188 results on '"Anne I. Sperling"'
Search Results
2. Lung cDC1 and cDC2 dendritic cells priming naive CD8+ T cells in situ prior to migration to draining lymph nodes
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Youhui Si, Yihan Wang, Qiaomu Tian, Qiang Wang, Jared M. Pollard, Pramod K. Srivastava, Aaron P. Esser-Kahn, Joel H. Collier, Anne I. Sperling, and Anita S. Chong
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CP: Immunology ,Biology (General) ,QH301-705.5 - Abstract
Summary: The current paradigm indicates that naive T cells are primed in secondary lymphoid organs. Here, we present evidence that intranasal administration of peptide antigens appended to nanofibers primes naive CD8+ T cells in the lung independently and prior to priming in the draining mediastinal lymph node (MLN). Notably, comparable accumulation and transcriptomic responses of CD8+ T cells in lung and MLN are observed in both Batf3KO and wild-type (WT) mice, indicating that, while cDC1 dendritic cells (DCs) are the major subset for cross-presentation, cDC2 DCs alone are capable of cross-priming CD8+ T cells both in the lung and draining MLN. Transcription analyses reveal distinct transcriptional responses in lung cDC1 and cDC2 to intranasal nanofiber immunization. However, both DC subsets acquire shared transcriptional responses upon migration into the lymph node, thus uncovering a stepwise activation process of cDC1 and cDC2 toward their ability to cross-prime effector and functional memory CD8+ T cell responses.
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- 2023
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3. Gut microbiota modulates bleomycin-induced acute lung injury response in mice
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Young me Yoon, Cara L. Hrusch, Na Fei, Gabriel M. Barrón, Kathleen A. M. Mills, Maile K. Hollinger, Tania E. Velez, Vanessa A. Leone, Eugene B. Chang, and Anne I. Sperling
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Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Airway instillation of bleomycin (BLM) in mice is a widely used, yet challenging, model for acute lung injury (ALI) with high variability in treatment scheme and animal outcomes among investigators. Whether the gut microbiota plays any role in the outcome of BLM-induced lung injury is currently unknown. Methods Intratracheal instillation of BLM into C57BL/6 mice was performed. Fecal microbiomes were analyzed by 16s rRNA amplicon and metagenomic sequencing. Germ-free mice conventionalization and fecal microbiota transfer between SPF mice were performed to determine dominant commensal species that are associated with more severe BLM response. Further, lungs and gut draining lymph nodes of the mice were analyzed by flow cytometry to define immunophenotypes associated with the BLM-sensitive microbiome. Results Mice from two SPF barrier facilities at the University of Chicago exhibited significantly different mortality and weight loss during BLM-induced lung injury. Conventionalizing germ-free mice with SPF microbiota from two different housing facilities recapitulated the respective donors’ response to BLM. Fecal microbiota transfer from the facility where the mice had worse mortality into the mice in the facility with more survival rendered recipient mice more susceptible to BLM-induced weight loss in a dominant negative manner. BLM-sensitive phenotype was associated with the presence of Helicobacter and Desulfovibrio in the gut, decreased Th17-neutrophil axis during steady state, and augmented lung neutrophil accumulation during the acute phase of the injury response. Conclusion The composition of gut microbiota has significant impact on BLM-induced wasting and death suggesting a role of the lung-gut axis in lung injury.
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- 2022
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4. Discerning asthma endotypes through comorbidity mapping
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Gengjie Jia, Xue Zhong, Hae Kyung Im, Nathan Schoettler, Milton Pividori, D. Kyle Hogarth, Anne I. Sperling, Steven R. White, Edward T. Naureckas, Christopher S. Lyttle, Chikashi Terao, Yoichiro Kamatani, Masato Akiyama, Koichi Matsuda, Michiaki Kubo, Nancy J. Cox, Carole Ober, Andrey Rzhetsky, and Julian Solway
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Science - Abstract
Asthma is a heterogeneous, complex syndrome that arises in individuals with various genetic and exposure variations. Here, the authors show that disease comorbidity patterns can serve as a surrogate for these variations, and identify asthma endotypes distinguished by comorbidity patterns, asthma risk loci, gene expression, and health-related phenotypes.
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- 2022
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5. IRF4 expression by lung dendritic cells drives acute but not Trm cell–dependent memory Th2 responses
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Daniel F. Camacho, Tania E. Velez, Maile K. Hollinger, Esther Wang, Chanie L. Howard, Eli P. Darnell, Domenick E. Kennedy, Paulette A. Krishack, Cara L. Hrusch, Marcus R. Clark, James J. Moon, and Anne I. Sperling
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Immunology ,Medicine - Abstract
Expression of the transcription factor interferon regulatory factor 4 (IRF4) is required for the development of lung conventional DCs type 2 (cDC2s) that elicit Th2 responses, yet how IRF4 functions in lung cDC2s throughout the acute and memory allergic response is not clear. Here, we used a mouse model that loses IRF4 expression after lung cDC2 development to demonstrate that mice with IRF4-deficient DCs display impaired memory responses to allergen. This defect in the memory response was a direct result of ineffective Th2 induction and impaired recruitment of activated effector T cells to the lung after sensitization. IRF4-deficient DCs demonstrated defects in their migration to the draining lymph node and in T cell priming. Finally, T cells primed by IRF4-competent DCs mediated potent memory responses independently of IRF4-expressing DCs, demonstrating that IRF4-expressing DCs are not necessary during the memory response. Thus, IRF4 controlled a program in mature DCs governing Th2 priming and effector responses, but IRF4-expressing DCs were dispensable during tissue-resident memory T cell–dependent memory responses.
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- 2022
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6. Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region
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Ivy Aneas, Donna C. Decker, Chanie L. Howard, Débora R. Sobreira, Noboru J. Sakabe, Kelly M. Blaine, Michelle M. Stein, Cara L. Hrusch, Lindsey E. Montefiori, Juan Tena, Kevin M. Magnaye, Selene M. Clay, James E. Gern, Daniel J. Jackson, Matthew C. Altman, Edward T. Naureckas, Douglas K. Hogarth, Steven R. White, Jose Luis Gomez-Skarmeta, Nathan Schoetler, Carole Ober, Anne I. Sperling, and Marcelo A. Nóbrega
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Science - Abstract
Susceptibility to asthma and severity of symptoms are regulated by a number of different genomic regions. Here the authors characterise a 5kb regulatory region and demonstrate genetic and topological regulation of IL33 and association with disease in different human cohorts.
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- 2021
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7. Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization
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Tzu-Han Lee, Chih-Fan Yeh, Ying-Tung Lee, Ying-Chun Shih, Yen-Ting Chen, Chen-Ting Hung, Ming-Yi You, Pei-Chen Wu, Tzu-Pin Shentu, Ru-Ting Huang, Yu-Shan Lin, Yueh-Feng Wu, Sung-Jan Lin, Frank-Leigh Lu, Po-Nien Tsao, Tzu-Hung Lin, Shen-Chuan Lo, Yi-Shuan Tseng, Wan-Lin Wu, Chiung-Nien Chen, Chau-Chung Wu, Shuei-Liong Lin, Anne I. Sperling, Robert D. Guzy, Yun Fang, and Kai-Chien Yang
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Science - Abstract
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.
