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Guillet S, Lazarov T, Jordan N, Boisson B, Tello M, Craddock B, Zhou T, Nishi C, Bareja R, Yang H, Rieux-Laucat F, Fregel Lorenzo RI, Dyall SD, Isenberg D, D'Cruz D, Lachmann N, Elemento O, Viale A, Socci ND, Abel L, Nagata S, Huse M, Miller WT, Casanova JL, Geissmann F. ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis. eLife 2024; 13:RP96085. [PMID: 39570652 PMCID: PMC11581429 DOI: 10.7554/elife.96085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients' ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.
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Affiliation(s)
- Stephanie Guillet
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
- Ecole doctorale Bio Sorbonne Paris Cité, Université Paris Descartes-Sorbonne Paris CitéParisFrance
| | - Tomi Lazarov
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical SciencesNew YorkUnited States
| | - Natasha Jordan
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ HospitalsLondonUnited Kingdom
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityNew YorkUnited States
- University of Paris Cité, Imagine InstituteParisFrance
| | - Maria Tello
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - Barbara Craddock
- SKI Stem Cell Research Core, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - Ting Zhou
- SKI Stem Cell Research Core, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - Chihiro Nishi
- Laboratory of Biochemistry & Immunology, World Premier International Immunology Frontier Research Center, Osaka UniversityOsakaJapan
| | - Rohan Bareja
- Cary and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Meyer Cancer Center Weill Cornell Medical CollegeNew YorkUnited States
| | - Hairu Yang
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | | | | | - Sabrina D Dyall
- Department of Biosciences and Ocean Studies, Faculty of Science, University of MauritiusReduitMauritius
| | - David Isenberg
- Bioinformatics Core, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - David D'Cruz
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ HospitalsLondonUnited Kingdom
| | - Nico Lachmann
- Centre for Rheumatology, Division of Medicine, University College London, The Rayne BuildingLondonUnited Kingdom
| | - Olivier Elemento
- Cary and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Meyer Cancer Center Weill Cornell Medical CollegeNew YorkUnited States
| | - Agnes Viale
- Institute of Experimental Hematology, REBIRTH Cluster of Excellence, Hannover Medical SchoolHannoverGermany
| | - Nicholas D Socci
- Institute of Experimental Hematology, REBIRTH Cluster of Excellence, Hannover Medical SchoolHannoverGermany
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - Laurent Abel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityNew YorkUnited States
- University of Paris Cité, Imagine InstituteParisFrance
| | - Shigekazu Nagata
- Laboratory of Biochemistry & Immunology, World Premier International Immunology Frontier Research Center, Osaka UniversityOsakaJapan
| | - Morgan Huse
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - W Todd Miller
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
- Department of Physiology and Biophysics, Stony Brook University School of MedicineStony BrookUnited States
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityNew YorkUnited States
- University of Paris Cité, Imagine InstituteParisFrance
- Howard Hughes Medical InstituteNew YorkUnited States
- Lab of Human Genetics of Infectious Diseases, INSERM, Necker Hospital for Sick ChildrenParisFrance
- Department of Pediatrics, Necker Hospital for Sick ChildrenParisFrance
| | - Frédéric Geissmann
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical SciencesNew YorkUnited States
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ HospitalsLondonUnited Kingdom
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2
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Guillet S, Lazarov T, Jordan N, Boisson B, Tello M, Craddock B, Zhou T, Nishi C, Bareja R, Yang H, Rieux-Laucat F, Lorenzo RIF, Dyall SD, Isenberg D, D’Cruz D, Lachmann N, Elemento O, Viale A, Socci ND, Abel L, Nagata S, Huse M, Miller WT, Casanova JL, Geissmann F. ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.02.15.24302255. [PMID: 38883731 PMCID: PMC11177913 DOI: 10.1101/2024.02.15.24302255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Abstract
Systemic Lupus Erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with systemic lupus erythematosus (SLE) we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, non-receptor tyrosine kinases (NRTKs) regulate activation, migration, and proliferation of immune cells. We found that the patients' ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced Pluripotent Stem Cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.
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Affiliation(s)
- Stephanie Guillet
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
- Ecole doctorale Bio Sorbonne Paris Cité, Université Paris Descartes-Sorbonne Paris Cité.Paris, France
| | - Tomi Lazarov
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of MedicalSciences, New York, New York 10065, USA
| | - Natasha Jordan
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ Hospitals, London SE1 1UL, UK
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA
- University of Paris Cité, Imagine Institute, Paris, France
| | - Maria Tello
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Barbara Craddock
- Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, NY, 11794-8661
| | - Ting Zhou
- SKI Stem Cell Research Core, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Chihiro Nishi
- Laboratory of Biochemistry & Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871
| | - Rohan Bareja
- Cary and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Meyer Cancer Center Weill Cornell Medical College, New York, New York 10065, USA
| | - Hairu Yang
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | | | | | - Sabrina D. Dyall
- Department of Biosciences and Ocean Studies, Faculty of Science, University of Mauritius, Reduit, Mauritius
| | - David Isenberg
- Centre for Rheumatology, Division of Medicine, University College London, The Rayne Building, University College London
| | - David D’Cruz
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ Hospitals, London SE1 1UL, UK
| | - Nico Lachmann
- Institute of Experimental Hematology, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany
| | - Olivier Elemento
- Cary and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Meyer Cancer Center Weill Cornell Medical College, New York, New York 10065, USA
| | - Agnes Viale
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Nicholas D. Socci
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
- Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Laurent Abel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA
- University of Paris Cité, Imagine Institute, Paris, France
| | - Shigekazu Nagata
- Laboratory of Biochemistry & Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871
| | - Morgan Huse
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - W. Todd Miller
- Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, NY, 11794-8661
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA
- University of Paris Cité, Imagine Institute, Paris, France
- Howard Hughes Medical Institute, New York, 10065 NY, USA
- Lab of Human Genetics of Infectious Diseases, INSERM, Necker Hospital for Sick Children, Paris, France, EU
- Department of Pediatrics, Necker Hospital for Sick Children, Paris, France, EU
| | - Frederic Geissmann
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of MedicalSciences, New York, New York 10065, USA
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ Hospitals, London SE1 1UL, UK
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Oprea Y, Kody S, Shakshouk H, Greiling TM, Anstey KM, Ortega-Loayza AG. What can inherited immunodeficiencies reveal about pyoderma gangrenosum? Exp Dermatol 2024; 33:e14954. [PMID: 37846943 PMCID: PMC10841371 DOI: 10.1111/exd.14954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 09/14/2023] [Accepted: 10/05/2023] [Indexed: 10/18/2023]
Abstract
Pyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis that is occasionally associated with primary immunodeficiency. Though contributions from dysregulation of the innate immune system, neutrophil dysfunction and genetic predisposition have been postulated, the precise pathogenesis of PG has not yet been elucidated. This article reviews reported cases of coexisting PG and primary immunodeficiency in order to gain insight into the complex pathophysiology of PG. Our findings suggest that variations in genes such as RAG1, ITGB2, IRF2BP2 and NFκB1 might play a role in genetically predisposing patients to develop PG. These studies support the feasibility of the role of somatic gene variation in the pathogenesis of PG which warrants further exploration to guide targeted therapeutics.
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Affiliation(s)
- Yasmine Oprea
- Albert Einstein College of Medicine, Bronx, New York, USA
| | - Shannon Kody
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon, USA
| | - Hadir Shakshouk
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon, USA
- Department of Dermatology and Andrology, Alexandria Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Teri M Greiling
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon, USA
| | - Karen M Anstey
- Department of Medicine, Section of Allergy and Clinical Immunology, Oregon Health & Science University, Portland, Oregon, USA
| | - Alex G. Ortega-Loayza
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon, USA
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4
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Kim J, Lee JY, Kim HG, Kwak MW, Kang TH. Fc Receptor Variants and Disease: A Crucial Factor to Consider in the Antibody Therapeutics in Clinic. Int J Mol Sci 2021; 22:9489. [PMID: 34502398 PMCID: PMC8431278 DOI: 10.3390/ijms22179489] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/27/2021] [Accepted: 08/28/2021] [Indexed: 12/19/2022] Open
Abstract
The fragment crystallizable (Fc) domain of antibodies is responsible for their protective function and long-lasting serum half-life via Fc-mediated effector function, transcytosis, and recycling through its interaction with Fc receptors (FcRs) expressed on various immune leukocytes, epithelial, and endothelial cells. Therefore, the Fc-FcRs interaction is a control point of both endogenous and therapeutic antibody function. There are a number of reported genetic variants of FcRs, which include polymorphisms in (i) extracellular domain of FcRs, which change their affinities to Fc domain of antibodies; (ii) both cytoplasmic and intracellular domain, which alters the extent of signal transduction; and (iii) the promoter region of the FcRs gene, which affects the expression level of FcRs, thus being associated with the pathogenesis of disease indications. In this review, we firstly describe the correlation between the genetic variants of FcRs and immunological disorders by individual differences in the extent of FcRs-mediated regulations. Secondly, we discuss the influence of the genetic variants of FcRs on the susceptibility to infectious diseases or cancer in the perspective of FcRs-induced effector functions. Overall, we concluded that the genetic variants of FcRs are one of the key elements in the design of antibody therapeutics due to their variety of clinical outcomes among individuals.
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Affiliation(s)
- Jin Kim
- Department of Interdisciplinary Program for Bio-Health Convergence, Kookmin University, Seoul 02707, Korea;
| | - Ji Young Lee
- Department of Chemistry, Kookmin University, Seoul 02707, Korea;
| | - Han Gil Kim
- Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Korea; (H.G.K.); (M.W.K.)
| | - Min Woo Kwak
- Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Korea; (H.G.K.); (M.W.K.)
| | - Tae Hyun Kang
- Department of Interdisciplinary Program for Bio-Health Convergence, Kookmin University, Seoul 02707, Korea;
- Department of Chemistry, Kookmin University, Seoul 02707, Korea;
- Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Korea; (H.G.K.); (M.W.K.)
