41 results on '"Hoffman, Hal M."'
Search Results
2. Inflammasome Activation in Children With Kawasaki Disease and Multisystem Inflammatory Syndrome
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Wang, Wei-Ting, He, Ming, Shimizu, Chisato, Croker, Ben A., Hoffman, Hal M., Tremoulet, Adriana H., Burns, Jane C., and Shyy, John Y.-J.
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- 2021
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3. Autoinflammatory disease: New mouse models and therapies.
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Hoffman, Hal M.
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- 2020
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4. TLR Activation Alters Bone Marrow-Derived Macrophage Differentiation
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Oppong-Nonterah, Gertrude O., Lakhdari, Omar, Yamamura, Asami, Hoffman, Hal M., and Prince, Lawrence S.
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Early exposure to inflammatory signals may have a lasting impact on immune function. Present throughout embryogenesis, macrophages are key cells providing innate immune protection to the developing fetus and newborn. Here, we have used an established model of macrophage development to test how early inflammatory signals can impact cellular differentiation and function. Bone marrow-derived macrophages were treated with Escherichia colilipopolysaccharide (LPS) 2 days after initial isolation and culture. LPS treatment during this early stage of differentiation decreased the expression of CSF1R and increased that of the mature macrophage marker F4/80. These early changes in macrophage differentiation were also measured in cells from mice lacking IKKβ, but the change in CSF1R expression after LPS treatment was blocked with MAPK inhibition. LPS-induced changes in macrophage marker expression persisted following LPS removal, suggesting that early inflammatory activation could induce a lasting developmental impact. Early LPS exposure inhibited macrophage phagocytosis of labeled E. coliwhile LPS had no effect on fully differentiated macrophages. Our data demonstrate that early inflammatory exposure to a microbial stimulus induce lasting phenotypic changes in macrophages.
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- 2018
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5. Sa1586 YKL-40 REGULATES NEUTROPHILS RECRUITMENT VIA NLRP3 INFLAMMASOME DURING LIVER INFLAMMATION.
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Kui, Lin, Kim, Andrea D., Hoffman, Hal M., and Feldstein, Ariel E.
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- 2023
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6. Sa1585 NLRP3 INFLAMMASOME ACTIVATION IN NEUTROPHILS DRIVES HEPATIC STELLATE CELL ACTIVATION IN MURINE NON-ALCOHOLIC STEATOHEPATITIS.
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Kaufmann, Benedikt, Booshehri, Laela M., Leszczynska, Aleksandra, Friess, Helmut, Hartmann, Daniel, Broderick, Lori, Hoffman, Hal M., and Feldstein, Ariel E.
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- 2023
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7. Selective inhibition of the p38α MAPK–MK2 axis inhibits inflammatory cues including inflammasome priming signals
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Wang, Chun, Hockerman, Susan, Jacobsen, E. Jon, Alippe, Yael, Selness, Shaun R., Hope, Heidi R., Hirsch, Jeffrey L., Mnich, Stephen J., Saabye, Matthew J., Hood, William F., Bonar, Sheri L., Abu-Amer, Yousef, Haimovich, Ariela, Hoffman, Hal M., Monahan, Joseph B., and Mbalaviele, Gabriel
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p38α activation of multiple effectors may underlie the failure of global p38α inhibitors in clinical trials. A unique inhibitor (CDD-450) was developed that selectively blocked p38α activation of the proinflammatory kinase MK2 while sparing p38α activation of PRAK and ATF2. Next, the hypothesis that the p38α–MK2 complex mediates inflammasome priming cues was tested. CDD-450 had no effect on NLRP3 expression, but it decreased IL-1β expression by promoting IL-1β mRNA degradation. Thus, IL-1β is regulated not only transcriptionally by NF-κB and posttranslationally by the inflammasomes but also posttranscriptionally by p38α–MK2. CDD-450 also accelerated TNF-α and IL-6 mRNA decay, inhibited inflammation in mice with cryopyrinopathy, and was as efficacious as global p38α inhibitors in attenuating arthritis in rats and cytokine expression by cells from patients with cryopyrinopathy and rheumatoid arthritis. These findings have clinical translation implications as CDD-450 offers the potential to avoid tachyphylaxis associated with global p38α inhibitors that may result from their inhibition of non-MK2 substrates involved in antiinflammatory and housekeeping responses.
