi-Shuan Tseng, and Tzu-Hung Lin
- Subjects
0301 basic medicine ,Male ,Protein Folding ,Molecular biology ,Pulmonary Fibrosis ,Receptor, Transforming Growth Factor-beta Type I ,General Physics and Astronomy ,02 engineering and technology ,Idiopathic pulmonary fibrosis ,chemistry.chemical_compound ,Mice ,Thioredoxins ,Pulmonary fibrosis ,Protein disulfide-isomerase ,lcsh:Science ,Mice, Knockout ,Multidisciplinary ,Protein Stability ,021001 nanoscience & nanotechnology ,Endoplasmic Reticulum Stress ,Up-Regulation ,medicine.anatomical_structure ,0210 nano-technology ,Signal Transduction ,Science ,Protein Disulfide-Isomerases ,Bleomycin ,General Biochemistry, Genetics and Molecular Biology ,Article ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Downregulation and upregulation ,medicine ,Animals ,Humans ,Respiratory tract diseases ,Lung ,business.industry ,Endoplasmic reticulum ,General Chemistry ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Unfolded protein response ,Cancer research ,lcsh:Q ,business ,Gene Deletion - Abstract
Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFβ1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFβ1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF., Pulmonary fibrosis is a major public health problem with unclear mechanism and limited therapeutic options. Here the authors show that a fibroblast-enriched endoplasmic reticulum protein, TXNDC5, promotes pulmonary fibrosis by stabilizing TGFBR1 and show the potential of TXNDC5 as a therapeutic target against pulmonary fibrosis.
- Published
- 2020
12. IL-33-Mediated Eosinophilia Protects Against Staphylococcus Aureus-Induced Lung Injury
- Author
-
Trevor S. Decker, Paulette A. Krishack, Cara L. Hrusch, Philip A. Verhoef, Timothy G. Kuzel, Tyler J. Louviere, and Anne I. Sperling
- Subjects
Interleukin 33 ,Staphylococcus aureus ,business.industry ,Immunology ,medicine ,Eosinophilia ,Lung injury ,medicine.symptom ,medicine.disease_cause ,business - Published
- 2020
13. Regional Disparities of Molecular Profiles and Cell Compositions in the Lungs of Idiopathic Pulmonary Fibrosis Patients
- Author
-
Milena S. Espindola, Catherine A. Bonham, Shwu Fan Ma, Robert D. Guzy, Yong Huang, Anne I. Sperling, Cory M. Hogaboam, Imre Noth, and Andrew J. Barros
- Subjects
Idiopathic pulmonary fibrosis ,Pathology ,medicine.medical_specialty ,medicine.anatomical_structure ,business.industry ,Cell ,medicine ,business ,medicine.disease - Published
- 2020
14. Immune development and environment: lessons from Amish and Hutterite children
- Author
-
Erika von Mutius, Carole Ober, Donata Vercelli, and Anne I. Sperling
- Subjects
Rural Population ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Farms ,animal diseases ,Population ,Immunology ,Ethnic group ,Context (language use) ,Article ,Atopy ,03 medical and health sciences ,Immune system ,Risk Factors ,Ethnicity ,Hypersensitivity ,Prevalence ,Humans ,Immunology and Allergy ,Medicine ,Child ,education ,Asthma ,education.field_of_study ,business.industry ,medicine.disease ,Immunity, Innate ,United States ,Early life ,Europe ,030104 developmental biology ,Lifestyle factors ,Amish ,business ,Demography - Abstract
Children who grow up in traditional farm environments are protected from developing asthma and allergy. This “farm effect” can be largely explained by the child’s early life contact with farm animals, in particular cows, and their microbes. Our studies in Amish and Hutterite school children living on farms in the U.S. have further demonstrated that this protection is mediated through innate immune pathways. Although very similar with respect to ancestry and many lifestyle factors that are associated with asthma risk, Amish and Hutterites follow farming practices that are associated with profound differences in the levels of house dust endotoxin, in the prevalence of asthma and atopy among school children, and in the proportions, phenotypes, and functions of immune cells from these children. In this review, we will consider our studies in Amish and Hutterites children in the context of the many previous studies in European farm children and discuss how these studies have advanced our understanding of the asthma-protective “farm effect”.
- Published
- 2017
15. IL-33 Drives Monocyte Recruitment to Lung Interstitium through Chemokine Upregulation
- Author
-
Anne I. Sperling, Melissa Y. Tjota, Heth R. Turnquist, and Daniel F. Camacho
- Subjects
CCR2 ,Chemokine ,Immunology ,CCL2 ,CCL7 ,Article ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Immunology and Allergy ,Medicine ,Monocyte extravasation ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,Monocyte ,General Medicine ,respiratory system ,respiratory tract diseases ,medicine.anatomical_structure ,biology.protein ,business ,CCL22 ,030215 immunology - Abstract
Tissue infiltration by circulating monocytes is a critical step in the initiation and augmentation of type 2 inflammatory responses in the lungs. Our studies demonstrate that IL-33−/− mice have a defect in monocyte extravasation from the vasculature to the lung interstitium during induction of type 2 inflammatory responses. This result suggests that monocyte migration to the lungs is IL-33 dependent, and we found that administration of exogenous recombinant IL-33 is sufficient to restore monocyte localization to the lung interstitium. Further investigation of the effect of early administration of recombinant IL-33 on the lungs identified upregulation of multiple chemokines including the monocyte chemoattractants CCL2, CCL7, and CCL22. Importantly, blockade of G-protein coupled receptor–dependent signaling, and thereby chemokine receptor activity, inhibited IL-33–driven monocyte recruitment. CCR2 deficiency prevented recruitment of monocytes to the lung extravascular space during allergic sensitization, and resulted in reduced eosinophilia after allergen challenge. Thus, IL-33 plays a critical role in the initiation of type 2 inflammatory responses by inducing upregulation of chemokines that promote monocyte recruitment to the lung interstitium.