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5
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Kelsen JR, Sullivan KE, Rabizadeh S, Singh N, Snapper S, Elkadri A, Grossman AB. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Position Paper on the Evaluation and Management for Patients With Very Early-onset Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2020; 70:389-403. [PMID: 32079889 PMCID: PMC12024488 DOI: 10.1097/mpg.0000000000002567] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The rate of pediatric inflammatory bowel disease (IBD) has been increasing over the last decade and this increase has occurred most rapidly in the youngest children diagnosed <6 years, known as very early-onset inflammatory bowel disease (VEO-IBD). These children can present with more extensive and severe disease than older children and adults. The contribution of host genetics in this population is underscored by the young age of onset and the distinct, aggressive phenotype. In fact, monogenic defects, often involving primary immunodeficiency genes, have been identified in children with VEO-IBD and have led to targeted and life-saving therapy. This position paper will discuss the phenotype of VEO-IBD and outline the approach and evaluation for these children and what factors should trigger concern for an underlying immunodeficiency. We will then review the immunological assays and genetic studies that can facilitate the identification of the underlying diagnosis in patients with VEO-IBD and how this evaluation may lead to directed therapies. The position paper will also aid the pediatric gastroenterologist in recognizing when a patient should be referred to a center specializing in the care of these patients. These guidelines are intended for pediatricians, allied health professionals caring for children, pediatric gastroenterologists, pediatric pathologists, and immunologists.
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Affiliation(s)
| | - Kathleen E. Sullivan
- Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Shervin Rabizadeh
- Division of Gastroenterology, Hepatology, and Nutrition, Cedar-Sinai Medical Center, Los Angeles, CA
| | - Namita Singh
- Division of Gastroenterology, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WA
| | - Scott Snapper
- Division of Gastroenterology, Hepatology, and Nutrition, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School
- Division of Gastroenterology, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA
| | - Abdul Elkadri
- Division of Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, WI
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Abstract
Primary disorders of neutrophil function result from impairment in neutrophil responses that are critical for host defense. This chapter summarizes inherited disorders of neutrophils that cause defects in neutrophil adhesion, migration, and oxidative killing. These include the leukocyte adhesion deficiencies, actin defects and other disorders of chemotaxis, hyperimmunoglobulin E syndrome, Chédiak-Higashi Syndrome, neutrophil specific granule deficiency, chronic granulomatous disease, and myeloperoxidase deficiency. Diagnostic tests and treatment approaches are also summarized for each neutrophil disorder.
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7
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Huang J, Wang Q, Hu Y, Qi Z, Lin Z, Ying W, Zhou M. Proteomic Profiling for Serum Biomarkers in Mice Exposed to Ionizing Radiation. Dose Response 2019; 17:1559325819894794. [PMID: 31853238 PMCID: PMC6909274 DOI: 10.1177/1559325819894794] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 10/30/2019] [Accepted: 11/06/2019] [Indexed: 12/11/2022] Open
Abstract
In response to large-scale radiological incidents, rapid, accurate, and early triage biodosimeters are urgently required. In this study, we investigated candidate radiation-responsive biomarkers using proteomics approaches in mouse models. A total of 452 dysregulated proteins were identified in the serum samples of mice exposed to 0, 2, 5.5, 7, and 8 Gy at 6, 24, and 72 hours postirradiation. Ninety-eight proteins, including 46 at 6 hours, 36 at 24 hours, and 36 at 72 hours, were identified as radiation-responsive proteins (RRPs). Gene Ontology analysis showed the RRPs were involved in proteolysis, extracellular space, hydrolase activity, and carbohydrate binding. Kyoto Encyclopedia of Genes and Genome enrichment showed the RRPs were regulated in "the pentose phosphate pathway," "the proteasome," and "AGE-RAGE signaling in diabetic complications." There were 3 proteins changed and overlapped at all the 3 time points, 8 proteins changed at 6 and 24 hours, 4 proteins changed at 24 and 72hours, and 2 proteins changed at both 6 and 72 hours. Of these proteins, ORM2, HP, SAA1, SAA2, MBL2, COL1A1, and APCS were identified as candidate biomarkers for biodosimeter-based diagnosis through Pearson correlation analysis.
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Affiliation(s)
- Jinfeng Huang
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People’s Republic of China
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, People’s Republic of China
| | - Qi Wang
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, People’s Republic of China
| | - Yingchun Hu
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, People’s Republic of China
| | - Zhenhua Qi
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, People’s Republic of China
| | - Zhongwu Lin
- Science Research Management Department of the Academy of Military Sciences, Beijing, People’s Republic of China
| | - Wantao Ying
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, People’s Republic of China
| | - Meijuan Zhou
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People’s Republic of China
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8
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Yonkof JR, Gupta A, Fu P, Garabedian E, Dalal J. Role of Allogeneic Hematopoietic Stem Cell Transplant for Chronic Granulomatous Disease (CGD): a Report of the United States Immunodeficiency Network. J Clin Immunol 2019; 39:448-458. [DOI: 10.1007/s10875-019-00635-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 04/21/2019] [Indexed: 12/16/2022]
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9
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Dinauer MC. Inflammatory consequences of inherited disorders affecting neutrophil function. Blood 2019; 133:2130-2139. [PMID: 30898864 PMCID: PMC6524563 DOI: 10.1182/blood-2018-11-844563] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 01/13/2019] [Indexed: 12/13/2022] Open
Abstract
Primary immunodeficiencies affecting the function of neutrophils and other phagocytic leukocytes are notable for an increased susceptibility to bacterial and fungal infections as a result of impaired leukocyte recruitment, ingestion, and/or killing of microbes. The underlying molecular defects can also impact other innate immune responses to infectious and inflammatory stimuli, leading to inflammatory and autoimmune complications that are not always directly related to infection. This review will provide an update on congenital disorders affecting neutrophil function in which a combination of host defense and inflammatory complications are prominent, including nicotinamide dinucleotide phosphate oxidase defects in chronic granulomatous disease and β2 integrin defects in leukocyte adhesion deficiency.
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Affiliation(s)
- Mary C Dinauer
- Department of Pediatrics and Department of Pathology & Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO
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10
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Abstract
PURPOSE OF REVIEW Inflammatory bowel disease (IBD) is a multifactorial disease caused by dysregulated immune responses to commensal or pathogenic intestinal microbes, resulting in chronic intestinal inflammation. However, a subset of patients with IBD diagnosed <6 years of age, known as very early-onset (VEO)-IBD, can be phenotypically and genetically distinct from older onset IBD. We aim to review the clinical presentation of children with VEO-IBD and recent discoveries that point to the underlying genomic and immunologic drivers of disease, and the significant impact on our therapeutic decisions. RECENT FINDINGS VEO-IBD is increasing in incidence and is associated with more severe disease, aggressive progression, and poor response to most conventional therapies. This article will review some of the genetic findings in this population and the subsequent impact on therapy, with targeted approaches. SUMMARY Children with VEO-IBD may present with a different phenotype and more severe disease than older children and adults. An integrated approach combining genetics, immunology, and traditional IBD evaluations can lead to the identification of causal defects that directly impact management. These strategies can also be employed in older onset refractory IBD.
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Affiliation(s)
- Maire A Conrad
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia Philadelphia, Pennsylvania,Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Judith R Kelsen
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia Philadelphia, Pennsylvania,Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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11
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Cachat J, Deffert C, Alessandrini M, Roux-Lombard P, Le Gouellec A, Stasia MJ, Hugues S, Krause KH. Altered Humoral Immune Responses and IgG Subtypes in NOX2-Deficient Mice and Patients: A Key Role for NOX2 in Antigen-Presenting Cells. Front Immunol 2018; 9:1555. [PMID: 30050527 PMCID: PMC6050363 DOI: 10.3389/fimmu.2018.01555] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 06/25/2018] [Indexed: 01/08/2023] Open
Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting from loss of function mutations in the reactive oxygen species generating phagocyte NADPH oxidase (NOX2). CGD patients are prone to infection, but also have an increased susceptibility to autoimmune diseases. The aim of this study was to investigate the role of NOX2 in the regulation of specific immunity. In both CGD patients and NOX2-deficient mice, we observed an alteration in the basal proportions of IgG subtypes. Upon immunization with curdlan-a dectin 1 agonist-NOX2-deficient mice showed increased production of IgG2c compared to controls, and restimulation of lymph node-derived cells led to increased production of IFNγ, but not IL-5, indicative hallmark of an enhanced Th1 response. T cell activation was increased in NOX2-deficient mice and a similar trend was observed in vitro when T cells were co-cultured with NOX2-deficient bone marrow-derived cells. In contrast, no difference in T cell activation was observed when NOX2-deficient T cells were co-cultured with wild-type BMDC. Following stimulation of NOX2-deficient dendritic cells (DCs), no difference in costimulatory molecules was observed, while there was an increase in the release of Th1-driving cytokines. In summary, both CGD patients and CGD mice have an altered IgG subtype distribution, which is associated with an increased IFNγ production. Thus, NOX2 within DCs appears to be an important regulator at the interface of innate and specific immunity, especially after activation of the dectin 1 pathway, limiting immune activation and the development of autoimmunity.