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- 2018
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8. New workflow for classification of genetic variants’ pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID)
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Van Gijn, Marielle E, Ceccherini, Isabella, Shinar, Yael, Carbo, Ellen C, Slofstra, Mariska, Arostegui, Juan I, Sarrabay, Guillaume, Rowczenio, Dorota, Omoyımnı, Ebun, Balci-Peynircioglu, Banu, Hoffman, Hal M, Milhavet, Florian, Swertz, Morris A, and Touitou, Isabelle
- Abstract
BackgroundHereditary recurrent fevers (HRFs) are rare inflammatory diseases sharing similar clinical symptoms and effectively treated with anti-inflammatory biological drugs. Accurate diagnosis of HRF relies heavily on genetic testing.ObjectivesThis study aimed to obtain an experts’ consensus on the clinical significance of gene variants in four well-known HRF genes: MEFV, TNFRSF1A, NLRP3and MVK.MethodsWe configured a MOLGENIS web platform to share and analyse pathogenicity classifications of the variants and to manage a consensus-based classification process. Four experts in HRF genetics submitted independent classifications of 858 variants. Classifications were driven to consensus by recruiting four more expert opinions and by targeting discordant classifications in five iterative rounds.ResultsConsensus classification was reached for 804/858 variants (94%). None of the unsolved variants (6%) remained with opposite classifications (eg, pathogenic vs benign). New mutational hotspots were found in all genes. We noted a lower pathogenic variant load and a higher fraction of variants with unknown or unsolved clinical significance in the MEFVgene.ConclusionApplying a consensus-driven process on the pathogenicity assessment of experts yielded rapid classification of almost all variants of four HRF genes. The high-throughput database will profoundly assist clinicians and geneticists in the diagnosis of HRFs. The configured MOLGENIS platform and consensus evolution protocol are usable for assembly of other variant pathogenicity databases. The MOLGENIS software is available for reuse at http://github.com/molgenis/molgenis; the specific HRF configuration is available at http://molgenis.org/said/.The HRF pathogenicity classifications will be published on the INFEVERS database at https://fmf.igh.cnrs.fr/ISSAID/infevers/.
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- 2018
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9. Constitutive IL-1RA production by modified immune cells protects against IL-1–mediated inflammatory disorders
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Colantuoni, Mariasilvia, Jofra Hernandez, Raisa, Pettinato, Emanuela, Basso-Ricci, Luca, Magnani, Laura, Andolfi, Grazia, Rigamonti, Chiara, Finardi, Annamaria, Romeo, Valentina, Soldi, Monica, Sergi Sergi, Lucia, Rocchi, Martina, Scala, Serena, Hoffman, Hal M., Gregori, Silvia, Kajaste-Rudnitski, Anna, Sanvito, Francesca, Muzio, Luca, Naldini, Luigi, Aiuti, Alessandro, and Mortellaro, Alessandra
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Dysregulation of the interleukin-1 (IL-1) pathway leads to immune diseases that can result in chronic tissue and organ inflammation. Although IL-1 blockade has shown promise in ameliorating these symptoms and improving patients’ quality of life, there is an urgent need for more effective, long-lasting treatments. We developed a lentivirus (LV)–mediated gene transfer strategy using transplanted autologous hematopoietic stem/progenitor cells (HSPCs) as a source of IL-1 receptor antagonist (IL-1RA) for systemic delivery to tissues and organs. Transplantation of mouse and human HSPCs transduced with an IL-1RA–encoding LV ensured stable IL-1RA production while maintaining the clonogenic and differentiation capacities of HSPCs in vivo. We examined the efficacy of cell-mediated IL-1RA delivery in three models of IL-1–dependent inflammation, for which treatment hindered neutrophil recruitment in an inducible model of gout, prevented systemic and multi-tissue inflammation in a genetic model of cryopyrin-associated periodic syndromes, and reduced disease severity in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Our findings demonstrate HSPC-mediated IL-1RA delivery as a potential therapeutic modality that can be exploited to suppress tissue and organ inflammation in diverse immune-related diseases involving IL-1–driven inflammation.
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- 2023
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10. The role of the inflammasome in patients with autoinflammatory diseases.
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Hoffman, Hal M. and Broderick, Lori
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Autoinflammatory diseases are disorders of the innate immune system, characterized by systemic inflammation often driven by inflammasomes, and independent of infection and autoreactive antibodies or antigen-specific T cells. These diseases are increasingly recognized as disorders of immune dysregulation, presenting with a constellation of fevers, rashes, and mucosal symptoms in many cases, which suggests that the allergist/immunologist is the appropriate specialist for these patients. However, many practicing physicians are unaware of these disorders in their pediatric and adult patient populations, leading to substantial delays in diagnosis. Recognizing autoinflammatory disease symptom patterns, performing appropriate diagnostic tests, and instituting early effective therapy are essential to reduce morbidity and mortality in these patients. This review will focus on understanding the molecular basis of inflammasomes, recognizing the distinguishing features of the classic autoinflammatory disorders, and appreciating the treatment modalities available. [ABSTRACT FROM AUTHOR]
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- 2016
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11. A guiding map for inflammation
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Netea, Mihai G, Balkwill, Frances, Chonchol, Michel, Cominelli, Fabio, Donath, Marc Y, Giamarellos-Bourboulis, Evangelos J, Golenbock, Douglas, Gresnigt, Mark S, Heneka, Michael T, Hoffman, Hal M, Hotchkiss, Richard, Joosten, Leo A B, Kastner, Daniel L, Korte, Martin, Latz, Eicke, Libby, Peter, Mandrup-Poulsen, Thomas, Mantovani, Alberto, Mills, Kingston H G, Nowak, Kristen L, O'Neill, Luke A, Pickkers, Peter, van der Poll, Tom, Ridker, Paul M, Schalkwijk, Joost, Schwartz, David A, Siegmund, Britta, Steer, Clifford J, Tilg, Herbert, van der Meer, Jos W M, van de Veerdonk, Frank L, and Dinarello, Charles A
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Netea and colleagues provide a general guide to the cellular and humoral contributors to inflammation as well as the pathways that characterize inflammation in specific organs and tissues.