- Published
- 2017
16. TEMPERATURE TRAJECTORY MAY BE AN INDICATOR OF BACTEREMIA IN PATIENTS WITH SEPTIC SHOCK
- Author
-
Julie Lin, Paola Lecompte Osorio, John P. Kress, Matthew M. Churpek, K. S. Wolfe, Sivasubramanium V. Bhavani, Bhakti K. Patel, Anne I. Sperling, and Philip A. Verhoef
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Septic shock ,business.industry ,Critical Care and Intensive Care Medicine ,medicine.disease ,Internal medicine ,Bacteremia ,Trajectory ,medicine ,Cardiology ,In patient ,Cardiology and Cardiovascular Medicine ,business - Published
- 2020
17. Pro-lymphangiogenic VEGFR-3 signaling modulates memory T cell responses in allergic airway inflammation
- Author
-
Cara L. Hrusch, Harri Nurmi, Katharina Maisel, Daniel F. Camacho, Rachel Gleyzer, Anne I. Sperling, David B. Chapel, Kari Alitalo, Jorge Emiliano Gomez Medellin, Lambert Potin, and Melody A. Swartz
- Subjects
0301 basic medicine ,Chemokine ,Immunology ,Vascular Endothelial Growth Factor C ,VEGF-C ,Inflammation ,VEGF-D ,medicine.disease_cause ,Article ,Immunophenotyping ,03 medical and health sciences ,Mice ,0302 clinical medicine ,T-Lymphocyte Subsets ,medicine ,Respiratory Hypersensitivity ,Immunology and Allergy ,Animals ,Lymphangiogenesis ,House dust mite ,biology ,business.industry ,Pyroglyphidae ,acute ,resolution ,Allergens ,Acquired immune system ,biology.organism_classification ,Vascular Endothelial Growth Factor Receptor-3 ,Asthma ,030104 developmental biology ,medicine.anatomical_structure ,Allergic response ,biology.protein ,Disease Susceptibility ,medicine.symptom ,business ,Memory T cell ,Immunologic Memory ,Biomarkers ,030215 immunology ,CCL21 ,Signal Transduction - Abstract
In allergic airway inflammation, VEGFR-3-mediated lymphangiogenesis occurs in humans and mouse models, yet its immunological roles, particularly in adaptive immunity, are poorly understood. Here, we explored how pro-lymphangiogenic signaling affects the allergic response to house dust mite (HDM). In the acute inflammatory phase, the lungs of mice treated with blocking antibodies against VEGFR-3 (mF4-31C1) displayed less inflammation overall, with dramatically reduced innate and T cell numbers and reduced inflammatory chemokine levels. However, when inflammation was allowed to resolve and memory recall was induced 2 months later, mice treated with mF4-31C1 as well as VEGF-C/-D knockout models showed exacerbated type 2 memory response to HDM, with increased Th2 cells, eosinophils, type 2 chemokines, and pathological inflammation scores. This was associated with lower CCL21 and decreased TRegs in the lymph nodes. Together, our data imply that VEGFR-3 activation in allergic airways both help initiate the acute inflammatory response as well as regulate the adaptive (memory) response, possibly in part by shifting the TReg/Th2 balance. This introduces new immunomodulatory roles for pro-lymphangiogenic VEGFR-3 signaling in allergic airway inflammation and suggests that airway lymphatics may be a novel target for treating allergic responses.
- Published
- 2019
18. Microbial Regulation of Lung Injury in Mice
- Author
-
Cara L. Hrusch, N. Fei, K.A.M. Mills, Jack A. Gilbert, Anne I. Sperling, Vanessa Leone, and G.M. Barron
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,Medicine ,Lung injury ,business - Published
- 2019
19. Association Between Temperature Trajectory and Cytokine Signatures in Patients with Staphylococcus Aureus Bacteremia
- Author
-
Matthew M. Churpek, Jared A. Greenberg, Philip A. Verhoef, Kyle A Carey, Anne I. Sperling, Sivasubramanium V. Bhavani, and Cara L. Hrusch
- Subjects
Cytokine ,business.industry ,medicine.medical_treatment ,Immunology ,Medicine ,Staphylococcus aureus bacteremia ,In patient ,business - Published
- 2019
20. Reciprocal Fungal and Bacterial Microbiota in Airways of Patients with T2-High Associated Asthma
- Author
-
Anne I. Sperling, Bharathi Laxman, Edward T. Naureckas, Julian Solway, Jack A. Gilbert, Douglas K. Hogarth, Ashokkumar M. Sharma, Steven R. White, and C. Ober
- Subjects
business.industry ,Immunology ,Medicine ,business ,medicine.disease ,Reciprocal ,Asthma - Published
- 2019
21. Eosinophilia Protects Against S. Aureus Systemic and Pneumonia Induced Bacteremia
- Author
-
Philip A. Verhoef, Paulette A. Krishack, Trevor S. Decker, Anne I. Sperling, Tyler J. Louviere, and Timothy G. Kuzel
- Subjects
Pneumonia ,business.industry ,Bacteremia ,Immunology ,medicine ,Eosinophilia ,medicine.symptom ,medicine.disease ,business - Published
- 2019
22. IL-5 Signaling Protects from Lung Edema and Mortality in Murine Models of Acute Respiratory Distress Syndrome
- Author
-
Kelly M. Blaine, Anne I. Sperling, Donna C. Decker, R. Voogt, Cara L. Hrusch, K.A.M. Mills, and Paulette A. Krishack
- Subjects
business.industry ,Immunology ,Medicine ,LUNG EDEMA ,Acute respiratory distress ,business ,Interleukin 5 - Published
- 2019
23. Evidence for an IL-6 high asthma phenotype in asthma patients of African ancestry
- Author
-
Edward T. Naureckas, Douglas K. Hogarth, Anne I. Sperling, C. Ober, Steven R. White, Bharathi Laxman, and Julian Solway
- Subjects
Adult ,Male ,Asthma phenotypes ,Immunology ,Black People ,Systemic inflammation ,Article ,Young Adult ,immune system diseases ,medicine ,Immunology and Allergy ,Asthmatic patient ,Humans ,Young adult ,Interleukin 6 ,Asthma ,biology ,business.industry ,Interleukin-6 ,Middle Aged ,medicine.disease ,Phenotype ,Obesity ,respiratory tract diseases ,biology.protein ,Observational study ,Female ,medicine.symptom ,business - Abstract
High circulating IL-6 may define a phenotype of asthma associated with obesity and systemic inflammation. We demonstrate that circulating IL-6 is higher in African-American patients with asthma, and that race-specific thresholds should be considered.
