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

AIRE deficiency causes a characteristic pattern of pulmonary immunopathology that is responsive to T and B lymphocyte–directed immunomodulation. A breath of fresh AIRE: Mutations in the AIRE gene lead to APECED, which presents with a variety of autoimmune symptoms. Ferré et al. prospectively studied a large cohort of patients with APECED and discovered that a substantial proportion of them suffered from pneumonitis, which had gone largely undiagnosed. The airways and lung tissue were characterized by infiltration of activated neutrophils and lymphocytes. This infiltration was also observed in Aire^−/− mice, and pneumonitis was ablated by T or B cell deficiency. Accordingly, patients treated with drugs to modulate T or B lymphocytes resolved pneumonitis symptoms and improved respiratory function. This study reveals a serious and previously unappreciated manifestation of AIRE deficiency and paves the way for interventions. 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. [ABSTRACT FROM AUTHOR]