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- 2017
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12. Mimickers of Classical Urticaria: Cryopyrin-Associated Autoinflammatory Syndrome Presenting as Isolated Urticaria in an Infant
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Solomon, Benjamin D., Skaljic, Meliha, Liu, Lucy Y., Yan, Di, Sheahon, Kathleen M., Broderick, Lori, Hoffman, Hal M., Beres, Shannon J., Brown, Ryanne A., Teng, Joyce M.C., and Gernez, Yael
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- 2023
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13. Cold Urticaria Syndromes: Diagnosis and Management
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Diaz, Vanessa L., Gribbons, K. Bates, Katayoun-Yazdi-Nejad, Kuemmerle-Deschner, Jasmin, Wanderer, Alan A., Broderick, Lori, and Hoffman, Hal M.
- Abstract
Cold urticaria is a chronic condition causing episodic symptoms of cold-induced wheals or angioedema in response to direct or indirect exposure to cold temperatures. While symptoms of cold urticaria are typically benign and self-limiting, severe systemic anaphylactic reactions are possible. Acquired, atypical, and hereditary forms have been described, each with variable triggers, symptoms and responses to therapy. Clinical testing, including response to cold stimulation, help define disease subtypes. More recently, monogenic disorders characterized by atypical forms of cold urticaria have been described. Here, we review the different forms of cold-induced urticaria and related syndromes, and propose a diagnostic algorithm to aid clinicians in making a timely diagnosis for appropriate management of these patients.
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- 2023
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14. Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease–Associated Abdominal Aortic Aneurysm
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Wakita, Daiko, Kurashima, Yosuke, Crother, Timothy R., Noval Rivas, Magali, Lee, Youngho, Chen, Shuang, Fury, Wen, Bai, Yu, Wagner, Shawn, Li, Debiao, Lehman, Thomas, Fishbein, Michael C., Hoffman, Hal M., Shah, Prediman K., Shimada, Kenichi, and Arditi, Moshe
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Supplemental Digital Content is available in the text.
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- 2016
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15. IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model
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Lee, Youngho, Wakita, Daiko, Dagvadorj, Jargalsaikhan, Shimada, Kenichi, Chen, Shuang, Huang, Ganghua, Lehman, Thomas J.A., Fishbein, Michael C., Hoffman, Hal M., Crother, Timothy R., and Arditi, Moshe
- Abstract
Supplemental Digital Content is available in the text.
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- 2015
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16. Recurrent fevers and failure to thrive in an infant.
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Scott, David R., Chan, Sarah, Chang, Johanna, Broderick, Lori, and Hoffman, Hal M.
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MOUTH injuries ,VIREMIA - Abstract
We describe a 2-year old boy with consanguineous parents who recently emigrated from India and presented with oral ulcers and lymphadenopathy. He also had a history of recurrent fevers, polyarticular arthritis, chronic diarrhea, failure to thrive, and developmental delay. Infectious workup revealed herpes simplex virus 1 viremia and radiological evaluation revealed osteopenia and erosions involving multiple joints. We describe the immunologic and genetic evaluation of this patient and discuss the diagnostic and therapeutic approach to an infant with recurrent fevers. [ABSTRACT FROM AUTHOR]
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- 2013
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17. Prolonged urticaria and fever in a toddler.
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Broderick, Lori, Tremoulet, Adriana H., Burns, Jane C., and Hoffman, Hal M.
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URTICARIA ,FEVER in children ,TODDLERS ,NEUTROPHILS ,LYMPHOCYTES ,DISEASES - Abstract
We describe a 14-month-old girl who initially presented with 8 days of fever, conjunctival injection, rash, and irritability, admitted with a presumptive diagnosis of Kawasaki disease. Further history revealed intermittent urticarial-like rash since 3 months of age and pathological evaluation showed a perivascular infiltrate of neutrophils and lymphocytes. Here, we discuss the key points surrounding her diagnostic workup and our therapeutic approach. [ABSTRACT FROM AUTHOR]
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- 2012
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18. Identification of EpCAM as the Gene for Congenital Tufting Enteropathy.
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Sivagnanam, Mamata, Mueller, James L., Lee, Hane, Chen, Zugen, Nelson, Stanley F., Turner, Dan, Zlotkin, Stanley H., Pencharz, Paul B., Ngan, Bo–Yee, Libiger, Ondrej, Schork, Nicholas J., Lavine, Joel E., Taylor, Sharon, Newbury, Robert O., Kolodner, Richard D., and Hoffman, Hal M.