- Published
- 2019
24. T cell Co-Stimulatory molecules ICOS and CD28 stratify idiopathic pulmonary fibrosis survival
- Author
-
Anne I. Sperling, Mary E. Strek, Catherine A. Bonham, Stephenie T. Manns, Rekha Vij, Cara L. Hrusch, Kelly M. Blaine, Justin M. Oldham, Imre Noth, and Matthew M. Churpek
- Subjects
Pulmonary and Respiratory Medicine ,lcsh:Immunologic diseases. Allergy ,CD28 ,medicine.medical_treatment ,T cell ,T cells ,Idiopathic pulmonary fibrosis ,chemical and pharmacologic phenomena ,Article ,Pulmonary function testing ,FEV1/FVC ratio ,DLCO ,medicine ,Lung transplantation ,lcsh:RC705-779 ,business.industry ,lcsh:Diseases of the respiratory system ,respiratory system ,medicine.disease ,Immune checkpoint ,respiratory tract diseases ,medicine.anatomical_structure ,ICOS ,Immunology ,business ,lcsh:RC581-607 - Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating disease that kills as many Americans as breast cancer each year. This study investigated whether lung function decline and survival associates with adaptive immunity in patients with IPF, specifically the expression of checkpoint molecules ICOS, CD28 and PD-1 on circulating CD4 T cells. Clinical data, blood samples and pulmonary function tests were collected prospectively and longitudinally from 59 patients with IPF over a study period of 5 years. Patients were followed until death, lung transplantation, or study end, and cell surface expression of CD45RO, CD28, ICOS, and PD-1 was measured on CD4 T cells via flow cytometry. Repeated measures of ICOS and CD28 on CD4 T cells revealed significant associations between declining ICOS and CD28 expression, and declining lung function parameters FVC and DLCO, independent of age, sex, race, smoking history, or immunosuppressant use. Strikingly, patients in the highest quintile of ICOS at study entry had markedly improved survival, while those with low CD28 fared poorly. No change in PD-1 expression was found. Analysis of ICOS and CD28 from the first blood draw identified three populations of IPF patients; those at high risk for early death, those with intermediate risk, and those at low risk. These results highlight the role of T cell mediated immunity in IPF survival, finding the assessment of two T cell stimulatory checkpoint molecules, CD28 and ICOS, was sufficient to discriminate three distinct survival trajectories over 5 years of patient follow up. Keywords: Idiopathic pulmonary fibrosis, T cells, ICOS, CD28, Immune checkpoint
- Published
- 2019
25. Preexisting Type 2 Immune Activation Protects against the Development of Sepsis
- Author
-
Julian Solway, Andrey Rzhetsky, Anne I. Sperling, Philip A. Verhoef, Kanix Wang, and Paulette A. Krishack
- Subjects
Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Staphylococcus aureus ,Clinical Biochemistry ,Sepsis ,03 medical and health sciences ,Th2 Cells ,0302 clinical medicine ,Text mining ,Correspondence ,medicine ,Animals ,Humans ,Molecular Biology ,business.industry ,Cell Biology ,Staphylococcal Infections ,medicine.disease ,030104 developmental biology ,030228 respiratory system ,Acute Disease ,Immunology ,Female ,business ,Immune activation - Published
- 2017
26. Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children
- Author
-
Fernando D. Martinez, Julie G. Ledford, Vadim Pivniouk, Michelle M. Stein, Jack A. Gilbert, Rebecca Anderson, Sean E. Murray, Cara L. Hrusch, Peter S. Thorne, Carole Ober, Mauricius Marques dos Santos, Julia W. Neilson, Erika von Mutius, Nervana Metwali, Raina M. Maier, Anne I. Sperling, Donata Vercelli, Mark Holbreich, Catherine Igartua, and Justyna Gozdz
- Subjects
0301 basic medicine ,Innate immune system ,Cross-sectional study ,business.industry ,Genetic genealogy ,General Medicine ,Environmental exposure ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,030228 respiratory system ,Immunity ,Immunology ,medicine ,Microbiome ,business ,Asthma - Abstract
BackgroundThe Amish and Hutterites are U.S. agricultural populations whose lifestyles are remarkably similar in many respects but whose farming practices, in particular, are distinct; the former follow traditional farming practices whereas the latter use industrialized farming practices. The populations also show striking disparities in the prevalence of asthma, and little is known about the immune responses underlying these disparities. MethodsWe studied environmental exposures, genetic ancestry, and immune profiles among 60 Amish and Hutterite children, measuring levels of allergens and endotoxins and assessing the microbiome composition of indoor dust samples. Whole blood was collected to measure serum IgE levels, cytokine responses, and gene expression, and peripheral-blood leukocytes were phenotyped with flow cytometry. The effects of dust extracts obtained from Amish and Hutterite homes on immune and airway responses were assessed in a murine model of experimental allergic asthma. ResultsDespite the...
- Published
- 2016
27. Allergen Exposure in Lymphopenic Fas-Deficient Mice Results in Persistent Eosinophilia Due to Defects in Resolution of Inflammation
- Author
-
Caroline M. Ferreira, Jesse W. Williams, Jiankun Tong, Crystal Rayon, Kelly M. Blaine, and Anne I. Sperling
- Subjects
lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,Adoptive cell transfer ,T cell ,Immunology ,Inflammation ,lung ,Mice ,03 medical and health sciences ,Th2 Cells ,0302 clinical medicine ,Antigen ,Eosinophilia ,medicine ,Animals ,Immunology and Allergy ,fas Receptor ,Original Research ,Mice, Knockout ,business.industry ,apoptosis ,asthma ,lymphopenia ,Allergens ,Th1 Cells ,Adoptive Transfer ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Apoptosis ,Knockout mouse ,Th1/Th2 cells ,eosinophils ,Disease Susceptibility ,medicine.symptom ,lcsh:RC581-607 ,business ,Homeostasis ,030215 immunology - Abstract
Asthma is characterized by chronic airway type-2 inflammation and eosinophilia, yet the mechanisms involved in chronic, non-resolving inflammation remain poorly defined. Previously, our group has found that when Rag-deficient mice were reconstituted with Fas-deficient B6 LPR T cells and sensitized and challenged, the mice developed a prolonged type-2-mediated airway inflammation that continued for more than 6 weeks after the last antigen exposure. Surprisingly, no defect in resolution was found when intact B6 LPR mice or T cell specific Fas-conditional knockout mice were sensitized and challenged. We hypothesize that the homeostatic proliferation induced by adoptive transfer of T cells into Rag-deficient mice may be an important mechanism involved in the lack of resolution. To investigate the role of homeostatic proliferation, we induced lymphopenia in the T cell-specific Fas-conditional knockout mice by non-lethal irradiation and sensitized them when T cells began to repopulate. Interestingly, we found that defective Fas signaling on T cells plus antigen exposure during homeostatic proliferation was sufficient to induce prolonged eosinophilic airway inflammation. In conclusion, our data show that the combination of transient lymphopenia, abnormal Fas-signaling, and antigen exposure leads to the development of a prolonged airway eosinophilic inflammatory phase in our mouse model of experimental asthma.
