Identification of an Autoantigen Demonstrates a Link Between Interstitial Lung Disease and a Defect in Central Tolerance

Abstract

Interstitial lung disease (ILD) is a common manifestation of systemic autoimmunity characterized by progressive inflammation or scarring of the lungs. Patients who develop these complications can exhibit significantly impaired gas exchange that may result in hypoxemia, pulmonary hypertension and even death. Unfortunately, little is understood about how these diseases arise, including the role of specific defects in immune tolerance. Another key question is whether autoimmune responses targeting the lung parenchyma are critical to ILD pathogenesis, including that of isolated, idiopathic forms. We show that a specific defect in central tolerance brought about by mutations in the autoimmune regulator gene (Aire) leads to an autoreactive T cell response to a lung antigen named vomeromodulin and the development of ILD. We found that a human patient and mice with defects in Aire develop lung pathology that is strikingly similar, demonstrating that the AIRE-deficient model of autoimmunity is a suitable translational system in which to unravel fundamental mechanisms of ILD pathogenesis.

Regulatory T cell defect in APECED patients is associated with loss of naive FOXP3+ precursors and impaired activated population

“…In particular, the Aire-deficient murine models have revealed Aire's role in regulating the ectopic transcription of tissue-restricted antigens in the thymus [3,4,35]. However, it is clear that Aire has other functions, too, and that the increased escape of autoreactive T cells from negative selection is not sufficient to cause APECED.…”

Serum biomarkers in idiopathic pulmonary fibrosis

“…CD4+ T cells from IPF patients show characteristics of an autoreactive immune process, and an autoreactive T cell response, due to mutations in the autoimmune regulator gene, is associated with the development of interstitial lung disease [46][47]. Furthermore, an association was found between exacerbations of IPF and a reaction to auto-antigens [48].…”

Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection

“…Both patients and mice with defects in Aire develop multiorgan autoimmunity, reinforcing the importance of this process in controlling immune tolerance (2). Several organ-specific autoimmune diseases in the Aire-deficient model can be linked to a failure in the appropriate thymic expression of a given TSA under the control of Aire (3)(4)(5)(6). Autoimmunity in the eyes of Aire-deficient mice arises as a response against the retina-specific protein interphotoreceptor retinoid binding protein (IRBP) (3).…”