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INTESTINAL diseases ,MALABSORPTION syndromes ,GENETIC disorders ,POLYMERASE chain reaction - Abstract
Background & Aims: Congenital tufting enteropathy (CTE) is a rare autosomal recessive diarrheal disorder presenting in the neonatal period. CTE is characterized by intestinal epithelial cell dysplasia leading to severe malabsorption and significant morbidity and mortality. The pathogenesis and genetics of this disorder are not well understood. The objective of this study was to identify the gene responsible for CTE. Methods: A family with 2 children affected with CTE was identified. The affected children are double second cousins providing significant statistical power for linkage. Using Affymetrix 50K single nucleotide polymorphism (SNP) chips, genotyping was performed on only 2 patients and 1 unaffected sibling. Direct DNA sequencing of candidate genes, reverse-transcription polymerase chain reaction, immunohistochemistry, and Western blotting were performed on specimens from patients and controls. Results: SNP homozygosity mapping identified a unique 6.5-Mbp haplotype of homozygous SNPs on chromosome 2p21 where approximately 40 genes are located. Direct sequencing of genes in this region revealed homozygous G>A substitution at the donor splice site of exon 4 in epithelial cell adhesion molecule (EpCAM) of affected patients. Reverse-transcription polymerase chain reaction of duodenal tissue demonstrated a novel alternative splice form with deletion of exon 4 in affected patients. Immunohistochemistry and Western blot of patient intestinal tissue revealed decreased expression of EpCAM. Direct sequencing of EpCAM from 2 additional unrelated patients revealed novel mutations in the gene. Conclusions: Mutations in the gene for EpCAM are responsible for CTE. This information will be used to gain further insight into the molecular mechanisms of this disease. [Copyright &y& Elsevier]
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- 2008
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19. Microbial Pathogen-Induced Necrotic Cell Death Mediated by the Inflammasome Components CIAS1/Cryopyrin/NLRP3 and ASC.
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Willingham, Stephen B., Bergstralh, Daniel T., O'Connor, William, Morrison, Amy C., Taxman, Debra J., Duncan, Joseph A., Barnoy, Shoshana, Venkatesan, Malabi M., Flavell, Richard A., Deshmukh, Mohanish, Hoffman, Hal M., and Ting, Jenny P.-Y.
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PATHOGENIC microorganisms ,MEDICAL microbiology ,GENES ,HEREDITY - Abstract
Summary: Cryopyrin (CIAS1, NLRP3) and ASC are components of the inflammasome, a multiprotein complex required for caspase-1 activation and cytokine IL-1β production. CIAS1 mutations underlie autoinflammation characterized by excessive IL-1β secretion. Disease-associated cryopyrin also causes a program of necrosis-like cell death in macrophages, the mechanistic details of which are unknown. We find that patient monocytes carrying disease-associated CIAS1 mutations exhibit excessive necrosis-like death by a process dependent on ASC and cathepsin B, resulting in spillage of the proinflammatory mediator HMGB1. Shigella flexneri infection also causes cryopyrin-dependent macrophage necrosis with features similar to the death caused by mutant CIAS1. This necrotic death is independent of caspase-1 and IL-1β, and thus independent of the inflammasome. Furthermore, necrosis of primary macrophages requires the presence of Shigella virulence genes. While similar proteins mediate pathogen-induced cell death in plants, this report identifies cryopyrin as an important host regulator of programmed pathogen-induced necrosis in animals, a process we term pyronecrosis. [Copyright &y& Elsevier]
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- 2007
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20. Monocytes from familial cold autoinflammatory syndrome patients are activated by mild hypothermia.
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Rosengren, Sanna, Mueller, James L., Anderson, Justin P., Niehaus, Brian L., Misaghi, Amirhossein, Anderson, Scott, Boyle, David L., and Hoffman, Hal M.
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COMMON cold ,MONOCYTES ,HYPOTHERMIA ,CELLULAR immunity - Abstract
Background: Familial cold autoinflammatory syndrome (FCAS) is characterized by rash, fever, and arthralgia in response to cold exposure. CIAS1, the gene that codes for cryopyrin, is mutated in FCAS. Treatment with anakinra (IL-1 receptor antagonist) prevents symptoms, indicating a crucial role for IL-1 in this disease. Objective: To study cytokine responses to cold exposure in monocytes from subjects with FCAS. Methods: Adherence-enriched monocytes were incubated at 32°C or 37°C. Transcription and release of IL-1β, IL-6, and TNF-α were monitored by quantitative PCR and ELISA. Results: The FCAS monocytes but not control cells responded to 4 h incubation at 32°C with significant secretion of IL-1β. At 16 h, IL-1β, IL-6, and TNF-α were all significantly elevated in FCAS monocytes at 32°C. Increased cytokine transcription was observed in all monocytes at 4 hours, but at 16 hours it was only seen in FCAS monocytes incubated at 32°C. Incubation at 32°C for as little as 1 hour sufficed to induce measurable IL-1β release. Caspase-1 inhibitors prevented the cold-induced IL-1β release, whereas a purinergic antagonist did not. Anakinra had no effect on the early IL-1β release but significantly reduced the late-phase transcription and release of all cytokines. Conclusion: FCAS monocytes respond to mild hypothermia with IL-1β release, which in turn induces autocrine transcription and secretion of IL-6 and TNF-α as well as stimulation of further IL-1β production. Clinical implications: These results confirm the central role of IL-1β in FCAS and support the use of IL-1 targeted therapy in these patients. [Copyright &y& Elsevier]
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- 2007
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21. Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity.