- Published
- 2018
28. Protection against Staphylococcus aureus bacteremia-induced mortality depends on ILC2s and eosinophils
- Author
-
Trevor S. Decker, Tyler J. Louviere, Daniel F. Camacho, Anne I. Sperling, Timothy G. Kuzel, Paulette A. Krishack, Jared A. Greenberg, Philip A. Verhoef, and Cara L. Hrusch
- Subjects
0301 basic medicine ,Staphylococcus aureus ,Neutrophils ,medicine.medical_treatment ,Stimulation ,Bacteremia ,Pulmonary Edema ,Sepsis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Th2 Cells ,medicine ,Hypersensitivity ,Eosinophilia ,Animals ,Humans ,Promyelocytic Leukemia Zinc Finger Protein ,Lung ,Asthma ,Mice, Knockout ,Interleukin-13 ,business.industry ,Innate lymphoid cell ,General Medicine ,Staphylococcal Infections ,medicine.disease ,Interleukin-33 ,Immunity, Innate ,Eosinophils ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Cytokine ,030220 oncology & carcinogenesis ,Immunology ,Cytokines ,Th17 Cells ,medicine.symptom ,Antigens, CD1d ,Interleukin-5 ,business ,Research Article - Abstract
The dysregulated, unbalanced immune response of sepsis results in a mortality exceeding 20%, yet recent findings by our group indicate that patients with allergic, type 2–mediated immune diseases are protected from developing sepsis. We evaluated CD4(+) Th cell polarization among patients with Staphylococcus aureus bacteremia and confirmed that survivors had a higher percentage of circulating Th2 cells but lower frequencies of Th17 cells and neutrophils early in the course of infection. To establish the mechanism of this protection, we used a mouse model of lethal S. aureus bacteremia and found that intratracheal pretreatment with the type 2–initiating cytokine IL-33 activated pulmonary type 2 innate lymphoid cells (ILC2s) and promoted eosinophilia. In addition, stimulation of type 2 immunity before lethal infection suppressed the pulmonary neutrophilic response to S. aureus. Mice lacking functional ILC2s did not respond to IL-33 and were not protected from lethal bacteremia, but treatment of these mice with the type 2 cytokines IL-5 and IL-13 rescued them from death. Depletion of eosinophils abrogated IL-33–mediated protection, indicating that eosinophilia is also necessary for the survival benefit. Thus, we have identified a potentially novel mechanism by which type 2 immunity can balance dysregulated septic inflammatory responses, thereby clarifying the protective benefit of type 2 immune diseases on sepsis mortality.
- Published
- 2018
29. Distinct T-helper cell responses to Staphylococcus aureus bacteremia reflect immunologic comorbidities and correlate with mortality
- Author
-
Anne I. Sperling, Jesse B. Hall, Philip A. Verhoef, Jared A. Greenberg, Mohammad R. Jaffery, Robert S. Daum, John P. Kress, Michael Z. David, and Cara L. Hrusch
- Subjects
Adult ,Male ,0301 basic medicine ,Staphylococcus aureus ,Lymphocyte ,medicine.medical_treatment ,Bacteremia ,Critical Care and Intensive Care Medicine ,T-Lymphocytes, Regulatory ,Statistics, Nonparametric ,Sepsis ,03 medical and health sciences ,Th2 Cells ,0302 clinical medicine ,Immune system ,Immunity ,medicine ,Humans ,Blood culture ,Lymphocyte Count ,Aged ,Proportional Hazards Models ,Chicago ,medicine.diagnostic_test ,business.industry ,Proportional hazards model ,Research ,lcsh:Medical emergencies. Critical care. Intensive care. First aid ,030208 emergency & critical care medicine ,lcsh:RC86-88.9 ,T helper cell ,Middle Aged ,Staphylococcal Infections ,Th1 Cells ,Flow Cytometry ,medicine.disease ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,Immunology ,Cytokines ,Th17 Cells ,Female ,Helper T cells ,business - Abstract
Background The dysregulated host immune response that defines sepsis varies as a function of both the immune status of the host and the distinct nature of the pathogen. The degree to which immunocompromising comorbidities or immunosuppressive medications affect the immune response to infection is poorly understood because these patients are often excluded from studies about septic immunity. The objectives of this study were to determine the immune response to a single pathogen (Staphylococcus aureus) among a diverse case mix of patients and to determine whether comorbidities affect immune and clinical outcomes. Methods Blood samples were drawn from 95 adult inpatients at multiple time points after the first positive S. aureus blood culture. Cox proportional hazards modeling was used to determine the associations between admission neutrophil counts, admission lymphocyte counts, cytokine levels, and 90-day mortality. A nested case-control flow cytometric analysis was conducted to determine T-helper type 1 (Th1), Th2, Th17, and regulatory T-cell (Treg) subsets among a subgroup of 28 patients. In a secondary analysis, we categorized patients as either having immunocompromising disorders (human immunodeficiency virus and hematologic malignancies), receiving immunosuppressive medications, or being not immunocompromised. Results Higher neutrophil-to-lymphocyte count ratios and higher Th17 cytokine responses relative to Th1 cytokine responses early after infection were independently associated with mortality and did not depend on the immune state of the patient (HR 1.93, 95% CI 1.17–3.17, p = 0.01; and HR 1.13, 95% CI 1.01–1.27, p = 0.03, respectively). On the basis of flow cytometric analysis of CD4 T-helper subsets, an increasing Th17/Treg response over the course of the infection was most strongly associated with increased mortality (HR 4.41, 95% CI 1.69–11.5, p
- Published
- 2018
30. ANTI-FIBROTIC THERAPY MODULATES MORTALITY RISK ASSOCIATED WITH CIRCULATING PLASMA BIOMARKERS IN PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS
- Author
-
Noelle Boctor, Shehabaldin Alqalyoobi, Angela L. Linderholm, Anne I. Sperling, Justin M. Oldham, Janelle Vu Pugashetti, Cara L. Hrusch, Imre Noth, Mary E. Strek, and Ayodeji Adegunsoye
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Anti fibrotic ,business.industry ,Critical Care and Intensive Care Medicine ,Plasma biomarkers ,medicine.disease ,Gastroenterology ,Idiopathic pulmonary fibrosis ,Internal medicine ,medicine ,In patient ,Cardiology and Cardiovascular Medicine ,business - Published
- 2019
31. Reply to Lescoat et al. and to Khamis et al
- Author
-
Imre Noth, Anne I. Sperling, Jonathan H. Chung, Mary E. Strek, Ayodeji Adegunsoye, and Justin M. Oldham
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,Extramural ,General surgery ,MEDLINE ,030204 cardiovascular system & hematology ,Critical Care and Intensive Care Medicine ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,030212 general & internal medicine ,business ,Cohort study - Published
- 2019
32. Elevated levels of soluble humanleukocyte antigen-G in the airways are a marker for a low-inflammatory endotype of asthma
- Author
-
Julian Solway, Edward T. Naureckas, Alexa Minc, Carole Ober, Steven R. White, Jessie Nicodemus-Johnson, Darcy R. Denner, D. Kyle Hogarth, Anne I. Sperling, Bharathi Laxman, and Randi Stern
- Subjects
0301 basic medicine ,Adult ,Male ,Endotype ,Immunology ,Nitric Oxide ,Article ,03 medical and health sciences ,Antigen ,Immunology and Allergy ,Medicine ,Humans ,Asthma ,HLA-G Antigens ,business.industry ,respiratory system ,Immunoglobulin E ,Middle Aged ,medicine.disease ,Eosinophils ,030104 developmental biology ,Female ,business ,Bronchoalveolar Lavage Fluid ,Biomarkers - Abstract
Soluble human leukocyte antigen-G (sHLA-G), an immunomodulatory molecule associated with suppression of inflammation, is elevated in the airways of asthmatic patients with a low inflammatory endotype as evidenced by low airway eosinophils and low exhaled nitric oxide.
