**2.1. The concept of interstitial lung disease**

ILD, also known as diffuse parenchymal lung disease (DPLD), is a generic term encompassing a broad spectrum of heterogenous lung disorders, either idiopathic or associated with injurious or inflammatory causes, in which the major site of damage is the lung interstitium [1–3]. Because of the nature of DPLD which involves the interstitium, the ILDs share common radiologic, pathologic, and clinical manifestations. Clinically, exertional dyspnea and nonproductive cough are most common manifestations. Bilateral inspiratory fine crackles, most prominent at the lung bases, are usually audible on auscultation. Clubbed fingers characterized by hypertrophy and enlargement of the distal phalanges of the hands are often seen and reported in 30–50% of patients with IPF (idiopathic pulmonary fibrosis; to be mentioned later) [8]. Clinical features suggestive of rheumatic disorders, such as arthralgia, Raynaud's phenomenon, and skin manifestations, might be observed in the setting of an underlying CTD. The plain chest radiograph shows reduced lung volumes with bilateral reticular or reticulonodular opacities. High-resolution computed tomography (HRCT), which offers better definition of the characteristic details of lung parenchyma, can reveal usually bilateral, peripheral, and basilar predominant abnormalities with reticulonodular infiltrates, often with honeycombing and cystic changes by IP type to be described later. Although chest radiography is less useful than HRCT in the detailed evaluation, it is helpful for evaluating disease distribution and its serial change during patient follow up [8]. Physiologically, the patients demonstrate diminished diffusion capacity (decreased DLco) with usually restrictive impairment in pulmonary function tests.

#### **2.2. Classification of interstitial lung disease**

refers to involvement of the lung parenchyma by varying combination of fibrosis and inflammation [1, 2]. IP is included in the "interstitial lung disease" (ILD), i.e., a heterogenous group of diffuse parenchymal lung disorders, either idiopathic or associated with injurious or inflammatory causes, in which the major site of damage is the lung interstitium [3]. Customarily, the designations IP and ILD are sometimes used interchangeably. To be accurate, however, ILD comprises a broader range of lung diseases which involves the pulmonary interstitium, including drug-induced pneumonitis and eosinophilic pneumonia, etc. Primarily, IP refers to the particular disease entities which belong to idiopathic interstitial pneumonia (IIP) defined by the 2002 and 2012 American Thoracic Society/European Respiratory Society (ATS/ERS) classification [1–4]. IIP was categorized into several forms of IPs, afterward each histopathologic pattern of which has been applied to the ILD associated with underlying diseases as

From the pathophysiological perspective, the pulmonary interstitium consists of area with minimal connective tissue matrix between the capillaries and the alveolar space that allows close apposition of gas and blood flow leading to efficient gas exchange. If any injury from a specific exposure of chemicals or proteins, an autoimmune-mediated inflammation, or unknown etiology occurs and persists, the lung may respond to the damage by repairing process with increased interstitial tissue resulting in histological remodeling. Thus, ILDs may cause serious pulmonary

ILD comprises a variety of disorders with diverse backgrounds. A part of ILD has no identifiable underlying cause and is regarded as idiopathic, whereas it is often associated with a specific environmental exposure or with underlying diseases such as connective tissue disease (CTD) [1]. The CTDs are a group of systemic, inflammatory, autoimmune disorder, in which autoimmune-mediated tissue injury leads to multiple organ impairment including respiratory system. Today, IP or ILD is one of the most serious pulmonary complications associated with CTDs, resulting in significant morbidity and mortality [5]. Despite growing, understanding of the details of pathology in IPs, as well as accumulating evidences which support an association between IP with CTD and the presence of autoantibodies, the pathogenesis of

During the last years, we have been exploring the possible involvement of adaptive immunity in the pathogenesis of IP associated with CTDs, and we found intriguing evidence which strongly suggests a pivotal role of T cells in triggering the development of pulmonary alveolitis through antigen-driven immune responses in early stage IP [6, 7]. In this chapter, first, we will overview the current concepts of ILD as well as CTD-associated IP, in order to comprehend the whole picture including pathological features. Then, novel findings demonstrated in our recent studies of IP associated with polymyositis/dermatomyositis will be discussed.

ILD, also known as diffuse parenchymal lung disease (DPLD), is a generic term encompassing a broad spectrum of heterogenous lung disorders, either idiopathic or associated with injurious

dysfunction, which is often associated with substantial morbidity and poor prognosis.

well; the details of these will be described later.

146 Contemporary Topics of Pneumonia

CTD-associated IP remains unclear.

**2. Understanding of interstitial lung disease**

**2.1. The concept of interstitial lung disease**

**Figure 1** provides an overview of the classification of ILD, based on the 2002 and 2012 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification statements [1–3]. Briefly, ILDs consist of disorders of known causes (underlying diseases, environmental, or drug related) as well as disorders of unknown causes. The latter include idiopathic interstitial pneumonias (IIPs), granulomatous lung disorders (e.g., sarcoidosis), and other forms of orphan ILD, i.e., lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis/histiocytosis X (PLCH), and eosinophilic pneumonia. Thus, the ILDs comprise a variety of disorders with diverse backgrounds. Whereas a part of ILD has no identifiable underlying cause, often, it is associated with a specific environmental exposure or with underlying CTD [5]. ILDs are classified according to specific clinical, radiological, and histopathological features. The ILDs, however, frequently have similar clinical features. As ILDs are often uneasy to distinguish each other, the updated guidelines in the 2013 ATS/ERS classification statement underlined the importance of multidisciplinary diagnosis (MDD) facilitated by professional experts [2, 3]. Adequate presentation and discussion of clinical and radiological data are essential for an accurate MDD. Among diagnostic modalities, high-resolution computed tomography (HRCT) makes it possible to characterize ILD with great precision. Surgical lung biopsy also remains the gold standard for evaluation of ILD.