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Liu, George Y., Essex, Anthony, Buchanan, John T., Datta, Vivekanand, Hoffman, Hal M., Bastian, John F., Fierer, Joshua, and Nizet, Victor
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STAPHYLOCOCCUS aureus ,NEUTROPHILS ,MICROBIAL virulence ,ANTIOXIDANTS ,CAROTENOIDS ,NAD (Coenzyme) ,STREPTOCOCCUS pyogenes ,ANTIBIOTICS - Abstract
Golden color imparted by carotenoid pigments is the eponymous feature of the human pathogen Staphylococcus aureus. Here we demonstrate a role of this hallmark phenotype in virulence. Compared with the wild-type (WT) bacterium, a S. aureus mutant with disrupted carotenoid biosynthesis is more susceptible to oxidant killing, has impaired neutrophil survival, and is less pathogenic in a mouse subcutaneous abscess model. The survival advantage of WT S. aureus over the carotenoid-deficient mutant is lost upon inhibition of neutrophil oxidative burst or in human or murine nicotinamide adenine dinucleotide phosphate oxidase-deficient hosts. Conversely, heterologous expression of the S. aureus carotenoid in the nonpigmented Streptococcus pyogenes confers enhanced oxidant and neutrophil resistance and increased animal virulence. Blocking S. aureus carotenogenesis increases oxidant sensitivity and decreases whole-blood survival, suggesting a novel target for antibiotic therapy. [ABSTRACT FROM AUTHOR]
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- 2005
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22. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist.
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Hoffman, Hal M, Rosengren, Sanna, Boyle, David L, Cho, Jae Y, Nayar, Jyothi, Mueller, James L, Anderson, Justin P, Wanderer, Alan A, and Firestein, Gary S
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Background Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant disorder characterised by recurrent episodes of rash, arthralgia, and fever after cold exposure. The genetic basis of this disease has been elucidated. Cryopyrin, the protein that is altered in FCAS, is one of the adaptor proteins that activate caspase 1, resulting in release of interleukin 1.Methods An experimental cold challenge protocol was developed to study the acute inflammatory mechanisms occurring after a general cold exposure in FCAS patients and to investigate the effects of pretreatment with an antagonist of interleukin 1 receptor (IL-1Ra). ELISA, real-time PCR, and immunohistochemistry were used to measure cytokine responses.Findings After cold challenge, untreated patients with FCAS developed rash, fever, and arthralgias within 1–4 h. Significant increases in serum concentrations of interleukin 6 and white-blood-cell counts were seen 4–8 h after cold challenge. Serum concentrations of interleukin 1 and cytokine mRNA in peripheral-blood leucocytes were not raised, but amounts of interleukin 1 protein and mRNA were high in affected skin. IL-1Ra administered before cold challenge blocked symptoms and increases in white-blood-cell counts and serum interleukin 6.Interpretation The ability of IL-1Ra to prevent the clinical features and haematological and biochemical changes in patients with FCAS indicates a central role for interleukin 1β in this disorder. Involvement of cryopyrin in activation of caspase 1 and NF-κB signalling suggests that it might have a role in many chronic inflammatory diseases.Relevance to practice These findings support a new therapy for a disorder with no previously known acceptable treatment. They also offer insights into the role of interleukin 1β in more common inflammatory diseases. [Copyright &y& Elsevier]
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- 2004
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23. From NAFLD to NASH to cirrhosis—new insights into disease mechanisms
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Wree, Alexander, Broderick, Lori, Canbay, Ali, Hoffman, Hal M., and Feldstein, Ariel E.
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NAFLD has evolved as a serious public health problem in the USA and around the world. In fact, NASH—the most serious form of NAFLD—is predicted to become the leading cause of liver transplantation in the USA by the year 2020. The pathogenesis of NAFLD and NASH, in particular the mechanisms responsible for liver injury and fibrosis, is the result of a complex interplay between host and environmental factors, and is at the centre of intense investigation. In this Review, we focus on recently uncovered aspects of the genetic, biochemical, immunological and molecular events that are responsible for the development and progression of this highly prevalent and potentially serious disease. These studies bring new insight into this complex disorder and have led to the development of novel therapeutic and diagnostic strategies that might enable a personalized approach in the management of this disease.
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- 2013
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24. Autoinflammation: translating mechanism to therapy
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Doherty, Taylor A., Brydges, Susannah D., and Hoffman, Hal M.
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Review discusses autoinflammatory diseases as a new classification of immune disorders due to dysregulated innate immunity yet sensitive to targeted cytokine therapy. Autoinflammatory syndromes are a clinically heterogeneous collection of diseases characterized by dysregulation of the innate immune system. The hereditary recurrent fever disorders were the first to be defined as autoinflammatory. Several of the responsible genes are now known to encode proteins forming multimeric complexes called inflammasomes, which are intracellular “danger sensors” that respond to a variety of different signals by activating caspase‐1, responsible for cleavage and subsequent release of bioactive IL‐1β. This discovery of the causative link between autoinflammation and IL‐1β maturation has led to a significantly improved understanding of the mechanisms of innate immunity, as well as life‐altering treatments for patients. Targeting IL‐1β for the treatment of autoinflammatory syndromes is an excellent example of the power of translational research. Given the central role of inflammation in many complex multigenic diseases, these treatments may benefit larger numbers of patients in the future. Here, we review current treatment strategies of autoinflammatory diseases with a focus on IL‐1 antagonism.