- Published
- 2016
33. Fas-positive T cells regulate the resolution of airway inflammation in a murine model of asthma
- Author
-
Rebecca A. Shilling, Diwakar D. Balachandran, Bohao Chen, Jiankun Tong, Joel V. Weinstock, Kimm J. Hamann, Anne I. Sperling, Julian Solway, Robert A. Anders, Hozefa S. Bandulwala, and Bryan S. Clay
- Subjects
Adoptive cell transfer ,Time Factors ,T-Lymphocytes ,Immunology ,Inflammation ,Article ,03 medical and health sciences ,Interleukin 21 ,Interferon-gamma ,Mice ,0302 clinical medicine ,Interferon ,Eosinophilia ,medicine ,Immunology and Allergy ,Animals ,Humans ,Interferon gamma ,fas Receptor ,Lung ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,business.industry ,Articles ,respiratory system ,Adoptive Transfer ,Asthma ,3. Good health ,Eosinophils ,Disease Models, Animal ,medicine.anatomical_structure ,Apoptosis ,Chronic Disease ,medicine.symptom ,business ,030215 immunology ,medicine.drug - Abstract
Persistent airway inflammation, mucus production, and airway hyperreactivity are the major contributors to the frequency and severity of asthma. Why lung inflammation persists in asthmatics remains unclear. It has been proposed that Fas-mediated apoptosis of inflammatory cells is a fundamental mechanism involved in the resolution of eosinophilic airway inflammation. Because infiltrating eosinophils are highly sensitive to Fas-mediated apoptosis, it has been presumed that direct ligation of Fas on eosinophils is involved. Here, we utilize adoptive transfers of T cells to demonstrate that the delayed resolution of eosinophilia in Fas-deficient mice is a downstream effect of Fas deficiency on T cells, not eosinophils. Interestingly, the mice that received Fas-deficient T cells, but not the controls, developed a persistent phase of inflammation that failed to resolve even 6 wk after the last challenge. This persistent phase correlated with decreased interferon (IFN)γ production by Fas-deficient T cells and could be reproduced with adoptive transfer of IFNγ-deficient T cells. These data demonstrate that Fas deficiency on T cells is sufficient for the development of long-term allergic airway disease in mice and implies that deregulation of death receptors such as Fas on human T cells could be an important factor in the development and/or chronic nature of asthma.
- Published
- 2006
34. Editorial overview: Allergy and hypersensitivity
- Author
-
Anne I. Sperling and Ansel Km
- Subjects
medicine.medical_specialty ,Allergy ,business.industry ,Immunology ,Adaptive Immunity ,medicine.disease ,Dermatology ,Immunity, Innate ,Hypersensitivity ,Immunology and Allergy ,Medicine ,Animals ,Humans ,business - Published
- 2014
35. The Role of Dendritic Cells and Monocytes in the Maintenance and Loss of Respiratory Tolerance
- Author
-
Cara L. Hrusch, Anne I. Sperling, and Melissa Y. Tjota
- Subjects
Pulmonary and Respiratory Medicine ,Allergy ,Immunology ,Inflammation ,Article ,Monocytes ,Dermatitis, Atopic ,Immune tolerance ,Atopy ,Antigen ,Immunity ,Immune Tolerance ,medicine ,Animals ,Humans ,Immunology and Allergy ,Respiratory system ,Sensitization ,business.industry ,Dendritic Cells ,medicine.disease ,Asthma ,Phenotype ,medicine.anatomical_structure ,medicine.symptom ,business - Abstract
Promoting tolerance to inhaled antigens is an active area of study with the potential to benefit the millions of Americans currently suffering from respiratory allergies and asthma. Interestingly, not all individuals with atopy are symptomatic, arguing that sensitization alone does not lead to an allergic clinical phenotype. Respiratory dendritic cells (rDCs), classically associated with inducing inflammatory responses, can actively promote tolerance. Tolerance can be broken when inflammatory stimuli, including viral infections and other environmental exposures, inhibit rDC-mediated tolerance by allowing innocuous antigen to be presented to initiate type-2 immunity. Importantly, rDCs are composed of multiple subsets, each with a unique response to an inhaled antigen that can lead to either tolerance or inflammation. In this review, we will discuss how rDC subsets actively maintain tolerance or, alternatively, break tolerance in response to environmental cues.
- Published
- 2014
36. Maternal asthma and microRNA regulation of soluble HLA-G in the airway
- Author
-
Carole Ober, Jyotsna Sudi, Julian Solway, Anne I. Sperling, Courtney N. Tierney, Lourdes Norwick, John F. McConville, Edward T. Naureckas, Douglas K. Hogarth, Jessie Nicodemus-Johnson, Dan L. Nicolae, Steven R. White, Bharathi Laxman, Randi Stern, and Jerry A. Krishnan
- Subjects
Adult ,Male ,Genotype ,Immunology ,Single-nucleotide polymorphism ,Human leukocyte antigen ,Respiratory Mucosa ,White People ,Article ,Young Adult ,medicine ,Immunology and Allergy ,Humans ,Young adult ,Lung ,Asthma ,HLA-G Antigens ,medicine.diagnostic_test ,business.industry ,Middle Aged ,medicine.disease ,respiratory tract diseases ,Black or African American ,MicroRNAs ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Maternal Exposure ,Female ,business ,Airway - Abstract
Background We previously reported an interaction between maternal asthma and the child's HLA-G genotype on the child's subsequent risk for asthma. The implicated single nucleotide polymorphism at +3142 disrupted a target site for the microRNA (miR)-152 family. We hypothesized that the interaction effect might be mediated by these miRs. Objective The objective of this study was to test this hypothesis in adults with asthma who are a subset of the same subjects who participated in our earlier family-based studies. Methods We measured soluble HLA-G (sHLA-G) concentrations in bronchoalveolar lavage fluid (n = 36) and plasma (n = 57) from adult asthmatic subjects with and without a mother with asthma, and HLA-G and miR-152 family ( miR-148a , miR-148b , and miR-152 ) transcript levels in airway epithelial cells from the same subjects. Results miR-148b levels were significantly increased in airway epithelial cells from asthmatic subjects with an asthmatic mother compared with those seen in asthmatic subjects without an asthmatic mother, and +3142 genotypes were associated with sHLA-G concentrations in bronchoalveolar lavage fluid among asthmatic subjects with an asthmatic mother but not among those with a nonasthmatic mother. Neither effect was observed in the plasma (sHLA-G) or white blood cells (miRNA). Conclusion These combined results are consistent with +3142 allele–specific targeting of HLA-G by the miR-152 family and support our hypothesis that miRNA regulation of sHLA-G in the airway is influenced by both the asthma status of the subject's mother and the subject's genotype. Moreover, we demonstrate that the effects of maternal asthma on the gene regulatory landscape in the airways of the mother's children persist into adulthood.