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Affiliation(s)
- Julien Cachat
- Department of Pathology and Immunology, Geneva University Hospitals (HUG) and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christine Deffert
- Division of Laboratory Medicine, Department of Genetic and Laboratory Medicine and Department of Medical Specialities, Geneva University Hospitals (HUG) and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Marco Alessandrini
- Department of Pathology and Immunology, Geneva University Hospitals (HUG) and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Pascale Roux-Lombard
- Division of Laboratory Medicine, Department of Genetic and Laboratory Medicine and Department of Medical Specialities, Geneva University Hospitals (HUG) and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Audrey Le Gouellec
- TheREx (Thérapeutique Recombinante Expérimentale), Laboratoire TIMC-IMAG, University Grenoble Alpes, CNRS, Grenoble, France.,Laboratoire BEP, Pôle Biologie, CHU Grenoble Alpes, Grenoble, France
| | - Marie-José Stasia
- TheREx (Thérapeutique Recombinante Expérimentale), Laboratoire TIMC-IMAG, University Grenoble Alpes, CNRS, Grenoble, France.,Laboratoire BEP, Pôle Biologie, CHU Grenoble Alpes, Grenoble, France
| | - Stéphanie Hugues
- Department of Pathology and Immunology, Geneva University Hospitals (HUG) and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Karl-Heinz Krause
- Department of Pathology and Immunology, Geneva University Hospitals (HUG) and Faculty of Medicine, University of Geneva, Geneva, Switzerland
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12
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Henrickson SE, Jongco AM, Thomsen KF, Garabedian EK, Thomsen IP. Noninfectious Manifestations and Complications of Chronic Granulomatous Disease. J Pediatric Infect Dis Soc 2018; 7:S18-S24. [PMID: 29746679 PMCID: PMC5946858 DOI: 10.1093/jpids/piy014] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Chronic granulomatous disease (CGD), a primary immunodeficiency characterized by a deficient neutrophil oxidative burst and the inadequate killing of microbes, is well known to cause a significantly increased risk of invasive infection. However, infectious complications are not the sole manifestations of CGD; substantial additional morbidity is driven by noninfectious complications also. These complications can include, for example, a wide range of inflammatory diseases that affect the gastrointestinal tract, lung, skin, and genitourinary tract and overt autoimmune disease. These diseases can occur at any age and are especially problematic in adolescents and adults with CGD. Many of these noninfectious complications present a highly challenging therapeutic conundrum, wherein immunosuppression must be balanced against an already markedly increased risk of invasive fungal and bacterial infections. In this review, the myriad noninfectious complications of CGD are discussed, as are important gaps in our understanding of these processes, which warrant further investigation.
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Affiliation(s)
- Sarah E Henrickson
- Division of Allergy and Immunology, Department of Pediatrics, Children’s Hospital of Philadelphia, Pennsylvania
| | - Artemio M Jongco
- Institute for Immunology, University of Pennsylvania, Philadelphia,Departments of Medicine and Pediatrics, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, New York
| | - Kelly F Thomsen
- Division of Gastroenterology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Elizabeth K Garabedian
- National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
| | - Isaac P Thomsen
- Division of Pediatric Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee,Correspondence: I. P. Thomsen, MD, MSCI, Division of Pediatric Infectious Diseases, Vanderbilt University School of Medicine, D-7235 MCN1161 21st Avenue South, Nashville, TN 37232-2581 ()
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13
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NADPH Oxidase Deficiency: A Multisystem Approach. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:4590127. [PMID: 29430280 PMCID: PMC5753020 DOI: 10.1155/2017/4590127] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 10/11/2017] [Accepted: 11/02/2017] [Indexed: 02/07/2023]
Abstract
The immune system is a complex system able to recognize a wide variety of host agents, through different biological processes. For example, controlled changes in the redox state are able to start different pathways in immune cells and are involved in the killing of microbes. The generation and release of ROS in the form of an “oxidative burst” represent the pivotal mechanism by which phagocytic cells are able to destroy pathogens. On the other hand, impaired oxidative balance is also implicated in the pathogenesis of inflammatory complications, which may affect the function of many body systems. NADPH oxidase (NOX) plays a pivotal role in the production of ROS, and the defect of its different subunits leads to the development of chronic granulomatous disease (CGD). The defect of the different NOX subunits in CGD affects different organs. In this context, this review will be focused on the description of the effect of NOX2 deficiency in different body systems. Moreover, we will also focus our attention on the novel insight in the pathogenesis of immunodeficiency and inflammation-related manifestations and on the protective role of NOX2 deficiency against the development of atherosclerosis.
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Abstract
PURPOSE OF REVIEW Inflammatory bowel disease (IBD) is a multifactorial disease caused by dysregulated immune responses to commensal or pathogenic intestinal microbes, resulting in chronic intestinal inflammation. Patients diagnosed with IBD occurring before the age of 5 are a unique population, known as very early onset (VEO)-IBD and can be phenotypically and genetically distinct from older-onset IBD. We aim to review the clinical presentation of children with VEO-IBD and recent discoveries that point to genomic drivers of disease that may impact our therapeutic decisions. RECENT FINDINGS VEO-IBD is increasing in incidence and is associated with more severe disease, aggressive progression and poor response to most conventional therapies. This article will review the advances in sequencing technology that have led to identification of novel gene variants associated with disease and potentially new targeted therapeutic options. SUMMARY Children with VEO-IBD may present with a different phenotype and more severe disease than older children and adults. Identification of the causal gene or pathways, these children may allow for true precision medicine with targeted therapy and improved disease course.
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15
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Pavkovic M, Petlichkovski A, Karanfilski O, Cevreska L, Stojanovic A. FC gamma receptor polymorphisms in patients with immune thrombocytopenia. ACTA ACUST UNITED AC 2017; 23:163-168. [PMID: 28942727 DOI: 10.1080/10245332.2017.1377902] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
INTRODUCTION Immune thrombocytopenia (ITP) is an autoimmune blood disease of unknown etiology. The aim of our study was to investigate a possible role of FCGR2A and FCGR3A polymorphisms in the development of primary ITP. METHODS We analyzed 125 adult patients with ITP and 120 healthy controls. Genotyping was performed by using PCR-RFLP methods. RESULTS Our results showed significantly higher frequency of high-affinity FCGR3A-158V allele in patients with ITP compared with control subjects (47.2% versus 37.5%; p = 0.037). We did not find significant differences in the genotype distribution or allele frequencies for FCGR2A-131H/R between patients and controls, p = 0.652 and p = 0.478. In the groups of patients with unresponsive and responsive ITP we found significantly different genotype distribution and allele frequencies for FCGR3A, p = 0.036 and p = 0.008 respectively. There was no significant difference in genotype and allele frequencies for FCGR2A between these two groups of patients. Our results confirmed that the combination of high-affinity FCGR2A-131H and FCGR3A-158V allele was more common in patients with ITP than in controls (55% versus 40%; p = 0.024). CONCLUSION Our results suggest possible role of FCGR3A polymorphism in the etiology, development and clinical outcome of ITP, but larger prospective studies are needed to confirm these results.
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Affiliation(s)
- Marica Pavkovic
- a University Clinic for Hematology , Faculty of Medicine , Skopje , Republic of Macedonia
| | - Aleksandar Petlichkovski
- b Institute for Immunobiology and Human Genetics , Faculty of Medicine , Skopje , Republic of Macedonia
| | - Oliver Karanfilski
- a University Clinic for Hematology , Faculty of Medicine , Skopje , Republic of Macedonia
| | - Lidija Cevreska
- a University Clinic for Hematology , Faculty of Medicine , Skopje , Republic of Macedonia
| | - Aleksandar Stojanovic
- a University Clinic for Hematology , Faculty of Medicine , Skopje , Republic of Macedonia
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16
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Cruz-Baquero A, Cárdenas Jaramillo LM, Gutiérrez-Meza M, Jarillo-Luna RA, Campos-Rodríguez R, Rivera-Aguilar V, Miliar-García A, Pacheco-Yepez J. Different behavior of myeloperoxidase in two rodent amoebic liver abscess models. PLoS One 2017; 12:e0182480. [PMID: 28796788 PMCID: PMC5552100 DOI: 10.1371/journal.pone.0182480] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 07/19/2017] [Indexed: 12/11/2022] Open
Abstract
The protozoan Entamoeba histolytica is the etiological agent of amoebiasis, which can spread to the liver and form amoebic liver abscesses. Histological studies conducted with resistant and susceptible models of amoebic liver abscesses (ALAs) have established that neutrophils are the first cells to contact invasive amoebae at the lesion site. Myeloperoxidase is the most abundant enzyme secreted by neutrophils. It uses hydrogen peroxide secreted by the same cells to oxidize chloride ions and produce hypochlorous acid, which is the most efficient microbicidal system of neutrophils. In a previous report, our group demonstrated that myeloperoxidase presents amoebicidal activity in vitro. The aim of the current contribution was to analyze in vivo the role of myeloperoxidase in a susceptible (hamsters) and resistant (Balb/c mice) animal models of ALAs. In liver samples of hamsters and mice inoculated intraportally with Entamoeba histolytica trophozoites, the number of neutrophils in ALAs was determined by enzymatic activity. The presence of myeloperoxidase was observed by staining, and its expression and activity were quantified in situ. A significant difference existed between the two animal models in the number of neutrophils and the expression and activity of myeloperoxidase, which may explain the distinct evolution of amoebic liver abscesses. Hamsters and mice were treated with an MPO inhibitor (4-aminobenzoic acid hydrazide). Hamsters treated with ABAH showed no significant differences in the percentage of lesions or in the percentage of amoebae damaged compared with the untreated hamsters. ABAH treated mice versus untreated mice showed larger abscesses and a decreased percentage of damaged amoebae in these lesion at all stages of evolution. Further studies are needed to elucidate the host and amoebic mechanisms involved in the adequate or inadequate activation and modulation of myeloperoxidase.