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- 2020
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8. Distinct T-helper cell responses to Staphylococcus aureus bacteremia reflect immunologic comorbidities and correlate with mortality
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Jared A. Greenberg, Cara L. Hrusch, Mohammad R. Jaffery, Michael Z. David, Robert S. Daum, Jesse B. Hall, John P. Kress, Anne I. Sperling, and Philip A. Verhoef
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Sepsis ,Staphylococcus aureus ,Helper T cells ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
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
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- 2018
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9. Non-apoptotic Fas (CD95) Signaling on T Cells Regulates the Resolution of Th2-Mediated Inflammation
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Jesse W. Williams, Caroline M. Ferreira, Kelly M. Blaine, Crystal Rayon, Francisco Velázquez, Jiankun Tong, Marcus E. Peter, and Anne I. Sperling
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allergy ,Asthma ,Eosinophilia ,Apoptosis ,Fas-FasL ,Th2 cells ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Fas (CD95/APO-1) and its ligand (FasL/CD95L) promote the resolution of type 2 lung inflammation and eosinophilia. We previously found that Fas-deficiency on T cells, but not eosinophils, delayed resolution of inflammation. However, Fas can signal both cell death and have a positive signaling function that can actually activate cells. In this study, we investigated whether Fas-induced death or Fas-activated signaling pathways promote resolution of allergic lung inflammation. By increasing T cell survival through two Fas-independent pathways, using Bim-deficient T cells or Bcl-xL overexpressing T cells, no differences in resolution of Th2-mediated inflammation was observed. Furthermore, Th2 cells were inherently resistant to Fas-mediated apoptosis and preferentially signaled through non-apoptotic pathways following FasL treatment. Utilizing Fas-mutant mice deficient in apoptotic but sufficient for non-apoptotic Fas signaling pathways, we demonstrate that non-apoptotic Fas signaling in T cells drives resolution of Th2-mediated airway inflammation. Our findings reveal a previously unknown role for non-apoptotic Fas signaling on Th2 cells in the induction of resolution of type 2 inflammation.
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- 2018
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10. Allergen Exposure in Lymphopenic Fas-Deficient Mice Results in Persistent Eosinophilia Due to Defects in Resolution of Inflammation
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Caroline M. Ferreira, Jesse W. Williams, Jiankun Tong, Crystal Rayon, Kelly M. Blaine, and Anne I. Sperling
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Th1/Th2 cells ,eosinophils ,apoptosis ,lung ,inflammation ,asthma ,Immunologic diseases. Allergy ,RC581-607 - 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.
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- 2018
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11. Antigenic responses are hallmarks of fibrotic interstitial lung diseases independent of underlying etiologies
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Young me Yoon, Tania E. Velez, Vaibhav Upadhyay, Sara E. Vazquez, Cathryn T. Lee, Kavitha C. Selvan, Christopher S. Law, Kelly M. Blaine, Maile K. Hollinger, Donna C. Decker, Marcus R. Clark, Mary E. Strek, Robert D. Guzy, Ayodeji Adegunsoye, Imre Noth, Paul J. Wolters, Mark Anderson, Joseph L. DeRisi, Anthony K. Shum, and Anne I. Sperling
- Abstract
SummaryInterstitial lung diseases (ILD) are heterogeneous conditions that may lead to progressive fibrosis and death of affected individuals. Despite diversity in clinical manifestations, enlargement of lung-associated lymph nodes (LLN) in fibrotic ILD patients predicts worse survival. Herein, we revealed a common adaptive immune landscape in LLNs of all ILD patients, characterized by highly activated germinal centers and antigen-activated T cells including regulatory T cells (Tregs). In support of these findings, we identified serum reactivity to 17 candidate auto-antigens in ILD patients through a proteome-wide screening using phage immunoprecipitation sequencing. Autoantibody responses to actin binding LIM protein 1 (ABLIM1), a protein highly expressed in aberrant basaloid cells of fibrotic lungs, were correlated with LLN frequencies of T follicular helper cells and Tregs in ILD patients. Together, we demonstrate that end-stage ILD patients have converging immune mechanisms, in part driven by antigen-specific immune responses, which may contribute to disease progression.
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- 2023
12. Advancing Lung Immunology Research An Official American Thoracic Society Workshop Report
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Rod A. Rahimi, Josalyn L. Cho, Claudia V. Jakubzick, Shabaana A. Khader, Bart N. Lambrecht, Clare M. Lloyd, Ari B. Molofsky, Sebastien Talbot, Catherine A. Bonham, Wonder P. Drake, Anne I. Sperling, Benjamin D. Singer, and Pulmonary Medicine
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Lung Diseases ,Pulmonary and Respiratory Medicine ,Respiratory System ,Clinical Biochemistry ,Cardiorespiratory Medicine and Haematology ,Vaccine Related ,SDG 3 - Good Health and Well-being ,Animals ,Humans ,2.1 Biological and endogenous factors ,Aetiology ,Lung ,Respiratory Tract Infections ,Molecular Biology ,Mammals ,Prevention ,Inflammatory and immune system ,Cell Biology ,Thorax ,Infectious Diseases ,allergy and immunology ,Respiratory ,mucosal immunity ,Particulate Matter ,Immunization - Abstract
The mammalian airways and lungs are exposed to a myriad of inhaled particulate matter, allergens, and pathogens. The immune system plays an essential role in protecting the host from respiratory pathogens, but a dysregulated immune response during respiratory infection can impair pathogen clearance and lead to immunopathology. Furthermore, inappropriate immunity to inhaled antigens can lead to pulmonary diseases. A complex network of epithelial, neural, stromal, and immune cells has evolved to sense and respond to inhaled antigens, including the decision to promote tolerance versus a rapid, robust, and targeted immune response. Although there has been great progress in understanding the mechanisms governing immunity to respiratory pathogens and aeroantigens, we are only beginning to develop an integrated understanding of the cellular networks governing tissue immunity within the lungs and how it changes after inflammation and over the human life course. An integrated model of airway and lung immunity will be necessary to improve mucosal vaccine design as well as prevent and treat acute and chronic inflammatory pulmonary diseases. Given the importance of immunology in pulmonary research, the American Thoracic Society convened a working group to highlight central areas of investigation to advance the science of lung immunology and improve human health.
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- 2022
13. PhIP-Seq uncovers novel autoantibodies and unique endotypes in interstitial lung disease
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Vaibhav Upadhyay, Young me Yoon, Sara E. Vazquez, Tania E. Velez, Kirk D. Jones, Cathryn T. Lee, Christopher S. Law, Paul J. Wolters, Seoyeon Lee, Monica M. Yang, Erica Farrand, Imre Noth, Mary E. Strek, Mark Anderson, Joseph DeRisi, Anne I. Sperling, and Anthony K. Shum
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Article - Abstract
Interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases (CTD). Establishing autoimmunity in ILD impacts prognosis and treatment. ILD patients are screened for autoimmunity by assaying for anti-nuclear autoantibodies, rheumatoid factors and other non-specific tests. However, this approach has not been rigorously validated and may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD. Here, we use Phage Immunoprecipitation-Sequencing (PhIP-Seq) to conduct a large, multi-center unbiased autoantibody discovery screen of ILD patients and controls. PhIP-Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among these 17 candidates, we validated Cadherin Related Family Member 5 (CDHR5) as an autoantigen and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, subjects not previously diagnosed with autoimmunity. Lung tissue of CDHR5 autoreactive patients showed transcriptional profiles consistent with activation of NFκB signaling and upregulation of chitotriosidase (CHIT1), a molecular pathway linked to fibrosis. Our study shows PhIP-Seq uncovers novel autoantibodies in ILD patients not revealed by standard clinical tests. Furthermore, CDHR5 autoantibodies may define a novel molecular endotype of ILD characterized by inflammation and fibrosis.