- Published
- 2012
37. Amish and Hutterite Environmental Farm Products Have Opposite Effects on Experimental Models of Asthma
- Author
-
Fernando D. Martinez, Nervana Metwali, Erika von Mutius, Justyna Gozdz, Carole Ober, Peter S. Thorne, Anne I. Sperling, Donata Vercelli, and Mark Holbreich
- Subjects
Pulmonary and Respiratory Medicine ,Abstracts ,03 medical and health sciences ,0302 clinical medicine ,030228 respiratory system ,business.industry ,Environmental health ,medicine ,medicine.disease ,business ,Bioinformatics ,030215 immunology ,Asthma - Published
- 2016
38. Circulating cytokines in sarcoidosis: phenotype-specific alterations for fibrotic and non-fibrotic pulmonary disease
- Author
-
Timothy B. Niewold, Joachim Müller-Quernheim, Karen C. Patterson, Nadera J. Sweiss, Beverly S. Franek, and Anne I. Sperling
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Sarcoidosis ,medicine.medical_treatment ,Pulmonary Fibrosis ,Immunology ,Pulmonary disease ,Biochemistry ,Article ,Pulmonary fibrosis ,medicine ,Immunology and Allergy ,Humans ,Lymphocyte Count ,Molecular Biology ,Interleukin 5 ,Aged ,Demography ,business.industry ,Case-control study ,Hematology ,Middle Aged ,medicine.disease ,Phenotype ,Cytokine ,Case-Control Studies ,Etiology ,Cytokines ,Female ,business - Abstract
Sarcoidosis is a granulomatous disease of unknown etiology marked by tremendous clinical heterogeneity. Many patients enter remission with good long-term outcomes. Yet, chronic disease is not uncommon, and this important phenotype remains understudied. Identified alterations in local and circulating cytokines--specifically targeted for study, and often in the acute phase of disease--have informed our growing understanding of the immunopathogenesis of sarcoidosis. Our aim was to evaluate a broad panel of circulating cytokines in patients with chronic sarcoidosis. Among those with chronic disease, pulmonary fibrosis occurs in only a subset. To gain more insight into the determinants of the fibrotic response, we also determined if the phenotypes of fibrotic and non-fibrotic pulmonary sarcoidosis have distinct cytokine profiles.In patients with sarcoidosis compared to controls, IL-5 was decreased, and IL-7 was increased. Both of these comparisons withstood rigorous statistical correction for multiple comparisons. GM-CSF met a nominal level of significance. We also detected an effect of phenotype, where IL-5 was significantly decreased in non-fibrotic compared to fibrotic pulmonary sarcoidosis, and compared to controls. Compared to controls, there was a trend towards a significant increase in IL-7 in fibrotic, but not in non-fibrotic pulmonary sarcoidosis. In contrast, compared to controls, there was a trend towards a significant increase in GM-CSF in non-fibrotic, but not in fibrotic pulmonary sarcoidosis.In a comprehensive evaluation of circulating cytokines in sarcoidosis, we found IL-5, IL-7, and GM-CSF to be altered. These findings provide a window into the immunopathogenesis of sarcoidosis. IL-7 is a novel sarcoidosis cytokine and, as a master regulator of lymphocytes, is an attractive target for further studies. By observing an effect of phenotype upon cytokine patterns, we also identify specific immune alterations which may contribute to clinical heterogeneity.
- Published
- 2012
39. The contribution of allergen-specific IgG to the development of th2-mediated airway inflammation
- Author
-
Jesse W. Williams, Anne I. Sperling, and Melissa Y. Tjota
- Subjects
0303 health sciences ,Allergy ,Innate immune system ,business.industry ,Review Article ,medicine.disease ,Subclass ,3. Good health ,Allergic inflammation ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Immune system ,Immunology ,medicine ,Immunology and Allergy ,Receptor ,business ,Antigen-presenting cell ,B cell ,030304 developmental biology ,030215 immunology - Abstract
In both human asthmatics and animal models of allergy, allergen-specific IgG can contribute to Th2-mediated allergic inflammation. Mouse models have elucidated an important role for IgG and Fc-gamma receptor (FcγR) signaling on antigen presenting cells (APC) for the induction of airway inflammation. These studies suggest a positive feedback loop between IgG produced by the adaptive B cell response and FcγR signaling on innate immune cells. Studies of IgG and FcγRs in humans with asthma or allergic lung disease have been more controversial. Some reports have identified associations between allergen-specific IgG and severity of allergic responses, while other studies have found associations of IgG subclass IgG4 with allergic tolerance. In this paper, we review the literature to help define the nature of IgG and FcγR signaling on innate immune cells and how it contributes to the development of allergic immune responses.