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- 2011
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25. Recurrent febrile syndromes—what a rheumatologist needs to know
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Hoffman, Hal M. and Simon, Anna
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Rheumatologists are likely to be asked to evaluate patients with recurrent febrile syndromes, so it is important that they are familiar with the clinical and diagnostic features, pathophysiology and therapeutic options for these rare autoinflammatory disorders. These syndromes are all characterized by recurrent episodes of fever and systemic inflammation; however, some syndromes have unique historical and physical features that can help with making a diagnosis. The primary associated morbidity is systemic amyloidosis, usually with renal involvement. Diagnostic testing is mostly limited to genetic testing. NSAIDs, colchicine and corticosteroids have roles in the treatment of some of these disorders, but biologic drugs that target interleukin-1ß are emerging as consistently effective therapies.
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- 2009
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26. Rilonacept for the treatment of cryopyrin-associated periodic syndromes (CAPS)
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Hoffman, Hal M
- Abstract
Background: Cryopyrin-associated periodic syndromes (CAPS) encompass a group of rare inherited, autoinflammatory disorders that represent a spectrum of one disease with varying degrees of severity. Until recently, there was no effective treatment for CAPS, but identification of the genetic basis of CAPS highlighted the pathogenic role of IL-1β. Objectives: Rilonacept is a recently FDA approved biologic therapy for CAPS with high affinity for IL-1β. Limited pharmacological data has been reported to date. Methods: A review of the phamacokinetics and pharmacodynamics data as well as the results of a pilot study and Phase III placebo-controlled trials of rilonacept in CAPS. Unpublished data on an open-label extension study in adult and pediatric subjects is also reviewed. Results: Rilonacept produced rapid and profound improvements in symptoms and also reduced high-sesitivity C-reactive protein levels and normalized elevated serum amyloid A concentrations, an important risk factor for amyloidosis. The primary adverse events were injection- site reactions and upper respiratory tract infections. Conclusion: Rilonacept, the only IL-1 Trap, is the first of many novel IL-1-targeted therapies being developed. In a very short time it has changed the lives of CAPS patients.
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- 2009
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27. Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome
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Stackowicz, Julien, Gaudenzio, Nicolas, Serhan, Nadine, Conde, Eva, Godon, Ophélie, Marichal, Thomas, Starkl, Philipp, Balbino, Bianca, Roers, Axel, Bruhns, Pierre, Jönsson, Friederike, Moguelet, Philippe, Georgin-Lavialle, Sophie, Broderick, Lori, Hoffman, Hal M., Galli, Stephen J., and Reber, Laurent L.
- Abstract
Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as “cryopyrin-associated periodic syndromes” (CAPS). Treatment of CAPS patients with IL-1–targeted therapies is effective, confirming a central pathogenic role for IL-1β. However, the specific myeloid cell population(s) exhibiting inflammasome activity and sustained IL-1β production in CAPS remains elusive. Previous reports suggested an important role for mast cells (MCs) in this process. Here, we report that, in mice, gain-of-function mutations in Nlrp3 restricted to neutrophils, and to a lesser extent macrophages/dendritic cells, but not MCs, are sufficient to trigger severe CAPS. Furthermore, in patients with clinically established CAPS, we show that skin-infiltrating neutrophils represent a substantial biological source of IL-1β. Together, our data indicate that neutrophils, rather than MCs, can represent the main cellular drivers of CAPS pathology.
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- 2021
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28. MDP‐induced interleukin‐1β processing requires Nod2 and CIAS1/NALP3
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Pan, Qilin, Mathison, John, Fearns, Colleen, Kravchenko, Vladimir V., Da Silva Correia, Jean, Hoffman, Hal M., Kobayashi, Koichi S., Bertin, John, Grant, Ethan P., Coyle, Anthony J., Sutterwala, Fayyaz S., Ogura, Yasunori, Flavell, Richard A., and Ulevitch, Richard J.
- Abstract
Nucleotide‐binding oligomerization domain (Nod)2 is a sensor of muramyl dipeptides (MDP) derived from bacterial peptidoglycan. Nod2 also plays a role in some autoinflammatory diseases. Cold‐induced autoinflammatory syndrome 1 (CIAS1)/NACHT domain, leucine‐rich repeat, and pyrin domain‐containing protein 3 (NALP3) has been suggested to be sufficient for MDP‐dependent release of mature IL‐1β, but the role of Nod2 in this process is unclear. Using mice bearing selective gene deletions, we provide in vitro and in vivo data showing that MDP‐induced IL‐1β release requires Nod2 and CIAS1/NALP3 as well as receptor‐interacting protein‐2 (Rip2), apoptosis‐associated speck‐like protein containing a caspase activation and recruitment domain (ASC), and caspase‐1. In contrast, MDP‐dependent IL‐6 production only requires Nod2 and Rip2. Together, our data provide a new understanding of this important pathway of IL‐1β production and allow for further studies of the role of these proteins within the broader context of inflammatory disease.
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- 2007
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29. A large kindred with familial cold autoinflammatory syndrome
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Johnstone, Reid F., Dolen, William K., and Hoffman, Hal M.