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- 2023
14. Androgen Signaling Restricts Glutaminolysis to Drive Sex-Specific Th17 Metabolism
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Nowrin U Chowdhury, Jacqueline-Yvonne Cephus, Matthew Z Madden, Melissa M Wolf, Channing Chi, Ayaka Sugiura, Matthew T Stier, Kelsey Voss, Xiang Ye, Shelby N Kuehnle, Kennedi Scales, Vivek D Gandhi, Robert D. Guzy, Katherine N Cahill, Anne I Sperling, R. Stokes Peebles, Jeffrey C Rathmell, and Dawn C Newcomb
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SummaryFemales have increased prevalence of many Th17-mediated diseases. While androgen signaling decreases Th17-mediated inflammation, the mechanisms are not fully understood. Th17 cells rely on glutaminolysis; however, it remains unclear whether androgen receptor (AR) signaling in males modifies glutamine metabolism to suppress Th17-mediated inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis.Using allergen-induced airway inflammation models, we determined females, but not males, had a critical reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake by reducing expression of glutamine transporters. These findings were confirmed in circulating human Th17 cells with minimal reliance on glutamine uptake in male compared to female Th17 cells. We found that AR signaling attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for design and implementation of Th17 or glutaminolysis targeted therapeutics.HighlightsHuman male CD4+ T cells have decreased expression of metabolic enzymes and decreased reliance on glutaminolysis compared to female CD4+ T cells.Androgen signaling decreased mitochondrial metabolism in Th17 cells and decreased airway inflammation.Androgen signaling decreased glutamine uptake and utilization in Th17 cells.
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- 2023
15. SARS-CoV-2 Infection Is Associated with Reduced Krüppel-like Factor 2 in Human Lung Autopsy
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Gökhan M. Mutlu, Ayodeji Adegunsoye, Yun Fang, Tzu-Han Lee, Robert D. Guzy, Aliya N. Husain, Nathan Schoettler, Anne I. Sperling, Ru-Ting Huang, David Wu, and Jeffrey Mueller
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Pulmonary and Respiratory Medicine ,2019-20 coronavirus outbreak ,Lung ,Kruppel-Like Transcription Factors ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Clinical Biochemistry ,Autopsy ,Cell Biology ,Virology ,Human lung ,medicine.anatomical_structure ,Krüppel ,medicine ,business ,Molecular Biology - Published
- 2021
16. Severe COVID-19 induces autoantibodies against angiotensin II that correlate with blood pressure dysregulation and disease severity
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Priscilla S. Briquez, Sherin J. Rouhani, Jovian Yu, Athalia R. Pyzer, Jonathan Trujillo, Haley L. Dugan, Christopher T. Stamper, Siriruk Changrob, Anne I. Sperling, Patrick C. Wilson, Thomas F. Gajewski, Jeffrey A. Hubbell, and Melody A. Swartz
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Multidisciplinary - Abstract
Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can experience life-threatening respiratory distress, blood pressure dysregulation, and thrombosis. This is thought to be associated with an impaired activity of angiotensin-converting enzyme 2 (ACE2), which is the main entry receptor of SARS-CoV-2 and which also tightly regulates blood pressure by converting the vasoconstrictive peptide angiotensin II (AngII) to a vasopressor peptide. Here, we show that a significant proportion of hospitalized patients with COVID-19 developed autoantibodies against AngII, whose presence correlates with lower blood oxygenation, blood pressure dysregulation, and overall higher disease severity. Anti-AngII antibodies can develop upon specific immune reaction to the SARS-CoV-2 proteins Spike or receptor-binding domain (RBD), to which they can cross-bind, suggesting some epitope mimicry between AngII and Spike/RBD. These results provide important insights on how an immune reaction against SARS-CoV-2 can impair blood pressure regulation.
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- 2022
17. Lymphatic coagulation and neutrophil extracellular traps in lung-draining lymph nodes of COVID-19 decedents
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Margo E. MacDonald, Rachel K. Weathered, Emma C. Stewart, Alexandra I. Magold, Anish Mukherjee, Sandeep Gurbuxani, Heather Smith, Phillip McMullen, Jeffrey Mueller, Aliya N. Husain, Calixto M. Salles, Priscilla S. Briquez, Sherin J. Rouhani, Jovian Yu, Jonathan Trujillo, Athalia R. Pyzer, Thomas F. Gajewski, Anne I. Sperling, Witold W. Kilarski, and Melody A. Swartz
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Hematology - Abstract
Clinical manifestations of severe COVID-19 include coagulopathies that are exacerbated by the formation of neutrophil extracellular traps (NETs). Here, we report that pulmonary lymphatic vessels, which traffic neutrophils and other immune cells to the lung-draining lymph node (LDLN), can also be blocked by fibrin clots in severe COVID-19. Immunostained tissue sections from COVID-19 decedents revealed widespread lymphatic clotting not only in the lung but also in the LDLN, where the extent of clotting correlated with the presence of abnormal, regressed, or missing germinal centers (GCs). It strongly correlated with the presence of intralymphatic NETs. In mice, tumor necrosis factor α induced intralymphatic fibrin clots; this could be inhibited by DNase I, which degrades NETs. In vitro, TNF-α induced lymphatic endothelial cell upregulation of ICAM-1 and CXCL8, among other neutrophil-recruiting factors, as well as thrombomodulin downregulation; in decedents, lymphatic clotting in LDLNs. In a separate cohort of hospitalized patients, serum levels of Myeloperoxidase-DNA (MPO-DNA, a NET marker) inversely correlated with antiviral antibody titers, but D-dimer levels, indicative of blood thrombosis, did not correlate with either. Patients with high MPO-DNA but low D-dimer levels generated poor antiviral antibody titers. This study introduces lymphatic coagulation in lungs and LDLNs as a clinical manifestation of severe COVID-19 and suggests the involvement of NETosis of lymphatic-trafficking neutrophils. It further suggests that lymphatic clotting may correlate with impaired formation or maintenance of GCs necessary for robust antiviral antibody responses, although further studies are needed to determine whether and how lymphatic coagulation affects adaptive immune responses.
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- 2022
18. Hypersensitivity pneumonitis: Current concepts in pathogenesis, diagnosis, and treatment
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Ian Glaspole, Mary E. Strek, Anne I. Sperling, Lauren K. Troy, Cathryn Lee, and Hayley Barnes
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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.