- Published
- 2012
40. Allergen-Specific IgG Augments Th2 Inflammation In The Lungs: Role Of IL-33 Production By Alveolar Macrophages And Respiratory Dendritic Cells
- Author
-
Donna C. Decker, Bryan S. Clay, Tiara Byrd, Tiffany Lu, Jesse W. Williams, Anne I. Sperling, and Melissa Y. Tjota
- Subjects
Interleukin 33 ,business.industry ,Th2 inflammation ,Immunology ,Medicine ,Respiratory system ,business ,Allergen specific IgG - Published
- 2012
41. BTLA, A T Cell Co-Inhibitory Receptor, Is A Potential Biomarker For Progressive Idiopathic Pulmonary Fibrosis
- Author
-
Imre Noth, Anne I. Sperling, Kelly M. Blaine, Rekha Vij, Shwu F. Ma, Stephenie M. Takahashi, and Yong Huang
- Subjects
business.industry ,T cell ,T-cell receptor ,BTLA ,respiratory system ,Acquired immune system ,medicine.disease ,Peripheral blood mononuclear cell ,respiratory tract diseases ,medicine.anatomical_structure ,Immunology ,Medicine ,Cytotoxic T cell ,business ,Receptor ,Progressive disease - Abstract
IPF has a heterogeneous course of disease in which some patients experience a slow or more stable course while others RATIONALE: experience rapid decline and early mortality. Currently we lack understanding of the mechanisms that underlie the pathogenesis responsible for the differences between stable IPF (S-IPF) and rapidly progressive IPF (RP-IPF). Previous studies examining whole genome expression arrays in PBMCs of IPF patients have demonstrated a signature that is predictive of progressive disease. The predominant pathways identified were altered gene expression in T cell activity and receptors. is to link these markers of The objective of our study progressive IPF to actual protein expression on peripheral lymphocytes, thereby determining potential mechanisms involved in disease progression. METHODS: We collected patient's peripheral blood mononuclear cells (PBMC) and classified patients as S-IPF or RP-IPF based on physiologic measures taken as part of their usual clinical care. We examined mRNA levels and cell surface protein expression by flow cytometry and correlated our findings with IPF severity, using the diffusing capacity of carbon monoxide (DLCO) as the physiological measurement. RESULTS: From our previous data sets, one of the T cell receptors with the highest alteration in gene expression patterns between S-IPF and RP-IPF was Band T-lymphocyte attenuator (BTLA), a surface co-inhibitory receptor on lymphocytes. A significant association was found between decreased BTLA mRNA levels and decreased predicted DLCO levels. Analysis of all samples demonstrated a significant and dramatically decreased BTLA surface expression on both peripheral CD4 and CD8 T cells, but not B cells, from RP-IPF patients compared to controls or S-IPF patients. CONCLUSION: Our data demonstrate that BTLA protein expression and mRNA levels are potential biomarkers and may have a predictive value for determining the patients most likely to rapidly progress. Decreased BTLA protein expression on peripheral blood T cells, may either be a cause of, or a result of, disease progression. Further, our data imply that the adaptive immune system, and T cells specifically, play a key role in the progression of IPF. Peripheral blood T cell biomarkers of rapid progression developed as a result of these efforts may be used in the development of personalized diagnostics. Furthermore, understanding these pathways may identify potential therapeutic targets and explain why the variability of disease course exists.
- Published
- 2012
42. [Untitled]
- Author
-
Philip A. Verhoef, Jared A. Greenberg, Paulette A. Krishack, Anne I. Sperling, and Cara L. Hrusch
- Subjects
business.industry ,Staphylococcus aureus ,Medicine ,Critical Care and Intensive Care Medicine ,business ,medicine.disease_cause ,Microbiology - Published
- 2015
43. T-cell costimulation blockade in immunologic diseases: role of CD28 family members
- Author
-
Anne I. Sperling and Bryan S. Clay
- Subjects
business.industry ,Effector ,T cell ,Immunology ,CD28 ,medicine.disease_cause ,Autoimmunity ,Blockade ,medicine.anatomical_structure ,Immune system ,Antigen ,CTLA-4 ,medicine ,Immunology and Allergy ,business - Abstract
The destruction of many immune-mediated diseases is a result of T-cell responses against usually harmless antigens. Extensive research has been conducted to discover new mechanisms to specifically modulate harmful effector T cells while leaving normal immune responses intact. Since proteins of the CD28 family members are expressed on T cells, blockade of these proteins has become a possible target for potential therapies. The CD28 family contains proteins that have the ability to both enhance and diminish T-cell responses. Therefore, blockade of targets that enhance T-cell signaling may reduce destructive autoimmune responses, while blockade of targets that diminish T-cell signaling may enhance antitumor responses. In this article, the function of these proteins will be reviewed and a sample of clinical trials highlighting the potential efficacy and drawbacks of their use in humans will be described briefly. Finally, inducible costimulator and programmed death-1, two future targets of T-cell therapies, will be highlighted.
- Published
- 2010
44. Allergen Exposure, Homeostatic Proliferation, And Fas Deficiency Lead To Defects In Resolution Of Th2-mediated Airway Inflammation
- Author
-
Anne I. Sperling, Caroline M. Ferreira, Alexander Chervonsky, Jiankun Tong, Rebecca A. Shilling, Kelly M. Blaine, and Jesse W. Williams
- Subjects
business.industry ,Immunology ,Airway inflammation ,Medicine ,ALLERGEN EXPOSURE ,business ,Homeostasis - Published
- 2010
45. Quantity of IL-13 Recovered from Bronchoalveolar Lavage Fluid of Obese and Non-Obese Asthmatics and Controls
- Author
-
Julian Solway, Anne I. Sperling, V Prachand, Rebecca A. Shilling, Steven R. White, J Alverdy, John F. McConville, Paul Kogut, and LG Ruiz
- Subjects
Bronchoalveolar lavage ,medicine.diagnostic_test ,Non obese ,business.industry ,Immunology ,Interleukin 13 ,medicine ,business - Published
- 2009
46. Gene Expression Profiling To Predict the Development of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients
- Author
-
Sangeeta Bhorade, Anita S. Chong, Anne I. Sperling, Edward R. Garrity, Maria-Luisa Alegre, W. Zhang, and Z. Xu
- Subjects
Pulmonary and Respiratory Medicine ,Transplantation ,Lung ,business.industry ,medicine.medical_treatment ,Bronchiolitis obliterans ,medicine.disease ,Peripheral blood mononuclear cell ,humanities ,Gene expression profiling ,Pathogenesis ,medicine.anatomical_structure ,Immunology ,Gene expression ,Medicine ,Lung transplantation ,Surgery ,Cardiology and Cardiovascular Medicine ,business - Abstract
Purpose Bronchiolitis Obliterans Syndrome (BOS) is the major limitation to long-term survival after lung transplantation. Its pathogenesis, however, is poorly understood and no effective predictive biomarkers have been identified. We hypothesized that peripheral blood mononuclear cell gene expression profiles could identify patients at risk of BOS. Methods and Materials Gene expression profiling was performed in PBMCs collected from 26 lung transplant recipients at 3 and 9 months after transplantation and prior to development of BOS. Differential gene expression was tested over time using a linear regression mixed effect model. Results A substantial proportion of genes (~1800, false discovery rate (FDR) Conclusions We postulate that differential patterns of gene expression associated with dysregulated biological pathways after lung transplantation predispose to, and may predict, BOS development.