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Affiliation(s)
- Andrea Cruz-Baquero
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luís y Díaz Mirón, CP, Ciudad de México, México
| | - Luz María Cárdenas Jaramillo
- Coordinación de Ciencias Morfológicas, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luís y Díaz Mirón, CP, Ciudad de México, México
| | - Manuel Gutiérrez-Meza
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luís y Díaz Mirón, CP, Ciudad de México, México
- Coordinación de Ciencias Morfológicas, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luís y Díaz Mirón, CP, Ciudad de México, México
| | - Rosa Adriana Jarillo-Luna
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luís y Díaz Mirón, CP, Ciudad de México, México
- Coordinación de Ciencias Morfológicas, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luís y Díaz Mirón, CP, Ciudad de México, México
| | - Rafael Campos-Rodríguez
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luís y Díaz Mirón, CP, Ciudad de México, México
| | - Víctor Rivera-Aguilar
- Departamento de Microbiología, UBIPRO, FES-Iztacala, UNAM, CP, Tlanepantla, Estado de México, México
| | - Angel Miliar-García
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luís y Díaz Mirón, CP, Ciudad de México, México
| | - Judith Pacheco-Yepez
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luís y Díaz Mirón, CP, Ciudad de México, México
- * E-mail:
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17
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Nanoudis S, Tsona A, Tsachouridou O, Morfesis P, Loli G, Georgiou A, Zebekakis P, Metallidis S. Pyoderma gangrenosum in a patient with chronic granulomatous disease: A case report. Medicine (Baltimore) 2017; 96:e7718. [PMID: 28767612 PMCID: PMC5626166 DOI: 10.1097/md.0000000000007718] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 07/04/2017] [Accepted: 07/06/2017] [Indexed: 12/27/2022] Open
Abstract
RATIONALE The simultaneous occurrence of pyoderma gangrenosum (PG) and chronic granulomatous disease (CGD) is uncommon and few cases have been reported worldwide. PATIENT CONCERNS PG is a rare, chronic, ulcerative, neutrophilic skin disease of unknown etiology that requires immunosuppressive treatment. CGD belongs to Primary Immune Deficiencies in which the main defect lies in an inability of the phagocytic cells to generate superoxide making patients susceptible to serious, potentially life-threatening bacterial and fungal infections. DIAGNOSES In this manuscript, we present a case of ulcerative pyoderma gangrenosum in a 28-year-old man with recent diagnosis of chronic granulomatous disease during hospitalization for resistant pulmonary tuberculosis complicated with Aspergillus infection. INTERVENTIONS Second-line therapy with dapsone and intravenous immunoglobulin was initially administered but eventually corticosteroids were added to treatment because of disease progression and further ulceration. OUTCOMES Patient's ulcers were gradually healed with no side effects. LESSONS Corticosteroids could be used under close monitoring for the treatment of PG in a patient with CGD, despite the increased risk for infections.
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18
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Miller TL, Lee D, Giefer M, Wahbeh G, Suskind DL. Nutritional Therapy in Very Early-Onset Inflammatory Bowel Disease: A Case Report. Dig Dis Sci 2017; 62:2196-2200. [PMID: 28551707 DOI: 10.1007/s10620-017-4616-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 05/12/2017] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract caused by a dysregulated immune response to the fecal microbiota. Very early-onset inflammatory bowel disease (VEO-IBD) refers to a subgroup of pediatric patients with IBD diagnosed before 6 years of age. This subgroup is often characterized by increased severity, aggressive progression, strong family history of IBD, and often poor response to conventional treatments. Nutritional therapies have been utilized to treat IBD, but their role in VEO-IBD is unclear. Disease behavior in VEO-IBD is often different from disease in adolescents and adults, as it is often restricted to the colon and refractory to standard medical therapies. Up to 25% of VEO-IBD patients have an identified underlying immunodeficiency, which may impact response to therapy. While specific mutations in interleukin 10 (IL-10), the IL-10 receptor (IL-10R), and mutations in NCF2, XIAP, LRBA, and TTC7 have been identified in VEO-IBD, polymorphisms in these genes are also associated with increased risk of developing IBD in adolescence or adulthood. We describe two cases in which infants presenting with VEO-IBD achieved clinical remission using exclusive enteral nutrition, a formula-based diet which has been shown to induce remission in older children with active Crohn's disease.
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Affiliation(s)
- Talya L Miller
- Department of Pediatrics, Seattle Children's Hospital and University of Washington, 4800 Sandpoint Way NE, Seattle, WA, 98105, USA.
| | - Dale Lee
- Department of Pediatrics, Seattle Children's Hospital and University of Washington, 4800 Sandpoint Way NE, Seattle, WA, 98105, USA
| | - Mathew Giefer
- Department of Pediatrics, Seattle Children's Hospital and University of Washington, 4800 Sandpoint Way NE, Seattle, WA, 98105, USA
| | - Ghassan Wahbeh
- Department of Pediatrics, Seattle Children's Hospital and University of Washington, 4800 Sandpoint Way NE, Seattle, WA, 98105, USA
| | - David L Suskind
- Department of Pediatrics, Seattle Children's Hospital and University of Washington, 4800 Sandpoint Way NE, Seattle, WA, 98105, USA
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19
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Dinauer MC. Primary immune deficiencies with defects in neutrophil function. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2016; 2016:43-50. [PMID: 27913461 PMCID: PMC6142438 DOI: 10.1182/asheducation-2016.1.43] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Immune deficiencies resulting from inherited defects in neutrophil function have revealed important features of the innate immune response. Although sharing an increased susceptibility to bacterial and fungal infections, these disorders each have distinctive features in their clinical manifestations and characteristic microbial pathogens. This review provides an update on several genetic disorders with impaired neutrophil function, their pathogenesis, and treatment strategies. These include chronic granulomatous disease, which results from inactivating mutations in the superoxide-generating nicotinamide dinucleotide phosphate oxidase. Superoxide-derived oxidants play an important role in the control of certain bacterial and fungal species, and also contribute to the regulation of inflammation. Also briefly summarized are updates on leukocyte adhesion deficiency, including the severe periodontal disease characteristic of this disorder, and a new immune deficiency associated with defects in caspase recruitment domain-containing protein 9, an adaptor protein that regulates signaling in neutrophils and other myeloid cells, leading to invasive fungal disease.
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Affiliation(s)
- Mary C Dinauer
- Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO
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20
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Genetic Risk for Inflammatory Bowel Disease Is a Determinant of Crohn's Disease Development in Chronic Granulomatous Disease. Inflamm Bowel Dis 2016; 22:2794-2801. [PMID: 27861181 PMCID: PMC5303573 DOI: 10.1097/mib.0000000000000966] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Approximately, one-third to one-half of children with chronic granulomatous disease (CGD) develop gastrointestinal inflammation characteristic of idiopathic inflammatory bowel disease (IBD), usually Crohn's disease. We hypothesized that the overall IBD genetic risk, determined by IBD genetic risk score (GRS), might in part determine IBD development in CGD. METHODS We reviewed medical records to establish IBD diagnoses in CGD subjects seen at NIAID. IBD risk single nucleotide polymorphism genotypes were determined using the Immunochip, and GRS were estimated by Mangrove. RESULTS Among 157 white patients with CGD, 55 were confirmed, 78 excluded, and 24 were uncertain for IBD. Two hundred one established, independent European IBD risk single nucleotide polymorphisms passed quality control. After sample quality control and removing non-IBD CGD patients with perianal disease, mean GRS for 40 unrelated patients with CGD-IBD was higher than 53 CGD non-IBD patients (in log2-scale 0.08 ± 1.62 versus -0.67 ± 1.64, P = 0.026) but lower than 239 IBD Genetics Consortium (IBDGC) young-onset Crohn's disease cases (0.76 ± 1.60, P = 0.025). GRS for non-IBD CGD was similar to 609 IBDGC controls (-0.69 ± 1.60, P = 0.95). Seven established IBD single nucleotide polymorphisms were nominally significant among CGD-IBD versus CGD non-IBD, including those near LACC1 (P = 0.005), CXCL14 (P = 0.007), and TNFSF15 (P = 0.016). CONCLUSIONS The weight of the common IBD risk alleles are significant determinants of IBD in CGD. However, IBD risk gene burden among CGD children with IBD is significantly lower than that in nonsyndromic pediatric Crohn's disease, congruent with the concept that defective superoxide production in CGD is also a major IBD risk factor. Individual IBD genes might interact with the CGD defect to cause IBD in CGD.
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21
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Broides A, Sagi O, Pinsk V, Levy J, Yerushalmi B. Subclinical intestinal inflammation in chronic granulomatous disease patients. Immunol Res 2016; 64:155-9. [PMID: 26603166 DOI: 10.1007/s12026-015-8733-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Chronic granulomatous disease is a primary immunodeficiency caused by impaired neutrophil production of reactive oxygen species. Non-infectious colitis is common in chronic granulomatous disease, and high levels of antimicrobial antibodies that are associated with Crohn's disease are common even without colitis. Fecal calprotectin concentration is a marker for intestinal inflammation. We sought to determine whether subclinical intestinal inflammation occurs in asymptomatic chronic granulomatous disease patients. Asymptomatic chronic granulomatous disease patients without overt gastrointestinal symptoms suggestive of colitis at the time of enrollment were studied for fecal calprotectin concentration, antibodies associated with Crohn's disease and systemic inflammatory markers. Eight patients were included, aged 54-176 months. In 7/8 (87.5 %) fecal calprotectin concentration was normal (<50) and elevated (137 mg/kg) in only one patient. This patient later developed colitis. In 7/8 (87.5 %) anti-Saccharomyces cerevisiae antibody was positive. C-reactive protein, albumin, complete blood count and p-anti-neutrophil cytoplasmic antibody were normal in all 8 patients. Subclinical colitis is not evident in most asymptomatic chronic granulomatous disease patients; however, in some patients, fecal calprotectin concentration may be elevated, possibly indicating the presence of subclinical colitis and predicting the occurrence of clinically relevant colitis. Serum anti-Saccharomyces cerevisiae antibody concentrations do not seem to correlate with fecal calprotectin concentration in asymptomatic chronic granulomatous disease patients.
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Affiliation(s)
- Arnon Broides
- Pediatric Immunology Clinic, Soroka University Medical Center, POB151, 84101, Beer Sheva, Israel.
- Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel.
| | - Orli Sagi
- Parasitology Laboratory, Soroka University Medical Center, 84101, Beer Sheva, Israel
- Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel
| | - Vered Pinsk
- Pediatric Gastroenterology Unit, Soroka University Medical Center, 84101, Beer Sheva, Israel
- Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel
| | - Jacov Levy
- Pediatric Immunology Clinic, Soroka University Medical Center, POB151, 84101, Beer Sheva, Israel
- Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel
| | - Baruch Yerushalmi
- Pediatric Gastroenterology Unit, Soroka University Medical Center, 84101, Beer Sheva, Israel
- Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel
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22
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Magnani A, Mahlaoui N. Managing Inflammatory Manifestations in Patients with Chronic Granulomatous Disease. Paediatr Drugs 2016; 18:335-45. [PMID: 27299584 DOI: 10.1007/s40272-016-0182-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by lack of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which results in inflammatory dysregulation and increased susceptibility to infections. Patients with CGD may develop severe obstructive disorders of the digestive tract as a result of their dysregulated inflammatory response. Despite a growing focus on inflammatory manifestations in CGD, the literature data on obstructive complications are far less extensive than those on infectious complications. Diagnosis and management of patients with concomitant predispositions to infections and hyperinflammation are particularly challenging. Although the inflammatory and granulomatous manifestations of CGD usually respond rapidly to steroid treatment, second-line therapies (immunosuppressants and biologics) may be required in refractory cases. Indeed, immunosuppressants (such as anti-tumor necrosis factor agents, thalidomide, and anakinra) have shown some efficacy, but the value of this approach is controversial, given the questionable risk-to-benefit ratio and the small numbers of patients treated to date. Significant progress in allogeneic hematopoietic stem cell transplantation (the only curative treatment for CGD) has been made through better supportive care and implementation of improved, reduced-intensity conditioning regimens. Gene therapy may eventually be an option for patients lacking a suitable donor; clinical trials with new, safer vectors are ongoing at a few centers.
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Affiliation(s)
- Alessandra Magnani
- Biotherapy Department, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. .,Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France.
| | - Nizar Mahlaoui
- Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France. .,French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. .,INSERM UMR 1163, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris, France. .,Pediatric Immunohematology and Rheumatology Unit, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
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23
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Fraser IP, Stuart L, Ezekowitz RAB. TLR-independent pattern recognition receptors and anti-inflammatory mechanisms. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/09680519040100020801] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pattern recognition receptors recognize molecular patterns associated with the surfaces of microbes and apoptotic cells. These receptors act alone and in concert to bind, phagocytose, and transduce cellular signals derived from these molecular patterns. The outcome of these interactions is dependent on the nature of the ligands, and upon the nature and combination of the ligated receptors. Whereas much attention has been focused on the properties and activities of the Toll-like receptors (TLRs) in this process, many other pattern recognition molecules have been described. Here we review some of these non-TLR receptors and their ligands, and focus attention on the mannose binding lectin, a humoral pattern recognition molecule. In addition, we describe how recognition of apopotic cells via pattern recognition receptors appears to result in responses that differ from those elicited by microbial ligands.
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Affiliation(s)
- Iain P. Fraser
- Laboratory of Developmental Immunology, MassGeneral Hospital for Children, Boston, Massachusetts, USA,
| | - Lynda Stuart
- Laboratory of Developmental Immunology, MassGeneral Hospital for Children, Boston, Massachusetts, USA, MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - R. Alan B. Ezekowitz
- Laboratory of Developmental Immunology, MassGeneral Hospital for Children, Boston, Massachusetts, USA
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24
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Leopard Skin-Like Colonic Mucosa: A Novel Endoscopic Finding of Chronic Granulomatous Disease-Associated Colitis. J Pediatr Gastroenterol Nutr 2016; 62:56-9. [PMID: 26164846 DOI: 10.1097/mpg.0000000000000905] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes are unable to eradicate pathogens because of a deficit of nicotinamide adenine dinucleotide phosphate oxidase. Among CGD patients, ∼ 30% to 50% develop severe gastrointestinal tract symptoms. Although characteristic histologic findings of CGD-associated colitis have been reported, information on endoscopic features remained vague. METHODS A total of 8 male patients with CGD (ages 2-23 years) from 2 Japanese institutions underwent colonoscopy for the evaluation of their fever, diarrhea, bloody stool, and abdominal pain. The endoscopic and histologic findings were retrospectively reviewed. RESULTS The endoscopic findings of CGD-associated colitis appeared varied. Notably, brownish dots over a yellowish edematous mucosa were observed in 3 of the 8 patients. Prominent pigment-laden macrophages were noted histologically on the mucosa. CONCLUSIONS Although nonspecific endoscopic findings of CGD-associated colitis have been reported before, our observation of brownish dots spread across a yellowish edematous mucosa, termed "leopard sign," could be a unique feature of this condition.
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25
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Mandal J, Malla B, Steffensen R, Costa L, Egli A, Trendelenburg M, Blasi F, Kostikas K, Welte T, Torres A, Louis R, Boersma W, Milenkovic B, Aerts J, Rohde GGU, Lacoma A, Rentsch K, Roth M, Tamm M, Stolz D. Mannose-binding lectin protein and its association to clinical outcomes in COPD: a longitudinal study. Respir Res 2015; 16:150. [PMID: 26684757 PMCID: PMC4750539 DOI: 10.1186/s12931-015-0306-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 11/26/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Functional deficiency of mannose-binding lectin (MBL) may contribute to the pathogenesis of chronic obstructive pulmonary disease. We hypothesized that specific MBL2 gene polymorphisms and circulating MBL protein levels are associated with clinically relevant outcomes in the Predicting Outcome using systemic Markers In Severe Exacerbations of COPD PROMISE-COPD cohort. METHODS We followed 277 patients with stable COPD GOLD stage II-IV COPD over a median period of 733 days (IQR 641-767) taking survival as the primary outcome parameter. Patients were dichotomized as frequent (≥ 2 AECOPD/year) or infrequent exacerbators. Serum MBL levels and single nucleotide polymorphisms of the MBL2 gene were assessed at baseline. RESULTS The MBL2-HYPD haplotype was significantly more prevalent in frequent exacerbators (OR: 3.33; 95% CI, 1.24-7.14, p = 0.01). The median serum MBL concentration was similar in frequent (607 ng/ml, [IQR; 363.0-896.0 ng/ml]) and infrequent exacerbators (615 ng/ml, [IQR; 371.0-942.0 ng/ml]). Serum MBL was not associated with lung function characteristics or bacterial colonization in sputum. However, high serum MBL at stable state was associated with better survival compared to low MBL (p = 0.046, log rank test). CONCLUSIONS In COPD, the HYPD haplotype of MBL2 gene is associated with frequent exacerbations and high serum MBL is linked to increased survival. The PROMISE-COPD study was registered at www.controlled-trials.com under the identifier ISRCTN99586989.
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Affiliation(s)
- Jyotshna Mandal
- Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital Basel, Petersgraben, 44031, Basel, Switzerland
| | - Bijaya Malla
- Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital Basel, Petersgraben, 44031, Basel, Switzerland
| | - Rudi Steffensen
- Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark
| | - Luigi Costa
- Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital Basel, Petersgraben, 44031, Basel, Switzerland
| | - Adrian Egli
- Infection Disease Department, University Hospital Basel, Basel, Switzerland
| | - Marten Trendelenburg
- Department of Biomedicine and Division of Internal Medicine, University Hospital Basel, Basel, Switzerland
| | - Francesco Blasi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, IRCCS Fondazione Cà Granda Policlinico, Milan, Italy
| | | | | | | | | | - Wim Boersma
- Medisch Centrum Alkmaar, Alkmaar, Netherlands
| | - Branislava Milenkovic
- Faculty of Medicine, University of Belgrade; Clinic for Pulmonary Diseases, Belgrade, Serbia
| | | | - Gernot G U Rohde
- Maastricht University Medical Center, Maastricht, The Netherlands
| | - Alicia Lacoma
- Department of Microbiology, Hospital Universitari Germans Trias i Pujol, CIBER Enfermedades Respiratorias, Badalona, Spain
| | - Katharina Rentsch
- Department of Laboratorial Medicine, University Hospital Basel, Basel, Switzerland
| | - Michael Roth
- Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital Basel, Petersgraben, 44031, Basel, Switzerland
| | - Michael Tamm
- Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital Basel, Petersgraben, 44031, Basel, Switzerland
| | - Daiana Stolz
- Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital Basel, Petersgraben, 44031, Basel, Switzerland.
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Abstract
Inflammatory bowel disease (IBD) is a multifactoral disease caused by dysregulated immune responses to commensal or pathogenic microbes in the intestine, resulting in chronic intestinal inflammation. An emerging population of patients with IBD occurring before the age of 5 represent a unique form of disease, termed Very Early Onset (VEO)-IBD, which is phenotypically- and genetically-distinct from older-onset IBD. VEO-IBD is associated with increased disease severity, aggressive progression and poor responsiveness to most conventional therapies. Further investigation into the causes and pathogenesis of VEO-IBD will help improve treatment strategies, and may lead to a better understanding of the mechanisms that are essential to maintain intestinal health or provoke the development of targeted therapeutic strategies to limit intestinal disease. Here we discuss the phenotypic nature of VEO-IBD, the recent identification of novel gene variants associated with disease, and functional immunologic studies interrogating the contribution of specific genetic variants to the development of chronic intestinal inflammation.
