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

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