- Published
- 2013
47. Antigen stimulation of TH2 cells augments acute bacterial sinusitis in mice
- Author
-
Kenneth Thompson, Robert M. Naclerio, Xiaohong Yu, Anne I. Sperling, and Christopher Blair
- Subjects
Adoptive cell transfer ,Allergy ,Ovalbumin ,Immunology ,medicine.disease_cause ,Mice ,Th2 Cells ,Antigen ,Streptococcus pneumoniae ,Immunology and Allergy ,Medicine ,Animals ,Sinusitis ,Mice, Inbred BALB C ,biology ,business.industry ,T lymphocyte ,Bacterial Infections ,respiratory system ,Th1 Cells ,medicine.disease ,Adoptive Transfer ,Allergic response ,Acute Disease ,biology.protein ,Nasal administration ,business - Abstract
Previously, we showed that an ongoing nasal allergic response augmented bacterial sinusitis in mice. In those experiments mice were sensitized to ovalbumin (OVA) by means of intraperitoneal injections of OVA-alum and then exposed to OVA intranasally before being infected with Streptococcus pneumoniae.We sought to study the importance of TH2 cells and to eliminate potential alum effects.In this study we sensitized mice by adoptively transferring OVA-specific TH2- or TH1-skewed cells.TH2 passive sensitization followed by intranasal OVA showed a robust local eosinophilic response (5-fold increase) compared with that seen in mice with only TH2 passive sensitization alone (P.001). Mice with TH2 passive sensitization and intranasal OVA exposure followed by infection showed an increase in the number of recovered S pneumoniae (P.05) and an increase in sinus inflammation compared with that seen in those with infection alone (P.01). In contrast, mice passively sensitized with TH1 followed by intranasal OVA exposure and infection showed no significant increase in the recovery of S pneumoniae and sinus inflammation compared with those with infection alone.These data support the importance of antigen-stimulated TH2 cells in the augmented response to infection in allergic mice. Whether the increased infection is related to the direct effect of TH2 cells and their cytokines or subsequent recruitment of other cells, such as eosinophils, will be determined in further studies.
- Published
- 2004
48. Post-Transplant Dynamics of Pulmonary Microbiota
- Author
-
Anne I. Sperling, Steve White, Anita S. Chong, Valeriy Poroyko, Sangeeta Bhorade, E. G. Semenyuk, Maria-Luisa Alegre, Edward R. Garrity, and Zhong-ping Xu
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,medicine ,Intensive care medicine ,business ,Post transplant - Published
- 2014
49. CTLA4Ig inhibits airway eosinophilia and hyperresponsiveness by regulating the development of Th1/Th2 subsets in a murine model of asthma
- Author
-
Joel V. Weinstock, Jeffrey A. Bluestone, Philip Padrid, Mudit Mathur, Karin Herrmann, Ashok Cattamanchi, Yimin Qin, Anne I. Sperling, David E. Elliott, and Xiantang Li
- Subjects
Immunoconjugates ,T-Lymphocytes ,Clinical Biochemistry ,Bronchoalveolar Lavage ,Bronchoconstrictor Agents ,Mice ,Eosinophilia ,CTLA-4 Antigen ,Lung ,Sensitization ,Methacholine Chloride ,medicine.diagnostic_test ,Interleukin ,CD28 ,Schistosoma mansoni ,respiratory system ,medicine.anatomical_structure ,Cytokines ,Female ,medicine.symptom ,Bronchial Hyperreactivity ,Bronchoalveolar Lavage Fluid ,Immunosuppressive Agents ,medicine.drug ,Pulmonary and Respiratory Medicine ,Recombinant Fusion Proteins ,Antibodies, Helminth ,Abatacept ,Th2 Cells ,Antigen ,In vivo ,Antigens, CD ,medicine ,Animals ,Humans ,Molecular Biology ,Dose-Response Relationship, Drug ,business.industry ,Airway Resistance ,Cell Biology ,Immunoglobulin E ,Th1 Cells ,Antigens, Differentiation ,Asthma ,respiratory tract diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,Bronchoalveolar lavage ,Antigens, Helminth ,Culture Media, Conditioned ,Immunology ,Methacholine ,business - Abstract
Complete T-cell activation requires two distinct signals, one delivered via the T-cell receptor, and the second "co-stimulatory" signal through CD28/B7 ligation. Previous studies showed that the blockade of CD28/B7 ligation alters differentiation of Th1/Th2 lymphocyte subsets in vitro and in vivo. The present study was designed to determine the effect of a CD28/B7 antagonist (CTLA4Ig) on Th1/Th2 development in Schistosoma mansoni-sensitized and airway-challenged mice. Treatment of mice with CTLA4Ig beginning 1 wk after sensitization abolished airway responsiveness to intravenous methacholine determined 96 h following antigen challenge. We also found a significant reduction in bronchoalveolar lavage (BAL) eosinophilia, and reduced peribronchial eosinophilic infiltration and mucoid-cell hyperplasia. Furthermore, CTLA4Ig treatment significantly decreased interleukin (IL)-4 and IL-5 content in BAL fluid in vivo, and the production of IL-5 by lung lymphocytes stimulated with soluble egg antigen (SEA) in vitro. In contrast, the content of interferon-gamma in BAL fluid and supernatant from SEA-stimulated lung lymphocytes from CTLA4Ig-treated mice was increased significantly compared with untreated animals. Thus, CTLA4Ig inhibits eosinophilic airway inflammation and airway hyperresponsiveness in S. mansoni-sensitized and airway-challenged mice, most likely due to attenuated secretion of Th2-type cytokines and increased secretion of Th1-type cytokines.
- Published
- 1998
50. The complexities of T-cell co-stimulation: CD28 and beyond
- Author
-
Anne I. Sperling and Jeffrey A. Bluestone
- Subjects
Graft Rejection ,Pediatrics ,medicine.medical_specialty ,Immunoconjugates ,T cell ,T-Lymphocytes ,Immunology ,Plasma protein binding ,Ligands ,Lymphocyte Activation ,Autoimmune Diseases ,Abatacept ,Mice ,Text mining ,Co-stimulation ,CD28 Antigens ,Antigens, CD ,medicine ,Immunology and Allergy ,Animals ,CTLA-4 Antigen ,Membrane Glycoproteins ,biology ,business.industry ,Models, Immunological ,CD28 ,Antigens, Differentiation ,Cell biology ,Membrane glycoproteins ,medicine.anatomical_structure ,biology.protein ,Lymphocyte activation ,B7-1 Antigen ,B7-2 Antigen ,business ,Immunosuppressive Agents ,Protein Binding - Published
- 1996
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.