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Key Words
- inflammatory bowel disease
- very early onset inflammatory bowel disease
- whole exome sequencing
- mucosal immunology
- adam17, a disintegrin and metalloproteinase domain 17
- cgd, chronic granulomatous disease
- col7a1, collagen, type vii, α1
- cvid, common variable immunodeficiency
- foxp3, forkhead box protein 3
- gucy2, guanylate cyclase 2
- gwas, genomewide association studies
- ibd, inflammatory bowel disease
- il, interleukin
- ilc, innate lymphoid cells
- ilc3, group 3 innate lymphoid cells
- iga, immunoglobulin a
- ikbkg, inhibitor of κ light polypeptide gene enhancer in b cells, kinase of, γ
- ipex, immunodysregulation, polyendocrinopathy, and enteropathy, x-linked
- mhcii, major histocompatibility complex class ii
- nemo, nuclear factor-κb essential modulator
- rag, recombination-activating gene
- stat, signal transducer and activator of transcription
- tnf, tumor necrosis factor
- treg, regulatory t cell
- ttc7a, tetratricopeptide repeat domain-containing protein 7a
- veo-ibd, very early onset inflammatory bowel disease
- wasp, wiskott-aldrich syndrome protein
- wes, whole exome sequencing
- xiap, x-linked inhibitor of apoptosis protein
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Moran CJ, Klein C, Muise AM, Snapper SB. Very early-onset inflammatory bowel disease: gaining insight through focused discovery. Inflamm Bowel Dis 2015; 21:1166-75. [PMID: 25895007 PMCID: PMC6165626 DOI: 10.1097/mib.0000000000000329] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The pathogenesis of pediatric inflammatory bowel disease (IBD) is only partially understood. Strong evidence implicates a strong genetic component including high monozygotic twin concordance and familial disease phenotype concordance rates. Genome-wide association studies have identified associations between >160 genetic loci and the risk for developing IBD. The roles of implicated genes are largely immune-mediated, although other functions include cellular migration, oxidative stress, and carbohydrate metabolism. Additionally, growing literature describes monogenic causes of IBD that frequently present as infantile or very early-onset IBD. The interplay between IBD risk single nucleotide polymorphisms and rare genetic variants has yet to be determined. Studying patients with very early-onset IBD may elicit genetic factors that could be applied to broader populations of IBD. This review describes what is known about the genetic causes of very early-onset IBD and genetic strategies that may unravel more of the genetic causes of IBD.
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Affiliation(s)
- Christopher J. Moran
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, MassGeneral Hospital for Children, Boston, Massachusetts
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
| | - Christoph Klein
- Dr von Hauner Children’s Hospital, Ludwig Maximilians University, Munich, Germany
| | - Aleixo M. Muise
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada
- SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada
| | - Scott B. Snapper
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Children’s Hospital Boston, Boston, Massachusetts
- Division of Gastroenterology and Hepatology, Brigham & Women’s Hospital, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
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28
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Abstract
The phagocyte NADPH oxidase NOX2 produces reactive oxygen species (ROS) and is a well-known player in host defence. However, there is also increasing evidence for a regulatory role of NOX2 in adaptive immunity. Deficiency in phagocyte NADPH oxidase causes chronic granulomatous disease (CGD) in humans, a condition that can also be studied in CGD mice. Clinical observations in CGD patients suggest a higher susceptibility to autoimmune diseases, in particular lupus, idiopathic thrombocytopenic purpura and rheumatoid arthritis. In mice, a strong correlation exists between a polymorphism in a NOX2 subunit and the development of autoimmune arthritis. NOX2 deficiency in mice also favours lupus development. Both CGD patients and CGD mice exhibit increased levels of immunoglobulins, including autoantibodies. Despite these phenotypes suggesting a role for NOX2 in specific immunity, mechanistic explanations for the typical increase of CGD in autoimmune disease and antibody levels are still preliminary. NOX2-dependent ROS generation is well documented for dendritic cells and B-lymphocytes. It is unclear whether T-lymphocytes produce ROS themselves or whether they are exposed to ROS derived from dendritic cells during the process of antigen presentation. ROS are signalling molecules in virtually any cell type, including T- and B-lymphocytes. However, knowledge about the impact of ROS-dependent signalling on T- and B-lymphocyte phenotype and response is still limited. ROS might contribute to Th1/Th2/Th17 cell fate decisions during T-lymphocyte activation and might enhance immunoglobulin production by B-lymphocytes. In dendritic cells, NOX2-derived ROS might be important for antigen processing and cell activation.
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29
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Podok P, Wang H, Xu L, Xu D, Lu L. Characterization of myeloid-specific peroxidase, keratin 8, and dual specificity phosphatase 1 as innate immune genes involved in the resistance of crucian carp (Carassius auratus gibelio) to Cyprinid herpesvirus 2 infection. FISH & SHELLFISH IMMUNOLOGY 2014; 41:531-540. [PMID: 25312688 DOI: 10.1016/j.fsi.2014.10.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 09/28/2014] [Accepted: 10/01/2014] [Indexed: 06/04/2023]
Abstract
Myeloid-specific peroxidase (MPO), keratin 8 (KRT-8), and dual specificity phosphatase 1 (DUSP-1) are believed to play essential roles in innate immunity. Through suppression subtractive hybridization (SSH) analysis, we previously identified MPO, KRT-8, and DUSP-1 as the three genes that were the most significantly upregulated in crucian carp (Carassius auratus gibelio) that survived Cyprinid herpesvirus 2 (CyHV-2) infection. Here, we have further characterized these three genes and their response to pathogen challenge. The open reading frames (ORF) of MPO, KRT-8, and DUSP-1 were cloned by RACE technique and sequenced. The full-length cDNAs of the three genes contained ORFs of 2289, 1575 and 1083 bp respectively. The polypeptides from each ORF were projected to contain 762 (MPO), 524 (KRT-8), and 360 (DUSP-1) amino acids. Phylogenetic analysis showed that the three genes were most closely related to zebrafish. We found that MPO, KRT-8, and DUSP-1 were expressed at low levels in all of the tissues examined in healthy crucian carp. Quantitative real-time RT-PCR analysis indicated that MPO, KRT-8, and DUSP-1 mRNA expression was significantly upregulated within 72 h of CyHV-2 infection compared to mock infected controls. Maximum expression of MPO was detected at 24 hpi (2.71-fold, P < 0.05). While, 12 hpi (3.80-fold, P < 0.01) and 6 hpi (8.70-fold, P < 0.01) were the highest expression time points for KRT-8 and DUSP-1, respectively. In contrast, after Aeromonas hydrophila challenge, the transcripts of these three genes remained unchanged or slightly down-regulated. For the fish survived from viral infection, expression levels of MPO and KRT-8 were 2.72 fold and 2.47 fold higher than those of fish died from acute infection, and similar level of DUSP-1 was observed in samples of survived fish. These data suggested MPO, KRT-8 and DUSP-1 might be involved in the antiviral, but not antibacterial innate immune response in crucian carp. These findings also support the use of MPO and KRT-8 as immunological markers for a response to viral infection in crucian carp.
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Affiliation(s)
- Patarida Podok
- Key Laboratory of Aquatic Genetic Resources of the Ministry of Agriculture, Shanghai Ocean University, 201306, PR China
| | - Hao Wang
- Key Laboratory of Aquatic Genetic Resources of the Ministry of Agriculture, Shanghai Ocean University, 201306, PR China
| | - Lijuan Xu
- Key Laboratory of Aquatic Genetic Resources of the Ministry of Agriculture, Shanghai Ocean University, 201306, PR China
| | - Dan Xu
- Key Laboratory of Aquatic Genetic Resources of the Ministry of Agriculture, Shanghai Ocean University, 201306, PR China
| | - Liqun Lu
- Key Laboratory of Aquatic Genetic Resources of the Ministry of Agriculture, Shanghai Ocean University, 201306, PR China.
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30
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Abstract
Chronic granulomatous disease is a primary immunodeficiency caused by mutations in
the genes encoding subunits of the phagocytic NADPH oxidase system. Patients can
present with severe, recurrent infections and noninfectious conditions. Among the
latter, inflammatory manifestations are predominant, especially granulomas and
colitis. In this article, we systematically review the possible mechanisms of
hyperinflammation in this rare primary immunodeficiency condition and their
correlations with clinical aspects.
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31
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Abstract
Primary disorders of neutrophil function result from impairment in neutrophil responses that are critical for host defense. This chapter summarizes inherited disorders of neutrophils that cause defects in neutrophil adhesion, migration, and oxidative killing. These include the leukocyte adhesion deficiencies, actin defects, and other disorders of chemotaxis, hyperimmunoglobulin E syndrome, Chédiak-Higashi syndrome, neutrophil-specific granule deficiency, chronic granulomatous disease, and myeloperoxidase deficiency. Diagnostic tests and treatment approaches are also summarized for each neutrophil disorder.
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Affiliation(s)
- Mary C Dinauer
- Departments of Pediatrics (Hematology/Oncology) and Pathology & Immunology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, USA
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32
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Battersby AC, Cale CM, Goldblatt D, Gennery AR. Clinical Manifestations of Disease in X-Linked Carriers of Chronic Granulomatous Disease. J Clin Immunol 2013; 33:1276-84. [DOI: 10.1007/s10875-013-9939-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 09/16/2013] [Indexed: 11/28/2022]
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Todoric K, Koontz JB, Mattox D, Tarrant TK. Autoimmunity in immunodeficiency. Curr Allergy Asthma Rep 2013; 13:361-70. [PMID: 23591608 DOI: 10.1007/s11882-013-0350-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Primary immunodeficiencies (PID) comprise a diverse group of clinical disorders with varied genetic defects. Paradoxically, a substantial proportion of PID patients develop autoimmune phenomena in addition to having increased susceptibility to infections from their impaired immunity. Although much of our understanding comes from data gathered through experimental models, there are several well-characterized PID that have improved our knowledge of the pathways that drive autoimmunity. The goals of this review will be to discuss these immunodeficiencies and to review the literature with respect to the proposed mechanisms for autoimmunity within each put forth to date.
