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Title: | Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance. | Authors: | Holland S.M.;Darnell D.N.;Ojaimi S. ;Cooper M.A.;Bozzola M.;Kleiner G.I.;Martinez J.C.;Deterding R.R.;Kuhns D.B.;Heller T.;Winer K.K.;Rajan A.;Snow L.N.;Notarangelo L.D.;Fennelly K.P.;Olivier K.N.;Lionakis M.S.;Folio L.R.;Mollura D.J.;Swamydas M.;Gu W.;Hunsberger S.;Lee C.-C.R.;Bondici A.;Hoffman K.W.;Lim J.K.;Dobbs K.;Niemela J.E.;Fleisher T.A.;Hsu A.P.;Ferre E.M.N.;Break T.J.;Burbelo P.D.;Allgauer M.;Kleiner D.E.;Jin D.;Xu Z. | Monash Health Department(s): | Infectious Diseases and Clinical Microbiology | Institution: | (Ferre, Break, Swamydas, Bondici, Snow, Darnell, Lionakis) Fungal Pathogenesis Section, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, United States (Burbelo) Dental Clinical Research Core, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, MD 20892, United States (Allgauer, Kleiner, Lee) Laboratory of Pathology, Center for Cancer Research, NCI, Bethesda, MD 20892, United States (Allgauer) Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany (Jin, Xu, Folio, Mollura) Radiology and Imaging Sciences, NIH Clinical Center (CC), NIH, Bethesda, MD 20892, United States (Gu, Hunsberger) Biostatistics Research Branch, Division of Clinical Research (DCR), NIAID, Bethesda, MD 20892, United States (Hoffman, Lim) Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States (Dobbs, Notarangelo) Immune Deficiency Genetics Section, LCIM, NIH, Bethesda, MD 20892, United States (Niemela, Fleisher) Immunology Service, Department of Laboratory Medicine (DLM), NIH CC, Bethesda, MD 20892, United States (Hsu, Holland) Immunopathogenesis Section, LCIM, NIAID, Bethesda, MD 20892, United States (Ojaimi) Department of Infectious Diseases, Monash Health, Melbourne, VIC 3800, Australia (Ojaimi) Centre for Inflammatory Diseases, Monash University, Melbourne, VIC 3800, Australia (Cooper) Department of Pediatrics, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, United States (Bozzola) Department of Pediatrics, British Hospital, Perdriel 74, CABA-Buenos Aires, Argentina (Kleiner) University of Miami Department of Pediatrics, Miami, FL 33136, United States (Martinez) Cystic Fibrosis, Pulmonary and Sleep Division, Joe DiMaggio Children's Hospital, Hollywood, FL 33021, United States (Deterding) Department of Pediatrics, University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO 80045, United States (Kuhns) Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, United States (Heller) Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States (Winer) Pediatric Growth and Nutrition Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD 20892, United States (Rajan) Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, NIH, Bethesda, MD 20892, United States (Fennelly, Olivier) Laboratory of Chronic Airway Infection, Pulmonary Branch, Blood Institute (NHLBI), Bethesda, MD 20892, United States | Issue Date: | 15-Jul-2019 | Copyright year: | 2019 | Publisher: | American Association for the Advancement of Science | Place of publication: | United States | Publication information: | Science Translational Medicine. 11 (495) (no pagination), 2019. Article Number: eaav5597. Date of Publication: 05 Jun 2019. | Journal: | Science Translational Medicine | Abstract: | Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967-979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune tolerance.Copyright © 2019 American Association for the Advancement of Science. All rights reserved. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1126/scitranslmed.aav5597 | PubMed URL: | 31167928 [http://www.ncbi.nlm.nih.gov/pubmed/?term=31167928] | ISSN: | 1946-6234 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/36103 | Type: | Article | Subjects: | prospective study protein depletion radiodiagnosis respiratory failure/co [Complication] respiratory tract disease school child symptom T lymphocyte thymoma autoantibody/ec [Endogenous Compound] autoimmune regulator protein/ec [Endogenous Compound] azathioprine/cb [Drug Combination] azathioprine/dt [Drug Therapy] diphenhydramine methylprednisolone/dt [Drug Therapy] mycophenolate mofetil/cb [Drug Combination] mycophenolate mofetil/dt [Drug Therapy] paracetamol rituximab/cb [Drug Combination] rituximab/dt [Drug Therapy] unclassified drug BPIFB1 antibody/ec [Endogenous Compound] KCNRG antibody/ec [Endogenous Compound] AIRE gene adolescent adverse drug reaction/dt [Drug Therapy] adverse drug reaction/pc [Prevention] article *autoimmune polyendocrinopathy candidiasis ectodermal dystrophy autoimmunity B lymphocyte bioaccumulation blood examination bronchiole bronchoalveolar lavage fluid bronchus biopsy cellular immunity child chronic disease clinical article clinical examination controlled study death diagnostic error female functional disease/di [Diagnosis] gene mutation homozygote human human cell human tissue hypoxemia/co [Complication] immune deficiency *immunological tolerance immunomodulation immunopathogenesis *immunopathology leukocyte activation lung biopsy lung epithelium lung function test lung interstitium lung mucosa lung parenchyma *lymphocyte function lymphocytic infiltration male molecular pathology observational study *pneumonia/di [Diagnosis] *pneumonia/dt [Drug Therapy] *pneumonia/et [Etiology] priority journal cellular immunity child chronic disease clinical article clinical examination controlled study death diagnostic error female functional disease / diagnosis gene mutation homozygote human human cell human tissue hypoxemia / complication immune deficiency *immunological tolerance immunomodulation immunopathogenesis *immunopathology leukocyte activation lung biopsy lung epithelium lung function test lung interstitium lung mucosa lung parenchyma *lymphocyte function lymphocytic infiltration male molecular pathology observational study Article priority journal prospective study protein depletion radiodiagnosis respiratory failure / complication respiratory tract disease school child symptom T lymphocyte thymoma adverse drug reaction / drug therapy / prevention adolescent *pneumonia / *diagnosis / *drug therapy / *etiology *autoimmune polyendocrinopathy candidiasis ectodermal dystrophy autoimmunity B lymphocyte bioaccumulation blood examination bronchiole bronchoalveolar lavage fluid bronchus biopsy |
Type of Clinical Study or Trial: | Observational study (cohort, case-control, cross sectional or survey) |
Appears in Collections: | Articles |
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