Plasma acute phase proteins with specific emphases on alpha1-antitrypsin polymers and transcriptome of blood neutrophils in PiMM and PiZZ COPD patients

Compared to normal PiMM, people with the α1-antitrypsin (AAT) deficiency genotype PiZZ (Glu342Lys) are at higher risk of developing early-onset neutrophilic inflammation-related and emphysema-like chronic obstructive pulmonary disease (COPD). Intravenous plasma-purified AAT (IV-AAT) is a specific therapy to increase AAT levels in emphysema patients with AAT deficiency. To compare the levels of systemic acute phase proteins and neutrophil transcriptome, age-, gender- and smoking status-matched COPD patients with PiMM and PiZZ genotypes (on and off IV-AAT) were selected. Nephelometric analysis of 7 plasma acute phase proteins in 67 PiMM and 44 PiZZ (21 on and 23 off IV-AAT), Western blot of Z-AAT polymers in 38 PiZZ and RNA sequencing of blood neutrophils from 6 PiMM and 10 PiZZ (4 on and 6 off IV-AAT) patients were performed. As expected, compared to PiMM, PiZZ patients had lower AAT but significantly higher plasma levels of α2-macroglobulin (A2MG). Plasma levels of Z-AAT polymers in PiZZ COPD were: 374 (169) µg/ml [mean (SD)]. Although IV-AAT therapy increased AAT, it had no effect on A2MG and Z-AAT polymer levels, which showed a direct correlation (r= 0.57, p= 0.003, n= 37). Furthermore, we found direct correlations between Z-AAT polymers and age (r= 0.47, p= 0.03) and an inverse correlation between Z-AAT polymers and FEV1/FVC pre% (r= -0.56, p= 0.01). PiZZ patients had a lower DLCO percentage that was unaffected by IV-AAT therapy. PiMM and PiZZ blood neutrophils showed extremely similar transcriptome profiles. The differentially expressed genes (n= 21) were only found between PiZZ off IV-AAT and PiMM. Taken together, low AAT but higher A2MG differentiate PiZZ from PiMM COPD. A typical feature of PiZZ carriers is circulating Z-AAT polymers, which appear to increase with age. The clinical value of A2MG and Z-AAT polymers in PiZZ COPD requires further attention.