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- 2021
19. A series of <scp>COVID</scp> ‐19 autopsies with clinical and pathologic comparisons to both seasonal and pandemic influenza
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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
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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
20. Skewed Lung CCR4 to CCR6 CD4+ T Cell Ratio in Idiopathic Pulmonary Fibrosis is Associated with Pulmonary Function
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Ayodeji Adegunsoye, Cara Hrusch, Catherine Bonham, Mohammad R Jaffrey, Kelly M Blaine, Meghan Sullivan, Matthew M Churpek, Mary E Strek, Imre Noth, and Anne I Sperling
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Idiopathic Pulmonary Fibrosis ,T cells ,CD4 ,Chemokine receptors ,Lung function ,forced vital capacity ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease. While it has been suggested that T cells may contribute to IPF pathogenesis, these studies have focused primarily on T cells outside of the pulmonary interstitium. Thus, the role of T cells in the diseased lung tissue remains unclear. Objective: To identify whether specific CD4 T cell subsets are differentially represented in lung tissue from patients with IPF. Methods: CD4 T cells subsets were measured in lung tissue obtained from patients with IPF at the time of lung transplantation, and from age- and gender-matched organ donors with no known lung disease. Subsets were identified by their surface expression of CCR4, CCR6, and CXCR3 chemokine receptors. CD4 T cell subsets were correlated with measurements of lung function obtained prior to transplantation.Results: Compared to controls, IPF patients had a higher proportion of lung CD4 T cells, a higher proportion of CCR4 CD4 T cells, and a lower proportion of CCR6 CD4 T cells. The increase in CCR4 CD4 T cells in IPF lung tissue was not due to increased Tregs. Intriguingly, the increase in the ratio of CCR4 cells to CCR6 cells correlated significantly with better lung function. Conclusions: Our findings suggest a new paradigm that not all T cell infiltrates in IPF lungs are detrimental, but instead, specialized subsets may actually be protective. Thus, augmentation of the chemokines that recruit protective T cells, while blocking chemokines that recruit detrimental T cells, may constitute a novel approach to IPF therapy.
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- 2016
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21. Central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosis
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Yong Huang, Rob Guzy, Shwu-Fan Ma, Catherine A Bonham, Jonathan Jou, Jefree J Schulte, John S Kim, Andrew J Barros, Milena S Espindola, Aliya N Husain, Cory M Hogaboam, Anne I Sperling, and Imre Noth
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Pulmonary and Respiratory Medicine - Abstract
RationaleContribution of central lung tissues to pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unknown.ObjectiveTo ascertain the relationship between cell types of IPF-central and IPF-peripheral lung explants using RNA sequencing (RNA-seq) transcriptome.MethodsBiopsies of paired IPF-central and IPF-peripheral along with non-IPF lungs were selected by reviewing H&E data. Criteria for differentially expressed genes (DEG) were set at false discovery rate 2. Computational cell composition deconvolution was performed. Signature scores were computed for each cell type.FindingsComparison of central IPF versus non-IPF identified 1723 DEG (1522 upregulated and 201 downregulated). Sixty-two per cent (938/1522) of the mutually upregulated genes in central IPF genes were also upregulated in peripheral IPF versus non-IPF. Moreover, 85 IPF central-associated genes (CAG) were upregulated in central IPF versus both peripheral IPF and central non-IPF. IPF single-cell RNA-seq analysis revealed the highest CAG signature score in myofibroblasts and significantly correlated with a previously published activated fibroblasts signature (r=0.88, p=1.6×10−4). CAG signature scores were significantly higher in IPF than in non-IPF myofibroblasts (p=0.013). Network analysis of central-IPF genes identified a module significantly correlated with the deconvoluted proportion of myofibroblasts in central IPF and anti-correlated with inflammation foci trait in peripheral IPF. The module genes were over-represented in idiopathic pulmonary fibrosis signalling pathways.InterpretationGene expression in central IPF lung regions demonstrates active myofibroblast features that contributes to disease progression. Further elucidation of pathological transcriptomic state of cells in the central regions of the IPF lung that are relatively spared from morphological rearrangements may provide insights into molecular changes in the IPF progression.
- Published
- 2023
22. Temperature Trajectory Subphenotypes Correlate With Immune Responses in Patients With Sepsis
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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
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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
23. Circulating Plasma Biomarkers of Progressive Interstitial Lung Disease
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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
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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
24. Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region
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Steven R. White, Juan J. Tena, James E. Gern, Débora R. Sobreira, Chanie L. Howard, Kevin M. Magnaye, Carole Ober, Kelly M. Blaine, José Luis Gómez-Skarmeta, Noboru J. Sakabe, Cara L. Hrusch, Anne I. Sperling, Michelle M. Stein, Marcelo A. Nobrega, Edward T. Naureckas, Donna C. Decker, Ivy Aneas, Nathan Schoetler, Lindsey E. Montefiori, Daniel J. Jackson, Douglas K. Hogarth, Matthew C. Altman, Selene M. Clay, and National Institutes of Health (US)
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Male ,Science ,General Physics and Astronomy ,Mice, Transgenic ,Locus (genetics) ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Genome-wide association studies ,Polymorphism, Single Nucleotide ,Article ,General Biochemistry, Genetics and Molecular Biology ,Chromosome conformation capture ,Gene expression ,Animals ,Humans ,Genetic Predisposition to Disease ,Allele ,Promoter Regions, Genetic ,Enhancer ,Alleles ,Zebrafish ,Genetic association ,Genetics ,Multidisciplinary ,Interleukins ,General Chemistry ,Interleukin-33 ,Asthma ,Chromatin ,Gene regulation ,Enhancer Elements, Genetic ,Female ,Octamer Transcription Factor-1 - Abstract
Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as an enhancer-blocking element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that the asthma-associated single nucleotide polymorphism (SNP) rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a mechanism through which a regulatory SNP contributes to genetic risk of asthma., This work was supported by NIH grants R01 HL118758, R01 HL128075, R01 HL119577, R01 HL085197, U19 AI095230, UG3 OD023282 and UM1 AI114271.
- Published
- 2021
25. Discerning asthma endotypes through comorbidity mapping
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Gengjie Jia, Xue Zhong, Hae Kyung Im, Nathan Schoettler, Milton Pividori, D. Kyle Hogarth, Anne I. Sperling, Steven R. White, Edward T. Naureckas, Christopher S. Lyttle, Chikashi Terao, Yoichiro Kamatani, Masato Akiyama, Koichi Matsuda, Michiaki Kubo, Nancy J. Cox, Carole Ober, Andrey Rzhetsky, and Julian Solway
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Multidisciplinary ,Phenotype ,Japan ,General Physics and Astronomy ,Humans ,General Chemistry ,Comorbidity ,General Biochemistry, Genetics and Molecular Biology ,Asthma ,Genome-Wide Association Study - Abstract
Asthma is a heterogeneous, complex syndrome, and identifying asthma endotypes has been challenging. We hypothesize that distinct endotypes of asthma arise in disparate genetic variation and life-time environmental exposure backgrounds, and that disease comorbidity patterns serve as a surrogate for such genetic and exposure variations. Here, we computationally discover 22 distinct comorbid disease patterns among individuals with asthma (asthma comorbidity subgroups) using diagnosis records for >151 M US residents, and re-identify 11 of the 22 subgroups in the much smaller UK Biobank. GWASs to discern asthma risk loci for individuals within each subgroup and in all subgroups combined reveal 109 independent risk loci, of which 52 are replicated in multi-ancestry meta-analysis across different ethnicity subsamples in UK Biobank, US BioVU, and BioBank Japan. Fourteen loci confer asthma risk in multiple subgroups and in all subgroups combined. Importantly, another six loci confer asthma risk in only one subgroup. The strength of association between asthma and each of 44 health-related phenotypes also varies dramatically across subgroups. This work reveals subpopulations of asthma patients distinguished by comorbidity patterns, asthma risk loci, gene expression, and health-related phenotypes, and so reveals different asthma endotypes.
