TY - JOUR
T1 - Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance
AU - Ferré, Elise M.N.
AU - Break, Timothy J.
AU - Burbelo, Peter D.
AU - Allgäuer, Michael
AU - Kleiner, David E.
AU - Jin, Dakai
AU - Xu, Ziyue
AU - Folio, Les R.
AU - Mollura, Daniel J.
AU - Swamydas, Muthulekha
AU - Gu, Wenjuan
AU - Hunsberger, Sally
AU - Lee, Chyi Chia R.
AU - Bondici, Anamaria
AU - Hoffman, Kevin W.
AU - Lim, Jean K.
AU - Dobbs, Kerry
AU - Niemela, Julie E.
AU - Fleisher, Thomas A.
AU - Hsu, Amy P.
AU - Snow, Laquita N.
AU - Darnell, Dirk N.
AU - Ojaimi, Samar
AU - Cooper, Megan A.
AU - Bozzola, Martin
AU - Kleiner, Gary I.
AU - Martinez, Juan C.
AU - Deterding, Robin R.
AU - Kuhns, Douglas B.
AU - Heller, Theo
AU - Winer, Karen K.
AU - Rajan, Arun
AU - Holland, Steven M.
AU - Notarangelo, Luigi D.
AU - Fennelly, Kevin P.
AU - Olivier, Kenneth N.
AU - Lionakis, Michail S.
N1 - Publisher Copyright:
© 2019 American Association for the Advancement of Science. All rights reserved.
PY - 2019/6/5
Y1 - 2019/6/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85067518595&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aav5597
DO - 10.1126/scitranslmed.aav5597
M3 - Article
C2 - 31167928
AN - SCOPUS:85067518595
SN - 1946-6234
VL - 11
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 495
M1 - eaav5597
ER -