An AIREless Breath: Pneumonitis Caused by Impaired Central Immune Tolerance.

Elise M N Ferré,Michail S Lionakis

doi:10.3389/fimmu.2020.609253

Abstract

Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by biallelic mutations in the AIRE gene, has historically been defined by the development of chronic mucocutaneous candidiasis together with autoimmune endocrinopathies, primarily hypoparathyroidism and adrenal insufficiency. Recent work has drawn attention to the development of life-threatening non-endocrine manifestations such as autoimmune pneumonitis, which has previously been poorly recognized and under-reported. In this review, we present the clinical, radiographic, autoantibody, and pulmonary function abnormalities associated with APECED pneumonitis, we highlight the cellular and molecular basis of the autoimmune attack in the AIRE-deficient lung, and we provide a diagnostic and a therapeutic roadmap for patients with APECED pneumonitis. Beyond APECED, we discuss the relevance and potential broader applicability of these findings to other interstitial lung diseases seen in secondary AIRE deficiency states such as thymoma and RAG deficiency or in common polygenic autoimmune disorders such as idiopathic Sjögren’s syndrome.

Highlights

Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), known as autoimmune polyglandular syndrome type-1 (APS-1), is a rare disorder resulting from biallelic mutations in the autoimmune regulator (AIRE) gene
We have proposed inclusion of an adjunct triad of early-onset manifestations, namely APECED rash, Autoimmune Pneumonitis in Patients With AIRE Deficiency intestinal dysfunction, and enamel hypoplasia, into expanded diagnostic criteria which would reduce the time to clinical diagnosis by half [3]
Beyond primary and secondary AIRE-deficiency states, interstitial lung disease (ILD) with a similar compartmentalized immunopathology consisting of airway neutrophil expansion and lymphocytic bronchiolitis develops among a subset of patients with certain polygenic autoimmune diseases such as Sjögren’s syndrome (SS), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and dermatomyositis (DM) [61,62,63,64]

Summary

Introduction

Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), known as autoimmune polyglandular syndrome type-1 (APS-1), is a rare disorder resulting from biallelic mutations in the autoimmune regulator (AIRE) gene. Ground-glass opacities (GGO) or mosaicism and bronchiectasis are the most common abnormalities; they are seen, either alone or in combination, in all patients with APECED pneumonitis, including those without respiratory symptoms and negative lung-targeted autoantibodies (see below) [5].

Results

Conclusion