17 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. 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
8. 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
9. 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
10. 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
- Abstract
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
11. 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
12. 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
13. 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.
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- 2023
14. Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region
- Author
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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.
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- 2021
15. 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.
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- 2022
16. 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
- Subjects
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
17. Central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosis
- Author
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Imre Noth, Yong Huang, Aliya N Husain, Shwu-Fan Ma, Jonathan Jou, Rob Guzy, Catherine A Bonham, Jefree J Schulte, John S Kim, Andrew J Barros, Milena S Espindola, Cory M Hogaboam, and Anne I Sperling
- Subjects
Medicine ,Diseases of the respiratory system ,RC705-779 - Abstract
Rationale Contribution of central lung tissues to pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unknown.Objective To ascertain the relationship between cell types of IPF-central and IPF-peripheral lung explants using RNA sequencing (RNA-seq) transcriptome.Methods Biopsies 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.Findings Comparison 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.Interpretation Gene 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
- Full Text
- View/download PDF
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