In addition to IPF (which is defined as idiopathic UIP), the histologic pattern of UIP is also found in asbestosis (in the context of a persistent inorganic irritant), hypersensitivity pneumonitis (recurrent exposure to exogenous antigens), and collagen vascular diseases such as rheumatoid arthritis or scleroderma (recurrent exposure to self antigens).14 Thus, in each of the illnesses when UIP is attributable to a known cause, it is the result of a persistent or repetitive insult that leads to chronic inflammation, epithelial and endothelial injury of the alveolar-capillary barrier with loss of its BM, alveolar collapse and fusion, and fibroblast/myofibroblast activation and ECM deposition.8–14 A gene microarray analysis38 of pulmonary fibrosis has found genes related to smooth muscle markers, proteins involved in ECM formation, degradation, and signaling; and genes normally associated with chronic inflammation and immune responses, such as cytokines, chemokines, antioxidants, complement, amyloid, and Igs. The latter findings are suggestive of a chronic inflammation/immune response in the lungs of patients with IPF. In support of this notion is the finding of tertiary lymphoid tissue with the accumulation of reactivated memory T cells, B cells, and locally maturing dendritic cells in the lungs of IPF patients.39 The presence of tertiary lymphoid tissue in IPF lungs represents an immunologic response that may play a central role in sustaining chronic inflammation that could be resistant to antiinflammatory agents. Further support of the concept of an immunologic response in the lungs of IPF patients has come from40,41 imaging studies that demonstrate a direct correlation of the presence of mediastinal lymphadenopathy on chest CT scans and fibrosis in patients with IPF. These studies40,41 independently demonstrated the baseline prevalence of mediastinal lymphadenopathy in IPF patients to be approximately 55%. Moreover, radiographic quantification of the magnitude of ground-glass opacities, fibrosis, and progression of fibrosis in IPF patients correlated directly with the degree of lymphadenopathy.40 Taken together, the above studies at the molecular, cellular, and imaging levels support the concept of the potential of a persistent or recurrent antigen exposure in the lungs of patients with IPF that correlates with the progression of fibrosis.