Circulating proteins in common variable immunodeficiency with granulomatous lymphocytic interstitial lung disease – A Nordic cross-sectional multi-centre study

Background Granulomatous lymphocytic interstitial lung disease (GLILD) is a non-infectious complication of common variable immunodeficiency (CVID) entailing increased morbidity and mortality. The pathogenesis of GLILD remain unclear, and optimal treatment strategies are lacking. We aimed to highlight GLILD pathogenesis and identify biomarkers by proteomics and immunoassays in two independent CVID cohorts. Methods We measured 183 proteins by plasma proteomics in a Norwegian discovery cohort . The most significantly upregulated proteins in GLILD were selected for enzyme immunoassays (EIA) or MesoScale analysis in a Nordic validation cohort , and again in the discovery cohort . Findings were correlated to pulmonary function, computed tomography findings and treatment data. Results The discovery cohort included 68 CVID patients (GLILD, n=23; other complications , n=24; infection only , n=21) and 20 healthy controls, and the validation cohort 189 patients (GLILD n=32; other complications , n=82; infection only, n=75). Fifty-seven proteins measured by proteomics in the discovery cohort were significantly higher in GLILD compared to the other groups. These proteins were functionally linked to T cell activation, and the proteomic signature of GLILD was distinct from other CVID related organ complications. Twenty-three proteins were selected for EIA/MesoScale measurement, confirming elevated CXCL13, soluble CD27, IL-10, CD25, IL18BPa, CD5, PD-1, Granzyme A and B in GLILD versus other complications and infection only in both cohorts. Eight of nine proteins correlated to CT score, and CXCL13 was higher in patients that subsequently needed treatment. Conclusions Circulating proteins in GLILD reflect T cell activation, and the germinal centre activity marker CXCL13 shows promise as prognostic biomarker.