Classification of idiopathic interstitial pneumonias using anti\u2013myxovirus resistance-protein 1 autoantibody

Yoshimasa Hamano,Toru Arai,Kenji Mizuguchi,Shôichi Ihara ,Noriyuki Tomiyama,Akihiro Murakami,Yoshito Takeda,Haruhiko Hirata,Hyota Takamatsu,Takashi Kijima,Izumi Nagatomo,Toshiyuki Minami,Tomoyuki Otsuka,Yukihiro Yano,Hiroyoshi Nishikawa,Osamu Honda,Masaki Hirose,Toshimitsu Hamasaki,Ken Ueda,Lokesh P Tripathi,Yoshikazu Inoue,Koji Inoue,Masahide Mori,Yasuhiro Kato,Masahiro Yanagawa,Tetsuya Kimura,Masanori Kitaichi,Hiroshi Kida,Atsushi Kumanogoh

doi:10.1038/srep43201

Abstract

Chronic fibrosing idiopathic interstitial pneumonia (IIP) can be divided into two main types: idiopathic pulmonary fibrosis (IPF), a steroid-resistant and progressive disease with a median survival of 2–3 years, and idiopathic non-specific interstitial pneumonia (INSIP), a steroid-sensitive and non-progressive autoimmune disease. Although the clinical courses of these two diseases differ, they may be difficult to distinguish at diagnosis. We performed a comprehensive analysis of serum autoantibodies from patients definitively diagnosed with IPF, INSIP, autoimmune pulmonary alveolar proteinosis, and sarcoidosis. We identified disease-specific autoantibodies and enriched KEGG pathways unique to each disease, and demonstrated that IPF and INSIP are serologically distinct. Furthermore, we discovered a new INSIP-specific autoantibody, anti–myxovirus resistance-1 (MX1) autoantibody. Patients positive for anti-MX1 autoantibody constituted 17.5% of all cases of chronic fibrosing IIPs. Notably, patients rarely simultaneously carried the anti-MX1 autoantibody and the anti–aminoacyl-transfer RNA synthetase autoantibody, which is common in chronic fibrosing IIPs. Because MX1 is one of the most important interferon-inducible anti-viral genes, we have not only identified a new diagnostic autoantibody of INSIP but also obtained new insight into the pathology of INSIP, which may be associated with viral infection and autoimmunity.

Highlights

We hypothesized that identification of new autoantibodies or a repertoire of autoantibodies associated with interstitial pneumonia (INSIP) might serve as biomarkers capable of distinguishing a unique subgroup of patients with chronic fibrosing interstitial pneumonia (IIP) who share some clinical characteristics with patients with INSIP
APAP is caused by anti–GM-CSF autoantibody, and was included as a positive control to confirm the validity of our screening method (Fig. 1A)
We identified idiopathic pulmonary fibrosis (IPF), INSIP, autoimmune pulmonary alveolar proteinosis (aPAP), and sarcoidosis-specific autoantibodies, with no overlap across diseases, by screening more than 8,000 autoantibodies

Summary

Introduction

Recent evidence revealed that even patients diagnosed with IPF follow different clinical courses[5,10] Other conditions, such as chronic hypersensitivity pneumonitis or interstitial pneumonia associated with collagen vascular disease (CVD), are often confused with IPF or INSIP2,11. An autoantibody against melanoma differentiation–associated gene-5 (MDA5) can be used to distinguish a unique subgroup of patients with polymyositis/dermatomyositis who exhibit clinically amyopathic dermatomyositis, when complicated by acute progressive interstitial lung disease[14]. We conducted three independent studies to clarify and discover autoantibodies that could serve as biomarkers for differential diagnosis in patients with IIPs. First, in our discovery cohort, we tried to identify a group of autoantibodies specific to each of the four independent inflammatory lung diseases [IPF, INSIP, autoimmune pulmonary alveolar proteinosis (aPAP), and sarcoidosis] using a protein array to search for serum autoantibody signatures unique to IPF and INSIP. We conducted a nested case– control study to elucidate the prognosis of anti-MX1 autoantibody–positive patients with chronic fibrosing IIPs

Methods

Results

Conclusion