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Familial cold autoinflammatory syndrome (FCAS), formerly known as familial cold urticaria, is a rare condition characterized by fever, rash, and arthralgias elicited by exposure to cold. Recently, mutations responsible for FCAS were identified in a novel gene (CIAS1), making it possible to confirm the diagnosis in most patients.
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- 2003
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30. Familial cold autoinflammatory syndrome: Phenotype and genotype of an autosomal dominant periodic fever
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Hoffman, Hal M., Wanderer, Alan A., and Broide, David H.
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Background:Familial cold autoinflammatory syndrome (FCAS), commonly known as familial cold urticaria, is a rare autosomal dominant inflammatory disorder with episodic symptoms precipitated by exposure to cold. Objective:The goal of this study was to formulate clinical diagnostic criteria for FCAS in a large cohort in whom the diagnosis of FCAS was supported by genetic linkage to chromosome 1q44. Methods:We assessed 45 affected and 68 unaffected members from 6 American families. DNA analysis was performed to confirm linkage to chromosome 1q44. Clinical characteristics were determined by means of analysis of detailed questionnaires and medical histories. Results:Pedigree and genetic analyses confirmed autosomal dominant transmission and linkage to chromosome 1q44 in all families. The most consistent symptoms during attacks were rash (100%), fever (93%), arthralgia (96%), and conjunctivitis (84%). Age of onset was within the first 6 months of life in 95% of affected subjects. The average delay between cold exposure and onset of symptoms was 2.5 hours, and the average duration of an episode was 12 hours. Renal disease with amyloidosis occurs infrequently in FCAS (2%). Conclusion:The most consistent clinical characteristics of FCAS that discriminate it from other periodic fevers are association with cold exposure, conjunctivitis, age of onset, duration of episodes, and an autosomal dominant inheritance pattern. On the basis of the analysis of genotype and phenotype of FCAS, we formulated clinical diagnostic criteria that can be used to distinguish FCAS from other hereditary periodic fever syndromes. (J Allergy Clin Immunol 2001;108:615-20.)
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- 2001
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31. Pediatric recurrent fever and autoinflammation from the perspective of an allergist/immunologist.
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Broderick, Lori and Hoffman, Hal M.
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Autoinflammatory diseases are monogenic and polygenic disorders due to dysregulation of the innate immune system. The inherited conditions have been clustered with primary immunodeficiencies in the latest practice parameters; however, these diseases have unique clinical presentations, genetics, and available therapies. Given the presentation of fevers, rashes, and mucosal symptoms observed in many of these syndromes, patients are likely to present to an allergist/immunologist. Although there has been attention in the literature to diagnosis and treatment of rare, genetically defined autoinflammatory disorders, physicians are challenged by increasing numbers of patients with intermittent or periodic fevers who face unnecessary morbidities due to a lack of a diagnosis. The broad differential of diseases presenting with fever includes autoinflammatory syndromes, infections associated with immunodeficiency and/or allergies complicated by infection, and less commonly, autoimmune disorders or malignancy. To address this challenge, we review the history of the medical approach to fever, current diagnostic paradigms, and controversies in management. We describe the spectrum of disorders referred to a recurrent fever disorders clinic established in an Allergy/Immunology division at a tertiary pediatric care center. Finally, we provide practical recommendations including historical features and initial laboratory investigations that can help clinicians appropriately manage these patients. [ABSTRACT FROM AUTHOR]
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- 2020
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32. Author Correction: A guiding map for inflammation
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Netea, Mihai G., Balkwill, Frances, Chonchol, Michel, Cominelli, Fabio, Donath, Marc Y., Giamarellos-Bourboulis, Evangelos J., Golenbock, Douglas, Gresnigt, Mark S., Heneka, Michael T., Hoffman, Hal M., Hotchkiss, Richard, Joosten, Leo A. B., Kastner, Daniel L., Korte, Martin, Latz, Eicke, Libby, Peter, Mandrup-Poulsen, Thomas, Mantovani, Alberto, Mills, Kingston H. G., Nowak, Kristen L., O’Neill, Luke A., Pickkers, Peter, van der Poll, Tom, Ridker, Paul M., Schalkwijk, Joost, Schwartz, David A., Siegmund, Britta, Steer, Clifford J., Tilg, Herbert, van der Meer, Jos W. M., van de Veerdonk, Frank L., and Dinarello, Charles A.
- Abstract
A Correction to this paper has been published: https://doi.org/10.1038/ni.3790
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- 2021
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33. Choline Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production.