- Published
- 2021
26. A
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Darshan N, Kasal, Zhitao, Liang, Maile K, Hollinger, Crystal Y, O'Leary, Wioletta, Lisicka, Anne I, Sperling, and Albert, Bendelac
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Inflammation ,Male ,Cell Differentiation ,Mice, Transgenic ,GATA3 Transcription Factor ,Biological Sciences ,Immunity, Innate ,Mice, Inbred C57BL ,Enhancer Elements, Genetic ,Th2 Cells ,Strongyloidiasis ,Animals ,Homeostasis ,Female ,Lymphocytes - Abstract
The type 2 helper effector program is driven by the master transcription factor GATA3 and can be expressed by subsets of both innate lymphoid cells (ILCs) and adaptive CD4(+) T helper (Th) cells. While ILC2s and Th2 cells acquire their type 2 differentiation program under very different contexts, the distinct regulatory mechanisms governing this common program are only partially understood. Here we show that the differentiation of ILC2s, and their concomitant high level of GATA3 expression, are controlled by a Gata3 enhancer, Gata3 +674/762, that plays only a minimal role in Th2 cell differentiation. Mice lacking this enhancer exhibited defects in several but not all type 2 inflammatory responses, depending on the respective degree of ILC2 and Th2 cell involvement. Our study provides molecular insights into the different gene regulatory pathways leading to the acquisition of the GATA3-driven type 2 helper effector program in innate and adaptive lymphocytes.
- Published
- 2021
27. A Gata3 enhancer necessary for ILC2 development and function
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Maile K. Hollinger, Anne I. Sperling, Darshan N. Kasal, Albert Bendelac, Zhitao Liang, Crystal Y O'Leary, and Wioletta Lisicka
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Multidisciplinary ,medicine.anatomical_structure ,Effector ,Cellular differentiation ,Cell ,Innate lymphoid cell ,medicine ,GATA3 ,Biology ,Enhancer ,Gene ,Transcription factor ,Cell biology - Abstract
The type 2 helper effector program is driven by the master transcription factor GATA3 and can be expressed by subsets of both innate lymphoid cells (ILCs) and adaptive CD4+ T helper (Th) cells. While ILC2s and Th2 cells acquire their type 2 differentiation program under very different contexts, the distinct regulatory mechanisms governing this common program are only partially understood. Here we show that the differentiation of ILC2s, and their concomitant high level of GATA3 expression, are controlled by a Gata3 enhancer, Gata3 +674/762, that plays only a minimal role in Th2 cell differentiation. Mice lacking this enhancer exhibited defects in several but not all type 2 inflammatory responses, depending on the respective degree of ILC2 and Th2 cell involvement. Our study provides molecular insights into the different gene regulatory pathways leading to the acquisition of the GATA3-driven type 2 helper effector program in innate and adaptive lymphocytes.
- Published
- 2021
28. Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis
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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
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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
29. Prognosticating Outcomes in Interstitial Lung Disease by Mediastinal Lymph Node Assessment. An Observational Cohort Study with Independent Validation
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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
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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
30. Improving the Quality and Reproducibility of Flow Cytometry in the Lung. An Official American Thoracic Society Workshop Report
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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
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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
31. VEGFR3-driven pulmonary lymphangiogenesis exacerbates induction of bronchus-associated lymphoid tissue in allergic airway disease
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Jorge E Gomez Medellin, Maile Kananiokala Hollinger, Jillian Rosenberg, Kelly Blaine, Trevin Kurtanich, Nick Ankenbruck, Cara Lynn Hrusch, Anne I Sperling, and Melody A Swartz
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Immunology ,Immunology and Allergy - Abstract
Asthmatic lung samples present with both a higher density of pulmonary lymphatic vessels and a higher incidence of bronchus associated lymphoid tissue (BALT). Here, we asked whether lymphangiogenesis, stimulated by the VEGF-C/VEGFR-3 signaling axis in lymphatic endothelial cells (LECs), plays a role in promoting BALT in mouse models of allergy. First, we determined that chronic intratracheal instillation of house dust mite (HDM), a clinically relevant allergen, recapitulates both lymphangiogenesis and BALT induction. Intratracheal stimulation of VEGFR-3 in LECs exacerbated BALT, while blocking VEGFR-3 signaling reduced BALT. Furthermore, in transgenic mice with an expanded pulmonary lymphatic network (induced prior to allergen challenge), we found an exacerbated BALT response upon chronic HDM inhalation. Recent studies have determined that LEC-derived CXCL13 plays an important role in secondary lymphoid structure organogenesis, and thus we pondered whether LEC-derived CXCL13 could play a role in the development of tertiary lymphoid structures. Indeed, we observed an increase in lung infiltration by CXCR5+ cells when we used VEGF-C to modulate the chronic allergic response. Finally, we found that the VEGF-C exacerbated BALT phenomenon was indeed CXCL13 dependent. Altogether, these results suggest a causative role for pulmonary lymphatics in mediating BALT induction in chronic allergic airway inflammation.
- Published
- 2022
32. Interstitial lung disease patients exhibit augmented germinal center responses in lung lymph nodes and increased serum reactivities to novel autoantigens
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Young me Yoon, Tania Velez, Vaibhav Upadhyay, Sara Vazquez, Cathryn T Lee, Kelly Blaine, Donna Decker, Robert Guzy, Ayodeji Adegunsoye, Mary Strek, Imre Noth, Mark S Anderson, Joseph DeRisi, Anthony Shum, and Anne I Sperling
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Immunology ,Immunology and Allergy - Abstract
Interstitial lung disease (ILD), a group of disorders characterized by scarring of the lungs, often leads to fatal impairment of respiratory function. While some patients exhibit features of autoimmunity, the role of the immune system within this heterogeneous group of disorders remains a matter of debate. We previously reported the enlargement of lung-draining lymph nodes (LLN) correlates with decreased survival in ILD patients, suggesting that activation of the adaptive immune system may contribute to pathophysiology. To investigate the composition and functional state of cells in the enlarged LLN, we performed flow cytometry analysis of LLN cells from endstage ILD patients undergoing transplantation (n=53) and control organ donors (n=36). We found that T cells from the ILD LLN exhibit effector memory phenotypes and significantly upregulate activation molecules including HLA-DR, CD38, CD154 and CD137, which are indicative of an ongoing immune response. Analyses of CD4 T cells revealed that Foxp3+CD25− regulatory T cells are specifically increased in ILD LLN. Moreover, follicular helper T cells and germinal center (GC) B cells are highly enriched, suggesting that antibody responses are activated in ILD LLN. To test the hypothesis that autoantigens may drive the augmented GC response, we screened circulating antibodies from ILD patients at two medical centers against the entire human peptidome using phage immunoprecipitation sequencing. We defined novel and shared autoantigens and experimentally validated antibody bindings to 5 protein antigens. Collectively, our findings suggest that antigen-specific immune responses may be involved in the pathophysiology and identify novel autoantigens for subsets of ILD.