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Affiliation(s)
- Krista Todoric
- Division of Allergy and Immunology, Dept of Pediatrics, University of North Carolina Hospitals, Chapel Hill, NC 27599, USA
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34
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Agarwal S, Mayer L. Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency. Clin Gastroenterol Hepatol 2013; 11:1050-63. [PMID: 23501398 PMCID: PMC3800204 DOI: 10.1016/j.cgh.2013.02.024] [Citation(s) in RCA: 124] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Revised: 02/08/2013] [Accepted: 02/15/2013] [Indexed: 02/06/2023]
Abstract
Gastrointestinal disorders such as chronic or acute diarrhea, malabsorption, abdominal pain, and inflammatory bowel diseases can indicate immune deficiency. The gastrointestinal tract is the largest lymphoid organ in the body, so it is not surprising that intestinal diseases are common among immunodeficient patients. Gastroenterologists therefore must be able to diagnose and treat patients with primary immunodeficiency. Immune-related gastrointestinal diseases can be classified as those that develop primarily via autoimmunity, infection, an inflammatory response, or malignancy. Immunodeficient and immunocompetent patients with gastrointestinal diseases present with similar symptoms. However, intestinal biopsy specimens from immunodeficient patients often have distinct histologic features, and these patients often fail to respond to conventional therapies. Therefore, early recognition of symptoms and referral to an immunologist for a basic immune evaluation is required to select appropriate treatments. Therapies for primary immunodeficiency comprise immunoglobulin replacement, antibiotics, and, in severe cases, bone marrow transplantation. Treatment of immunodeficient patients with concomitant gastrointestinal disease can be challenging, and therapy with immunomodulators often is required for severe disease. This review aims to guide gastroenterologists in the diagnosis and treatment of patients with primary immunodeficiency.
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Affiliation(s)
- Shradha Agarwal
- Division of Clinical Immunology, Mount Sinai School of Medicine, New York, New York 10029, USA.
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35
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Mahdaviani SA, Mohajerani SA, Rezaei N, Casanova JL, Mansouri SD, Velayati AA. Pulmonary manifestations of chronic granulomatous disease. Expert Rev Clin Immunol 2013; 9:153-60. [PMID: 23390946 DOI: 10.1586/eci.12.98] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Chronic granulomatous disease (CGD) is an inherited disorder, characterized by defects in superoxide-generating NADPH oxidase of phagocytes. The genetic defects in CGD induce failure to activate the respiratory burst in the phagocytes, leading to severe recurrent infections and unexplained prolonged inflammatory reactions that may produce granulomatous lesions. A noble advance in curative therapy for CGD is hematopoietic stem cell transplantation. Since the most common site of involvement in CGD is the lung, the pulmonologists (pediatrics or adult) may be among the first to recognize the pattern of infection, inflammation and granuloma formation, leading to diagnosis of CGD. Pulmonologists need to be aware of different lung manifestations of CGD.
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Affiliation(s)
- Seyed Alireza Mahdaviani
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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36
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Tefik T, Kucukgergin C, Sanli O, Oktar T, Seckin S, Ozsoy C. Manganese superoxide dismutase Ile58Thr, catalase C-262T and myeloperoxidase G-463A gene polymorphisms in patients with prostate cancer: relation to advanced and metastatic disease. BJU Int 2013; 112:E406-14. [PMID: 23773345 DOI: 10.1111/bju.12176] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To evaluate the relationship between manganese superoxide dismutase (MnSOD) Ile58Thr, catalase (CAT) C-262T and myeloperoxidase (MPO) G-463A gene polymorphisms and the susceptibility and clinicopathological characteristics of prostate cancer. PATIENTS AND METHODS In all, 155 patients diagnosed with prostate cancer and 195 controls with negative digital rectal examinations and PSA levels of <4 ng/dL were enrolled in this study. MnSOD, CAT and MPO gene polymorphisms were identified by polymerase chain reaction restriction-fragment length polymorphism methods. RESULTS The TT genotype in MnSOD Ile58Thr polymorphism, CC genotype in the CAT C-262T polymorphism and the GG genotype in the MPO G-463A polymorphism were the predominant genotypes amongst this Turkish male population. There was no association between MnSOD Ile58Thr polymorphism and prostate cancer. For the CAT C-262T polymorphism, the TT genotype had significantly increased prostate cancer risk compared with the CC genotype. Similarly, the TT genotype had a 1.94- and 3.83-fold increased risk for high-stage disease and metastasis, respectively, when compared with the CC genotype. For the MPO G-463A polymorphism, the GG genotype had 1.78-fold increased risk of prostate cancer compared with the AA genotype. However, no association was found regarding Gleason score, advanced and metastatic prostate cancer risk. CONCLUSIONS It seems that there is no association of prostate cancer with MnSOD Ile58Thr polymorphism, whereas the TT genotype in the CAT C-262T polymorphism and the GG genotype in the MPO G-463A polymorphism may be associated with increased prostate cancer risk. The TT genotype in the CAT C-262T gene polymorphism may also be a risk factor in tumour progression and metastasis among Turkish men.
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Affiliation(s)
- Tzevat Tefik
- Department of Urology, Istanbul University, Istanbul, Turkey.
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Kotsias F, Hoffmann E, Amigorena S, Savina A. Reactive oxygen species production in the phagosome: impact on antigen presentation in dendritic cells. Antioxid Redox Signal 2013; 18:714-29. [PMID: 22827577 DOI: 10.1089/ars.2012.4557] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
SIGNIFICANCE The NADPH oxidase 2 (NOX2) is known to play a major role in innate immunity for several decades. Phagocytic cells provide host defense by ingesting microbes and destroy them by different mechanisms, including the generation of reactive oxygen species (ROS) by NOX2, a process known as oxidative burst. The phagocytic pathway of dendritic cells (DCs), highly adapted to antigen processing, has been shown to display remarkable differences compared to other phagocytes. Contrary to macrophages and neutrophils, the main function of DC phagosomes is antigen presentation rather than pathogen killing or clearance of cell debris. RECENT ADVANCES In the last few years, it became clear that NOX2 is also involved in the establishment of adaptive immunity. Several studies support the idea of a relationship between antigen presentation and the level of antigen degradation, the latter one being regulated by the pH and ROS within phagosomes. CRITICAL ISSUES The regulation of phagosomal pH exerted by NOX2, and thereby of the efficacy of antigen cross-presentation in DCs, represents a clear illustration of how NOX2 can influence CD8(+) T lymphocyte responses. In this review, we want to put emphasis on the relationship between ROS generation and antigen processing and presentation, since there is growing evidence that the low levels of ROS generated by DCs play an important role in these processes. FUTURE DIRECTIONS In the next years, it will be interesting to unravel possible mechanisms involved and to find other possible connections between NOX family members and adaptive immune responses.
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38
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Chronic granulomatous disease presenting as aseptic ascites in a 2-year-old child. Case Reports Immunol 2013; 2013:927897. [PMID: 25379308 PMCID: PMC4207586 DOI: 10.1155/2013/927897] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 12/27/2012] [Indexed: 11/29/2022] Open
Abstract
Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency syndrome that results from abnormal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function. This defect leads to recurrent catalase-positive bacterial and fungal infections as well as associated granuloma formation. We review the case of a 2-year-old boy who presented with ascites and fever of an unknown origin as manifestations of CGD. Cultures were negative for infection throughout his course, and CGD was suspected after identification of granulomas on peritoneal biopsy. Genetic testing revealed a novel mutation in the CYBB gene underlying his condition. This paper highlights the importance of considering CGD in the differential diagnosis of fever of unknown origin and ascites in children.
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Jakobsen MA, Katzenstein TL, Valerius NH, Roos D, Fisker N, Mogensen TH, Jensen PØ, Barington T. Genetical Analysis of All Danish Patients Diagnosed with Chronic Granulomatous Disease. Scand J Immunol 2012; 76:505-11. [DOI: 10.1111/j.1365-3083.2012.02771.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- M. A. Jakobsen
- Department of Clinical Immunology; Odense University Hospital; Odense; Denmark
| | - T. L. Katzenstein
- Department of Infectious Diseases; Copenhagen University Hospital Righospitalet; Copenhagen; Denmark
| | - N. H. Valerius
- Department of Paediatrics; Copenhagen University Hospital; Hvidovre; Copenhagen; Denmark
| | - D. Roos
- Sanquin Research; Landsteiner Laboratory, Academic Medical Centre; University of Amsterdam; Amsterdam; The Netherlands
| | - N. Fisker
- H.C. Andersen Children's Hospital; Odense University Hospital; Odense; Denmark
| | - T. H. Mogensen
- Department of Infectious Diseases; Aarhus University Hospital; Skejby; Aarhus; Denmark
| | - P. Ø. Jensen
- Department of Clinical Microbiology; Copenhagen University Hospital Rigshospitalet; Copenhagen; Denmark
| | - T. Barington
- Department of Clinical Immunology; Odense University Hospital; Odense; Denmark
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40
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Roesler J, Segerer F, Morbach H, Kleinert S, Thieme S, Rösen-Wolff A, Liese JG. P67-phox (NCF2) lacking exons 11 and 12 is functionally active and leads to an extremely late diagnosis of chronic granulomatous disease (CGD). PLoS One 2012; 7:e34296. [PMID: 22514628 PMCID: PMC3326000 DOI: 10.1371/journal.pone.0034296] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Accepted: 02/27/2012] [Indexed: 01/23/2023] Open
Abstract
Two brothers in their fifties presented with a medical history of suspected fungal allergy, allergic bronchopulmonary aspergillosis, alveolitis, and invasive aspergillosis and pulmonary fistula, respectively. Eventually, after a delay of 50 years, chronic granulomatous disease (CGD) was diagnosed in the index patient. We found a new splice mutation in the NCF2 (p67-phox) gene, c.1000+2T→G, that led to several splice products one of which lacked exons 11 and 12. This deletion was in frame and allowed for remarkable residual NADPH oxidase activity as determined by transduction experiments using a retroviral vector. We conclude that p67-phox which lacks the 34 amino acids encoded by the two exons can still exert considerable functional activity. This activity can partially explain the long-term survival of the patients without adequate diagnosis and treatment, but could not prevent progressing lung damage.
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Affiliation(s)
- Joachim Roesler
- Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany.