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Sanchez-Lopez, Elsa, Zhong, Zhenyu, Stubelius, Alexandra, Sweeney, Shannon R., Booshehri, Laela M., Antonucci, Laura, Liu-Bryan, Ru, Lodi, Alessia, Terkeltaub, Robert, Lacal, Juan Carlos, Murphy, Anne N., Hoffman, Hal M., Tiziani, Stefano, Guma, Monica, and Karin, Michael
- Abstract
Choline is a vitamin-like nutrient that is taken up via specific transporters and metabolized by choline kinase, which converts it to phosphocholine needed for de novo synthesis of phosphatidylcholine (PC), the main phospholipid of cellular membranes. We found that Toll-like receptor (TLR) activation enhances choline uptake by macrophages and microglia through induction of the choline transporter CTL1. Inhibition of CTL1 expression or choline phosphorylation attenuated NLRP3 inflammasome activation and IL-1β and IL-18 production in stimulated macrophages. Mechanistically, reduced choline uptake altered mitochondrial lipid profile, attenuated mitochondrial ATP synthesis, and activated the energy sensor AMP-activated protein kinase (AMPK). By potentiating mitochondrial recruitment of DRP1, AMPK stimulates mitophagy, which contributes to termination of NLRP3 inflammasome activation. Correspondingly, choline kinase inhibitors ameliorated acute and chronic models of IL-1β-dependent inflammation. • LPS stimulates choline uptake and phosphorylation via CTL1 induction • Impaired choline uptake or phosphorylation reduces mitochondrial ATP synthesis • Reduced ATP synthesis leads to AMPK activation and induction of mitophagy • By causing mitophagy, ChoKα inhibition prevents NLRP3-dependent inflammation Sanchez-Lopez et al. have found that inhibition of choline uptake and phosphorylation in activated macrophages prevent NLRP3 inflammasome activation and IL-1β and IL-18 production. Inhibition of choline incorporation into phosphatidylcholine in the mitochondrial membranes and decreased ATP synthase activity lead to enhanced AMPK-dependent mitophagy that prevents acute and chronic inflammation. [ABSTRACT FROM AUTHOR]
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- 2019
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34. Transplantation: Outcomes of prenatal immunosuppression
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Mak, Robert H. and Hoffman, Hal M.
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- 2015
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35. Anakinra for the treatment of neonatal-onset multisystem inflammatory disease
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Hoffman, Hal M and Firestein, Gary S
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- 2006
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36. A Group A Streptococcus ADP-Ribosyltransferase Toxin Stimulates a Protective Interleukin 1β-Dependent Macrophage Immune Response
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Lin, Ann E., Beasley, Federico C., Keller, Nadia, Hollands, Andrew, Urbano, Rodolfo, Troemel, Emily R., Hoffman, Hal M., and Nizet, Victor
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ABSTRACTThe M1T1 clone of group A Streptococcus (GAS) is associated with severe invasive infections, including necrotizing fasciitis and septicemia. During invasive M1T1 GAS disease, mutations in the covRSregulatory system led to upregulation of an ADP-ribosyltransferase, SpyA. Surprisingly, a GAS ΔspyAmutant was resistant to killing by macrophages and caused higher mortality with impaired bacterial clearance in a mouse intravenous challenge model. GAS expression of SpyA triggered macrophage cell death in association with caspase-1-dependent interleukin 1β (IL-1β) production, and differences between wild-type (WT) and ΔspyAGAS macrophage survival levels were lost in cells lacking caspase-1, NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), or pro-IL-1β. Similar in vitrofindings were identified in macrophage studies performed with pseudomonal exotoxin A, another ADP-ribosylating toxin. Thus, SpyA triggers caspase-1-dependent inflammatory cell death in macrophages, revealing a toxin-triggered IL-1β-dependent innate immune response pathway critical in defense against invasive bacterial infection.IMPORTANCEGroup A Streptococcus (GAS) is a leading human pathogen capable of producing invasive infections even in healthy individuals. GAS bacteria produce a toxin called SpyA that modifies host proteins through a process called ADP ribosylation. We describe how macrophages, frontline defenders of the host innate immune system, respond to SpyA by undergoing a specialized form of cell death in which they are activated to release the proinflammatory cytokine molecule interleukin 1β (IL-1β). Release of IL-1β activates host immune cell clearance of GAS, as we demonstrated in tissue culture models of macrophage bacterial killing and in vivomouse infectious-challenge experiments. Similar macrophage responses to a related toxin of Pseudomonasbacteria were also shown. Thus, macrophages recognize certain bacterial toxins to activate a protective immune response in the host.
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- 2015
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37. A Transforming Growth Factor Beta-1 Gene Single Nucleotide Polymorphism May Influence Phenotype in Pediatric Eosinophilic Esophagitis.
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Anilkumar, Arjun Andrew, Newbury, Robert, Dohil, Ranjan, Mueller, James, Hoffman, Hal M., Broide, David H., and Aceves, Seema Sharma
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- 2013
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38. Genetics of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome.
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Broderick, Lori, Carvalho, Daniela, Magit, Anthony, Jiang, Wen, Leuin, Shelby, Bothwell, Marcella, Kearns, Donald, Pransky, Seth, and Hoffman, Hal M.
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- 2013
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39. Mo1982 Epcam Deficient Mice Demonstrate Intestinal Permeability Defects.
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Sivagnanam, Mamata, Mueller, James L., McGeough, Matthew D., Pena, Carla, and Hoffman, Hal M.
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- 2012
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40. Epcam Deficient Mice Show Significant Morbidity and Pathology Resembling Congenital Tufting Enteropathy.
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Sivagnanam, Mamata, Mueller, James L., Mcgeough, Matthew D., Pena, Carla, and Hoffman, Hal M.
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- 2011
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41. Possible Cold Autoinflammatory Syndrome
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Lieberman, Phillip and Hoffman, Hal M.
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- 2014
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