- Published
- 2022
33. SARS-CoV-2 infection reduces Krüppel-Like Factor 2 in human lung autopsy
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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
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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
34. Modeling human adaptive immune responses with tonsil organoids
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Mario Cortese, Gregory B. Hammer, Sean N. Tucker, Katharina Röltgen, Anne I. Sperling, Christian McCrory Constantz, Scott D. Boyd, Mark M. Davis, Krishna M. Roskin, Julia Z. Adamska, D. Huw Davies, Neha Gupta, Philip L. Felgner, Iram N. Ahmad, Aarti Jain, Ben S. Wendel, Kelly M. Blaine, Fan Yang, Michael Lyons, Ameen A. Salahudeen, Lisa K. Blum, Kara D. Meister, Emery G. Dora, Lauren P. Jatt, Vamsee Mallajosyula, Katherine J. L. Jackson, William H. Robinson, Calvin J. Kuo, Peter S. Kim, and Lisa E. Wagar
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0301 basic medicine ,Influenza Virus ,and promotion of well-being ,T-Lymphocytes ,Palatine Tonsil ,Hemagglutinin Glycoproteins, Influenza Virus ,Medical and Health Sciences ,0302 clinical medicine ,Rabies vaccine ,Immunologic ,B-Lymphocytes ,General Medicine ,Acquired immune system ,Organoids ,Infectious Diseases ,3.4 Vaccines ,Influenza Vaccines ,030220 oncology & carcinogenesis ,Pneumonia & Influenza ,Infection ,medicine.drug ,Biotechnology ,Hemagglutinin Glycoproteins ,COVID-19 Vaccines ,Influenza vaccine ,Lymphoid Tissue ,1.1 Normal biological development and functioning ,Immunology ,Somatic hypermutation ,Biology ,In Vitro Techniques ,Article ,General Biochemistry, Genetics and Molecular Biology ,Affinity maturation ,Vaccine Related ,03 medical and health sciences ,Immune system ,Antigen ,Adjuvants, Immunologic ,Underpinning research ,Biodefense ,medicine ,Humans ,Adjuvants ,Prevention ,Inflammatory and immune system ,Immunity ,Germinal center ,Germinal Center ,Prevention of disease and conditions ,Influenza ,030104 developmental biology ,Emerging Infectious Diseases ,Good Health and Well Being ,Rabies Vaccines ,Immunization ,Measles-Mumps-Rubella Vaccine - Abstract
Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymphoid organs, to develop a functional organotypic system that recapitulates key germinal center features in vitro, including the production of antigen-specific antibodies, somatic hypermutation and affinity maturation, plasmablast differentiation and class-switch recombination. We use this system to define the essential cellular components necessary to produce an influenza vaccine response. We also show that it can be used to evaluate humoral immune responses to two priming antigens, rabies vaccine and an adenovirus-based severe acute respiratory syndrome coronavirus 2 vaccine, and to assess the effects of different adjuvants. This system should prove useful for studying critical mechanisms underlying adaptive immunity in much greater depth than previously possible and to rapidly test vaccine candidates and adjuvants in an entirely human system.
- Published
- 2021
35. PKCθ regulates T cell motility via ezrin-radixin-moesin localization to the uropod.
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Judy L Cannon, Francois Asperti-Boursin, Kenneth A Letendre, Ivy K Brown, Katy E Korzekwa, Kelly M Blaine, Sreenivasa R Oruganti, Anne I Sperling, and Melanie E Moses
- Subjects
Medicine ,Science - Abstract
Cell motility is a fundamental process crucial for function in many cell types, including T cells. T cell motility is critical for T cell-mediated immune responses, including initiation, activation, and effector function. While many extracellular receptors and cytoskeletal regulators have been shown to control T cell migration, relatively few signaling mediators have been identified that can modulate T cell motility. In this study, we find a previously unknown role for PKCθ in regulating T cell migration to lymph nodes. PKCθ localizes to the migrating T cell uropod and regulates localization of the MTOC, CD43 and ERM proteins to the uropod. Furthermore, PKCθ-deficient T cells are less responsive to chemokine induced migration and are defective in migration to lymph nodes. Our results reveal a novel role for PKCθ in regulating T cell migration and demonstrate that PKCθ signals downstream of CCR7 to regulate protein localization and uropod formation.
- Published
- 2013
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36. ICOS-expressing lymphocytes promote resolution of CD8-mediated lung injury in a mouse model of lung rejection.
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Qiang Wu, Gail J Gardiner, Elizabeth Berry, Sarah R Wagner, Tiffany Lu, Bryan S Clay, Tamson V Moore, Caroline M Ferreira, Jesse W Williams, Andrew D Luster, Benjamin D Medoff, Judy L Cannon, Anne I Sperling, and Rebecca A Shilling
- Subjects
Medicine ,Science - Abstract
Acute rejection, a common complication of lung transplantation, may promote obliterative bronchiolitis leading to graft failure in lung transplant recipients. During acute rejection episodes, CD8(+) T cells can contribute to lung epithelial injury but the mechanisms promoting and controlling CD8-mediated injury in the lung are not well understood. To study the mechanisms regulating CD8(+) T cell-mediated lung rejection, we used a transgenic model in which adoptively transferred ovalbumin (OVA)-specific cytotoxic T lymphocytes (CTL) induce lung injury in mice expressing an ovalbumin transgene in the small airway epithelium of the lungs (CC10-OVA mice). The lung pathology is similar to findings in humans with acute lung transplant. In the presence of an intact immune response the inflammation resolves by day 30. Using CC10-OVA.RAG(-/-) mice, we found that CD4(+) T cells and ICOS(+/+) T cells were required for protection against lethal lung injury, while neutrophil depletion was not protective. In addition, CD4(+)Foxp3 (+) ICOS(+) T cells were enriched in the lungs of animals surviving lung injury and ICOS(+/+) Tregs promoted survival in animals that received ICOS(-/-) T cells. Direct comparison of ICOS(-/-) Tregs to ICOS(+/+) Tregs found defects in vitro but no differences in the ability of ICOS(-/-) Tregs to protect from lethal lung injury. These data suggest that ICOS affects Treg development but is not necessarily required for Treg effector function.
- Published
- 2013
- Full Text
- View/download PDF
37. Asthma-associated genetic variants induce IL33 differential expression through a novel regulatory region
- Author
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Douglas K. Hogarth, José Luis Gómez-Skarmeta, Nathan Schoettler, Débora R. Sobreira, Cara L. Hrusch, Michelle M. Stein, Juan J. Tena, Donna C. Decker, Selene M. Clay, Noboru J. Sakabe, Kevin M. Magnaye, Edward T. Naurekas, Daniel J. Jackson, Marcelo A. Nobrega, Lindsey E. Montefiori, Steven R. White, Carole Ober, Ivy Aneas, Anne I. Sperling, Kelly M. Blaine, Matthew C. Altman, James E. Gern, and Chanie L. Howard
- Subjects
Genetics ,Genetic variants ,medicine ,Biology ,Differential expression ,medicine.disease ,Regulatory region ,Asthma - Abstract
Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as a strong regulatory element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that genotype at the asthma-associated SNP rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a novel mechanism through which a regulatory SNP contributes to genetic risk of asthma.
- Published
- 2020
38. Circulating Plasma Biomarkers of Survival in Antifibrotic-Treated Patients With Idiopathic Pulmonary Fibrosis
- Author
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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
39. Asthma-associated variants induce IL33 differential expression through a novel regulatory region
- Author
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Selene M. Clay, Nathan Schoetler, Daniel J. Jackson, Michelle M. Stein, Noboru J. Sakabe, Lindsey E. Montefiori, Juan J. Tena, Steven R. White, Ivy Aneas, Anne I. Sperling, Chanie L. Howard, Kelly M. Blaine, Marcelo A. Nobrega, Matthew C. Altman, Edward T. Naureckas, Donna C. Decker, Débora R. Sobreira, Carole Ober, Douglas K. Hogarth, James E. Gern, José Luis Gómez-Skarmeta, Kevin M. Magnaye, and Cara L. Hrusch
- Subjects
Chromosome conformation capture ,Genetics ,Genotype ,Gene expression ,SNP ,Locus (genetics) ,Genome-wide association study ,Allele ,Biology ,Genetic association - Abstract
Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as a strong regulatory element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. Supporting this notion, we show that genotype at an asthma-associated SNP, rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a novel mechanism through which a regulatory SNP contributes to genetic risk of asthma.
