A74-43 Identification of an Idiopathic Pulmonary Fibrosis Subpopulation With Dysregulated Mucosal Immunity

Abstract

Recent evidence suggests that mucosal immunity could be dysregulated in idiopathic pulmonary fibrosis (IPF). However, local autoimmunity remains to be fully characterized. In this study, we screened IPF patients for the presence of lung IgA autoantibodies and studied molecular, clinical, radiological and pathological data for potential correlations. We hypothetized that a subgroup of IPF would elicit local autoimmunity and constitute a specific endotype. We screened all 198 patients prospectively included in our progressive fibrosis biobank (PNEU-ILD-01, 2017/04JAN/010) and included subjects with a definite diagnosis of IPF according to ATS-ERS guidelines, for whom bronchoalveolar fluid (BALF), serum, lung HRCT and ≥24-month follow-up data were available. We quantified BALF IgA autoantibodies by indirect immunofluorescence on HEp2 cells (HEp2-IFA) and identified their molecular targets using ImmunoDots. We used BALF from age-matched controls to determine the detection threshold of IgA autoantibodies. Total IgA and B-cell-related cytokines were measured by ELISA in BALF and serum. Two experienced radiologists centrally reviewed HRCT images for the presence of mediastinal lymph nodes enlargement (≥10 mm short axis). We included 50 patients (41 men, 82%) and 13 biopsies were available for analysis. All patients met ATS-ERS criteria for IPF without criteria for IPAF or connective-tissue disease. We detected significant levels of BALF IgA autoantibodies in 27/50 patients (54%). Levels of IgA autoantibodies and APRIL, a B-cell related cytokine, correlated in BALF. Identified targets of autoantibodies included OJ, PM-Scl75 and PM-Scl100. Patients with local autoantibodies had a significantly lower baseline FVC (P < 0.05) and displayed more lymph node enlargement (P < 0.05). Finally, we performed a multiple correspondence analysis with unsupervised hierarchical clustering, leading to the identification of two significantly different clusters: cluster 1 included most auto-antibodies-positive patients, with lower FVC and enlarged lymph nodes while cluster 2 included the majority of our cohort’s women, few IgA auto-antibodies-positive patients and better FVC. In conclusion, our study led to the identification of an IPF subgroup that elicits local autoimmunity and significant differences in relevant clinical features. On top of paving the way for endotypes identification in IPF, our findings highlight potentially relevant therapeutic targets.

This abstract is funded by: FNRS