Active Antigen-Specific Adaptive Immune Responses Are Shared among Patients with Progressive Fibrotic Interstitial Lung Disease

<b>Rationale:</b> Enlargement of lung-associated lymph nodes (LNs) predicts worse survival in all patients with interstitial lung disease (ILD). This phenomenon occurs in both connective tissue disease-associated ILD and, surprisingly, idiopathic pulmonary fibrosis (IPF), where immune-driven pathogenesis is controversial. <b>Objectives:</b> To determine whether immune responses in the lung LNs of patients with ILD are antigen-specific and significant to pathology and etiology. <b>Methods:</b> ILD lung LNs excised at transplant (30 IPF, 7 interstitial pneumonia with autoimmune features, 4 hypersensitivity pneumonitis, 5 connective tissue disease-associated ILD, 5 other ILD) and 36 donor control lung LNs were analyzed by spectral flow cytometry. Formalin-fixed lung LNs and OCT-fixed lung samples of patients with IPF were used to determine germinal center (GC) and antigen-specific responses. Serum autoantibody responses were measured by radioligand binding assay. <b>Measurements and Main Results:</b> All patients with ILD revealed a common adaptive immune landscape of antigen responses in lung LNs characterized by the presence of GC B cells, T follicular helper cells, and activated T cells. Immunological synapses identified in the lung LNs demonstrated that antigen stimulation is ongoing in patients with ILD. Lung LN frequencies of T follicular helper and T regulatory cells correlated with circulating antibody concentrations to ABLIM1, a recently identified autoantigen expressed widely, including in aberrant basaloid cells that are uniquely found in fibrotic lungs. <b>Conclusions:</b> Antigen-induced activation and development of GC in enlarged lung LNs represents a shared immunopathologic mechanism associated with progressive pulmonary fibrosis among patients with ILD, regardless of etiology. Autoantigens overexpressed in progressive pulmonary fibrosis may be key drivers of these GC responses.