- Published
- 2020
40. Adjuvant-free nanofiber vaccine induces in situ lung dendritic cell activation and TH17 responses
- Author
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Qiaomu Tian, Joel H. Collier, Sean H. Kelly, Anita S. Chong, Daniel F. Camacho, Lucas S. Shores, Michael S. Andrade, Anne I. Sperling, Fan Zhao, and Youhui Si
- Subjects
0303 health sciences ,Multidisciplinary ,Innate immune system ,Chemistry ,medicine.medical_treatment ,Immunogenicity ,chemical and pharmacologic phenomena ,02 engineering and technology ,Dendritic cell ,021001 nanoscience & nanotechnology ,03 medical and health sciences ,Antigen ,Immunity ,Immunology ,medicine ,Nasal administration ,0210 nano-technology ,Adjuvant ,CD80 ,030304 developmental biology - Abstract
The current paradigm that subunit vaccines require adjuvants to optimally activate innate immunity implies that increased vaccine reactogenicity will invariably be linked to improved immunogenicity. Countering this paradigm, nanoparticulate vaccines have been reported to act as delivery systems for vaccine antigens and induce immunity without the need for exogenous adjuvants or local inflammation; however, the mechanisms underlying the immunogenicity of nanoparticle vaccines are incompletely identified. Here, we show that antigens displayed on self-assembling nanofiber scaffolds and delivered intranasally are presented by CD103+ and CD11b+ lung dendritic cells that up-regulate CD80 and migrate into the draining lymph node (LN). This was accompanied by a nearly exclusive priming and accumulation of antigen-specific TH17 cells occurring independently in both LN and lung. Thus, self-assembling peptide nanofiber vaccines may represent a novel, needle- and adjuvant-free means of eliciting protective immunity against fungal and bacterial infections at skin and mucosal barrier surfaces.
- Published
- 2020
41. Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization
- Author
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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
42. IRF4 expression by lung dendritic cells drives acute but not Trm cell-dependent memory Th2 responses
- Author
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Daniel F. Camacho, Tania E. Velez, Maile K. Hollinger, Esther Wang, Chanie L. Howard, Eli P. Darnell, Domenick E. Kennedy, Paulette A. Krishack, Cara L. Hrusch, Marcus R. Clark, James J. Moon, and Anne I. Sperling
- Subjects
Mice ,Memory T Cells ,Th2 Cells ,Gene Expression Regulation ,Interferon Regulatory Factors ,Animals ,General Medicine ,Dendritic Cells ,Allergens ,Lung ,Immunologic Memory - Abstract
Expression of the transcription factor interferon regulatory factor 4 (IRF4) is required for the development of lung conventional DCs type 2 (cDC2s) that elicit Th2 responses, yet how IRF4 functions in lung cDC2s throughout the acute and memory allergic response is not clear. Here, we used a mouse model that loses IRF4 expression after lung cDC2 development to demonstrate that mice with IRF4-deficient DCs display impaired memory responses to allergen. This defect in the memory response was a direct result of ineffective Th2 induction and impaired recruitment of activated effector T cells to the lung after sensitization. IRF4-deficient DCs demonstrated defects in their migration to the draining lymph node and in T cell priming. Finally, T cells primed by IRF4-competent DCs mediated potent memory responses independently of IRF4-expressing DCs, demonstrating that IRF4-expressing DCs are not necessary during the memory response. Thus, IRF4 controlled a program in mature DCs governing Th2 priming and effector responses, but IRF4-expressing DCs were dispensable during tissue-resident memory T cell-dependent memory responses.
- Published
- 2020
43. IL-33-Mediated Eosinophilia Protects Against Staphylococcus Aureus-Induced Lung Injury
- Author
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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
44. Regional Disparities of Molecular Profiles and Cell Compositions in the Lungs of Idiopathic Pulmonary Fibrosis Patients
- Author
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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
45. Adjuvant-free nanofiber vaccine induces in situ lung dendritic cell activation and T
- Author
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Youhui, Si, Qiaomu, Tian, Fan, Zhao, Sean H, Kelly, Lucas S, Shores, Daniel F, Camacho, Anne I, Sperling, Michael S, Andrade, Joel H, Collier, and Anita S, Chong
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Adjuvants, Immunologic ,Vaccines, Subunit ,Immunology ,Materials Science ,Nanofibers ,SciAdv r-articles ,Dendritic Cells ,respiratory system ,Lung ,Research Articles ,respiratory tract diseases ,Research Article - Abstract
Intranasal Q11 nanofiber vaccination activates lung dendritic cell antigen presentation and TH17 priming in both lung and lymph nodes., The current paradigm that subunit vaccines require adjuvants to optimally activate innate immunity implies that increased vaccine reactogenicity will invariably be linked to improved immunogenicity. Countering this paradigm, nanoparticulate vaccines have been reported to act as delivery systems for vaccine antigens and induce immunity without the need for exogenous adjuvants or local inflammation; however, the mechanisms underlying the immunogenicity of nanoparticle vaccines are incompletely identified. Here, we show that antigens displayed on self-assembling nanofiber scaffolds and delivered intranasally are presented by CD103+ and CD11b+ lung dendritic cells that up-regulate CD80 and migrate into the draining lymph node (LN). This was accompanied by a nearly exclusive priming and accumulation of antigen-specific TH17 cells occurring independently in both LN and lung. Thus, self-assembling peptide nanofiber vaccines may represent a novel, needle- and adjuvant-free means of eliciting protective immunity against fungal and bacterial infections at skin and mucosal barrier surfaces.
- Published
- 2019
46. Transcriptional programming and T cell receptor repertoires distinguish human lung and lymph node memory T cells
- Author
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Nathan Schoettler, Cara L. Hrusch, Carole Ober, Anne I. Sperling, and Kelly M. Blaine
- Subjects
0301 basic medicine ,Transcription, Genetic ,Medicine (miscellaneous) ,Biology ,Immunological memory ,General Biochemistry, Genetics and Molecular Biology ,Article ,Immunophenotyping ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,T-Lymphocyte Subsets ,medicine ,Immunogenetics ,Humans ,Receptor ,lcsh:QH301-705.5 ,Lymph node ,Lung ,Innate immune system ,Gene Expression Profiling ,T-cell receptor ,Reproducibility of Results ,respiratory system ,Cellular Reprogramming ,V(D)J Recombination ,respiratory tract diseases ,Genes, T-Cell Receptor ,030104 developmental biology ,medicine.anatomical_structure ,Gene Ontology ,lcsh:Biology (General) ,Immunology ,Mucosal immunology ,Lymph Nodes ,General Agricultural and Biological Sciences ,Memory T cell ,Immunologic Memory ,030217 neurology & neurosurgery ,CD8 ,Biomarkers - Abstract
Antigen-specific memory T cells persist for years after exposure to a pathogen and provide effective recall responses. Many memory T cell subsets have been identified and differ in abundance throughout tissues. This study focused on CD4 and CD8 memory T cells from paired human lung and lung draining lymph node (LDLN) samples and identified substantial differences in the transcriptional landscape of these subsets, including higher expression of an array of innate immune receptors in lung T cells which were further validated by flow cytometry. Using T cell receptor analysis, we determined the clonal overlap between memory T cell subsets within the lung and within the LDLN, and this was greater than the clonal overlap observed between memory T cell subsets compared across tissues. Our results suggest that lung and LDLN memory T cells originate from different precursor pools, recognize distinct antigens and likely have separate roles in immune responses., Schoettler et al. show that specific memory T cell subsets from the lung have distinct transcriptional programming and T cell receptor repertoires when compared with memory T cell subsets from the lung draining lymph nodes (LDLNs). This study suggests that memory T cell subsets from the lung and LDLN are derived from distinct progenitor pools.