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41
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Liu Y, Liu FL, Bai ZJ, Zhao N, Zhang LY, Lu X, Chen ZL. Defective activities, but not secretions, resulting from gene point mutations of human mannan-binding lectin. Mol Med Rep 2012; 5:1121-7. [PMID: 22323042 PMCID: PMC3493102 DOI: 10.3892/mmr.2012.782] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Accepted: 02/03/2012] [Indexed: 11/25/2022] Open
Abstract
Human mannan-binding lectin (MBL) plays a pivotal role in innate immunity. Substantial literature supports the belief that three point mutations, CGT52TGT, GGC54GAC and GGA57GAA, in the collagen-like region (CLR) of the human MBL gene, are associated with increased susceptibility to infection, autoimmunity and carcinogenesis. To investigate the mechanisms of MBL deficiency, human wild-type and three variant MBL genes were expressed in COS-7 and Chinese hamster ovary (CHO) cells. Results showed that no apparent differences were found among the levels of gene transcription and protein secretion of four forms of MBL. However, the degree of oligomerization of variant forms of MBL was found to be much lower than that of recombinant human wild-type MBL. The ability of variant MBL proteins to bind mannan was much weaker than that of the wild-type MBL protein, and the MBL variants failed to effectively activate the complement lectin pathway. These data suggested that a lower order oligomer, but not decreased plasma levels of MBL, may be the main result of MBL gene mutations and may be associated with immunodeficiency.
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Affiliation(s)
- Ying Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, PR China
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Morton M, Edmonds S, Doherty AM, Dhaygude A, Helbert M, Venning M. Factors associated with major infections in patients with granulomatosis with polyangiitis and systemic lupus erythematosus treated for deep organ involvement. Rheumatol Int 2011; 32:3373-82. [DOI: 10.1007/s00296-011-2151-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2011] [Accepted: 09/10/2011] [Indexed: 10/15/2022]
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Song E, Jaishankar GB, Saleh H, Jithpratuck W, Sahni R, Krishnaswamy G. Chronic granulomatous disease: a review of the infectious and inflammatory complications. Clin Mol Allergy 2011; 9:10. [PMID: 21624140 PMCID: PMC3128843 DOI: 10.1186/1476-7961-9-10] [Citation(s) in RCA: 122] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Accepted: 05/31/2011] [Indexed: 01/18/2023] Open
Abstract
Chronic Granulomatous Disease is the most commonly encountered immunodeficiency involving the phagocyte, and is characterized by repeated infections with bacterial and fungal pathogens, as well as the formation of granulomas in tissue. The disease is the result of a disorder of the NADPH oxidase system, culminating in an inability of the phagocyte to generate superoxide, leading to the defective killing of pathogenic organisms. This can lead to infections with Staphylococcus aureus, Psedomonas species, Nocardia species, and fungi (such as Aspergillus species and Candida albicans). Involvement of vital or large organs can contribute to morbidity and/or mortality in the affected patients. Major advances have occurred in the diagnosis and treatment of this disease, with the potential for gene therapy or stem cell transplantation looming on the horizon.
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Affiliation(s)
- Eunkyung Song
- Department of Pediatrics, Division of Allergy and Clinical Immunology, Quillen College of Medicine, East Tennessee State University, USA.
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Inflammatory Bowel Disease and Other Systemic Inflammatory Diseases. Cornea 2011. [DOI: 10.1016/b978-0-323-06387-6.00068-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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45
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Kuhns DB, Alvord WG, Heller T, Feld JJ, Pike KM, Marciano BE, Uzel G, DeRavin SS, Priel DAL, Soule BP, Zarember KA, Malech HL, Holland SM, Gallin JI. Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med 2010; 363:2600-10. [PMID: 21190454 PMCID: PMC3069846 DOI: 10.1056/nejmoa1007097] [Citation(s) in RCA: 396] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Failure to generate phagocyte-derived superoxide and related reactive oxygen intermediates (ROIs) is the major defect in chronic granulomatous disease, causing recurrent infections and granulomatous complications. Chronic granulomatous disease is caused by missense, nonsense, frameshift, splice, or deletion mutations in the genes for p22(phox), p40(phox), p47(phox), p67(phox) (autosomal chronic granulomatous disease), or gp91(phox) (X-linked chronic granulomatous disease), which result in variable production of neutrophil-derived ROIs. We hypothesized that residual ROI production might be linked to survival in patients with chronic granulomatous disease. METHODS We assessed the risks of illness and death among 287 patients with chronic granulomatous disease from 244 kindreds. Residual ROI production was measured with the use of superoxide-dependent ferricytochrome c reduction and flow cytometry with dihydrorhodamine oxidation assays. Expression of NADPH oxidase component protein was detected by means of immunoblotting, and the affected genes were sequenced to identify causal mutations. RESULTS Survival of patients with chronic granulomatous disease was strongly associated with residual ROI production as a continuous variable, independently of the specific gene affected. Patients with mutations in p47(phox) and most missense mutations in gp91(phox) (with the exception of missense mutations in the nucleotide-binding and heme-binding domains) had more residual ROI production than patients with nonsense, frameshift, splice, or deletion mutations in gp91(phox). After adolescence, mortality curves diverged according to the extent of residual ROI production. CONCLUSIONS Patients with chronic granulomatous disease and modest residual production of ROI have significantly less severe illness and a greater likelihood of long-term survival than patients with little residual ROI production. The production of residual ROI is predicted by the specific NADPH oxidase mutation, regardless of the specific gene affected, and it is a predictor of survival in patients with chronic granulomatous disease. (Funded by the National Institutes of Health.).
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Affiliation(s)
- Douglas B Kuhns
- Clinical Services Program, SAIC-Frederick, Frederick, Maryland, USA
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Chehata VJ, Domeier PP, Weilnau JN, Lappas CM. Adenosine A(2A) receptor activation limits chronic granulomatous disease-induced hyperinflammation. Cell Immunol 2010; 267:39-49. [PMID: 21130984 DOI: 10.1016/j.cellimm.2010.11.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Revised: 10/27/2010] [Accepted: 11/08/2010] [Indexed: 12/24/2022]
Abstract
Chronic granulomatous disease (CGD) is caused by defects in the NADPH oxidase complex and is characterized by an increased susceptibility to infection. Other significant complications of CGD include autoimmunity and non-infectious hyperinflammatory disorders. We show that a gp91(phox) deficiency leads to the development of phenotypically altered T lymphocytes in mice and that this abnormal, hyperactive phenotype can be modulated by activation of the adenosine A(2A) receptor. T cells isolated from CGD mice produce significantly higher levels of the pro-inflammatory cytokines IFN-γ, IL-2, TNF-α, IL-4 and IL-13 than do WT cells after TCR-mediated activation; treatment with the selective adenosine A(2A) receptor agonist, CGS21680, potently inhibits this response. Additionally, the over exuberant inflammatory response elicited by thioglycollate challenge in gp91(phox) deficient mice is attenuated by CGS21680. These data suggest that treatment with A(2A)R agonists may be an effective therapy by which to regulate the immune system hyperactivity that results from a gp91(phox) deficiency.
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Hematopoietic stem cell transplantation for chronic granulomatous disease. Immunol Allergy Clin North Am 2010; 30:195-208. [PMID: 20493396 DOI: 10.1016/j.iac.2010.01.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency disease that is caused by the lack of 1 of 5 subunits of the superoxide-producing nicotinamide adenine dinucleotide phosphate oxidase of neutrophils, macrophages, and eosinophils. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for CGD and can be offered to selected patients. Improved outcome with supportive care and high clinical variability in the disease course, however, make selection of eligible patients for HSCT difficult. This article addresses recent progress in HSCT for CGD, delineates present limitations, and points to future developments.
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Lam GY, Huang J, Brumell JH. The many roles of NOX2 NADPH oxidase-derived ROS in immunity. Semin Immunopathol 2010; 32:415-30. [DOI: 10.1007/s00281-010-0221-0] [Citation(s) in RCA: 163] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2010] [Accepted: 08/08/2010] [Indexed: 12/27/2022]
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Estrogen receptor signaling and its relationship to cytokines in systemic lupus erythematosus. J Biomed Biotechnol 2010; 2010:317452. [PMID: 20617147 PMCID: PMC2896666 DOI: 10.1155/2010/317452] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2010] [Revised: 03/18/2010] [Accepted: 03/31/2010] [Indexed: 01/19/2023] Open
Abstract
Dysregulation of cytokines is among the main abnormalities in Systemic Lupus Erythematosus (SLE). However, although, estrogens, which are known to be involved in lupus disease,
influence cytokine production, the underlying molecular mechanisms remain poorly defined.
Recent evidence demonstrates the presence of estrogen receptor in various cell types of the
immune system, while divergent effects of estrogens on the cytokine regulation are thought to be
implicated. In this paper, we provide an overview of the current knowledge as to how estrogen-induced
modulation of cytokine production in SLE is mediated by the estrogen receptor while
simultaneously clarifying various aspects of estrogen receptor signaling in this disease. The
estrogen receptor subtypes, their structure, and the mode of action of estrogens by gene activation
and via extranuclear effects are briefly presented. Results regarding the possible correlation
between estrogen receptor gene polymorphisms and quantitative changes in the receptor protein
to SLE pathology and cytokine production are reviewed.
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Hamajima N, Hishida A. Genetic traits for the persistence of Helicobacter pylori infection. Per Med 2010; 7:249-262. [PMID: 29776221 DOI: 10.2217/pme.10.14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Helicobacter pylori infection elevates the risk of gastric diseases, including peptic ulcer and gastric cancer. Persistent infection is the first step to induce H. pylori-induced multistage diseases. Although the roles of genetic traits on persistent infection have not yet been elucidated, some individuals escape from persistent infection. Possible favorable conditions for H. pylori seem to be low acid secretion, reduced innate immune responses, and easier binding to gastric epithelial cells. IL-1β and TNF-α inhibit acid secretion. The genetic polymorphisms associated with both molecules have the potential to be the genetic traits underlying persistent infection. Functional polymorphisms associated with innate immune responses could also be involved with the genetic traits, but no polymorphisms with consistent associations have been identified so far. The polymorphisms associated with molecules for adhesion to epithelial cells are candidates of genetic traits, but more research is needed.
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Affiliation(s)
| | - Asahi Hishida
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
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