Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance

• Verfasst von: Ferré, Elise [VerfasserIn]
• Verfasst von: Allgäuer, Michael [VerfasserIn]
• Titel: Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance
• Verf.angabe: Elise M. N. Ferré, Timothy J. Break, Peter D. Burbelo, Michael Allgäuer, David E. Kleiner, Dakai Jin, Ziyue Xu, Les R. Folio, Daniel J. Mollura, Muthulekha Swamydas, Wenjuan Gu, Sally Hunsberger, Chyi-Chia R. Lee, Anamaria Bondici, Kevin W. Hoffman, Jean K. Lim, Kerry Dobbs, Julie E. Niemela, Thomas A. Fleisher, Amy P. Hsu, Laquita N. Snow, Dirk N. Darnell, Samar Ojaimi, Megan A. Cooper, Martin Bozzola, Gary I. Kleiner, Juan C. Martinez, Robin R. Deterding, Douglas B. Kuhns, Theo Heller, Karen K. Winer, Arun Rajan, Steven M. Holland, Luigi D. Notarangelo, Kevin P. Fennelly, Kenneth N. Olivier, Michail S. Lionakis
• E-Jahr: 2019
• Jahr: 5 June 2019
• Umfang: 16 S.
• Fussnoten: Gesehen am 16.08.2019
• Titel Quelle: Enthalten in: Science translational medicine
• Ort Quelle: Washington, DC : AAAS, 2009
• Jahr Quelle: 2019
• Band/Heft Quelle: 11(2019,495) Artikel-Nummer eaav5597, 16 Seiten
• ISSN Quelle: 1946-6242
• DOI: doi:10.1126/scitranslmed.aav5597
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1671527356

Abstract

<p>Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by <i>AIRE</i> 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 <i>AIRE</i> 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.</p>