- Published
- 2019
47. Protective effector memory CD4 T cells depend on ICOS for survival.
- Author
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Tamson V Moore, Bryan S Clay, Caroline M Ferreira, Jesse W Williams, Magdalena Rogozinska, Judy L Cannon, Rebecca A Shilling, Amanda L Marzo, and Anne I Sperling
- Subjects
Medicine ,Science - Abstract
Memory CD4 T cells play a vital role in protection against re-infection by pathogens as diverse as helminthes or influenza viruses. Inducible costimulator (ICOS) is highly expressed on memory CD4 T cells and has been shown to augment proliferation and survival of activated CD4 T cells. However, the role of ICOS costimulation on the development and maintenance of memory CD4 T cells remains controversial. Herein, we describe a significant defect in the number of effector memory (EM) phenotype cells in ICOS(-/-) and ICOSL(-/-) mice that becomes progressively more dramatic as the mice age. This decrease was not due to a defect in the homeostatic proliferation of EM phenotype CD4 T cells in ICOS(-/-) or ICOSL(-/-) mice. To determine whether ICOS regulated the development or survival of EM CD4 T cells, we utilized an adoptive transfer model. We found no defect in development of EM CD4 T cells, but long-term survival of ICOS(-/-) EM CD4 T cells was significantly compromised compared to wild-type cells. The defect in survival was specific to EM cells as the central memory (CM) ICOS(-/-) CD4 T cells persisted as well as wild type cells. To determine the physiological consequences of a specific defect in EM CD4 T cells, wild-type and ICOS(-/-) mice were infected with influenza virus. ICOS(-/-) mice developed significantly fewer influenza-specific EM CD4 T cells and were more susceptible to re-infection than wild-type mice. Collectively, our findings demonstrate a role for ICOS costimulation in the maintenance of EM but not CM CD4 T cells.
- Published
- 2011
- Full Text
- View/download PDF
48. Inducible costimulator expression regulates the magnitude of Th2-mediated airway inflammation by regulating the number of Th2 cells.
- Author
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Bryan S Clay, Rebecca A Shilling, Hozefa S Bandukwala, Tamson V Moore, Judy L Cannon, Andrew A Welcher, Joel V Weinstock, and Anne I Sperling
- Subjects
Medicine ,Science - Abstract
Inducible Costimulator (ICOS) is an important regulator of Th2 lymphocyte function and a potential immunotherapeutic target for allergy and asthma. A SNP in the ICOS 5' promoter in humans is associated with increased atopy and serum IgE in a founder population and increased ICOS surface expression and Th2 cytokine production from peripheral blood mononuclear cells. However, it is unknown if increased ICOS expression contributes to disease progression or is a result of disease pathology.We developed a mouse model in which ICOS surface expression levels are genetically predetermined to test our hypothesis that genetic regulation of ICOS expression controls the severity of Th2 responses in vivo. Using ICOS+/+ and ICOS+/- mice in a Th2 model of airway inflammation, we found that T cells from the ICOS+/- mice had reduced ICOS expression and decreased Th2-mediated inflammation in vivo. Although the activation status of the T cells did not differ, T cells isolated from the lungs and draining lymph nodes of ICOS+/- mice at the peak of inflammation produced less Th2 cytokines upon stimulation ex vivo. Using 4get mice, which express GFP upon IL-4 transcription, we determined that the decreased Th2 cytokines in ICOS+/- is due to reduced percentage of Th2 cells and not a defect in their ability to produce IL-4.These data suggest that in both mice and humans, the level of ICOS surface expression regulates the magnitude of the in vivo Th2 response, perhaps by influencing Th2 differentiation.
- Published
- 2009
- Full Text
- View/download PDF
49. Inhibition of TH2 responses by a secreted component of a common farm bacterium
- Author
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Maile Kananiokala Hollinger, Daniel F Camacho, Cara L Hrusch, Gabriel M Barron, Tania Estefania Velez, Jesus Bernabe Zamora-Pineda, Katherine Knight, and Anne I Sperling
- Subjects
Immunology ,Immunology and Allergy - Abstract
The rise in incidence of asthma and allergic diseases over the past half century has led to the development of the hygiene hypothesis, which posits that lack of exposure to environmental microbes during childhood leads to inappropriate immune responses to innocuous antigens. Evidence for the hygiene hypothesis is particularly compelling in studies of rural farm children, where infants that live on farms had reduced prevalence of asthma at school age, as compared to their non-farming counterparts. In particular, the presence of exopolysaccharide (EPS) in farm dust independently predicted lower rates of asthma diagnosis. The purpose of this study is to investigate the protective effects of EPS from a common farm microorganism, the hay bacillus B. subtilis, in limiting TH2-type inflammation in a mouse model of asthma. Treatment of house dust mite (HDM)-sensitized mice with EPS was sufficient to block eosinophilia and TH2 accumulation in the lungs, without affecting accumulation of other TH subsets. These effects were dependent on TLR4, the putative receptor for EPS, as EPS no longer protected against eosinophilia and TH2 infiltration in Tlr4−\− mice. Additionally, lung-derived dendritic cells exposed to EPS and HDM in vivo were phenotypically distinct from dendritic cells recovered from mice treated with HDM alone. These data support a protective role for EPS in the inhibition of allergic asthma, potentially by affecting TLR4-dependent dendritic cell priming of TH2 responses.
- Published
- 2021
50. Gut microbiota modulate susceptibility to bleomycin-induced lung injury
- Author
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Young me Yoon, Gabe M Barrón, Cara L Hrusch, Na Fei, Vanessa A Leone, and Anne I Sperling
- Subjects
Immunology ,Immunology and Allergy - Abstract
Acute lung injury (ALI) resulting in acute respiratory distress syndrome (ARDS) affects almost 200,000 people in the US each year, leading to 75,000 deaths. Airway instillation of bleomycin (BLM) in mice is a widely used, yet challenging model for ALI due to high variability. We have observed that B6 mice from two SPF facilities at our University exhibit significantly different mortality and weight loss in response to BLM. To test whether the facility-dependent response to BLM can be transferred by the microbiome, we conventionalized germ-free (GF) B6 littermates in each facility and challenged with BLM. Conventionalized GF mice recapitulated the respective donors’ response to BLM. Further, fecal microbiota transfer from the facility where the mice had worse mortality into the mice in the facility with more survival rendered recipient mice more susceptible to BLM compared to controls, indicating that the differential gut microbiome between two facilities were sufficient to modulate BLM response. To identify microorganisms that drive the phenotype, we compared gut microbial community memberships by 16S rRNA and metagenomics sequencing. Interestingly, BLM highly susceptible mice had greater alpha diversity and harbored specific species of Bacteroides, Prevotella, and Helicobacter genera. Flow cytometry of the lung immune cell landscape at baseline revealed comparable composition and phenotype of adaptive immune cells regardless of facility. However, lung NK cells were significantly increased BLM highly susceptible mice. Thus, we demonstrate that distinct gut microbiota communities modulate death and weight loss in response to BLM-induced lung injury, implicating host-commensal interactions in regulating ALI outcomes.
- Published
- 2021
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