Serum free light chains and the adaptive immune response in usual and alpha-1-antitrypsin deficiency-related chronic obstructive pulmonary disease

Abstract

BackgroundChronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition with a complex pathophysiology. In COPD, the immune response involves the adaptive immune system, although the antigenic stimulus driving this response is unknown. During the process of antibody synthesis an excess of free light chains (FLCs) are produced and secreted into the circulation. High polyclonal FLC concentrations have been found in several autoimmune and inflammatory conditions such as systemic lupus erythematosus and rheumatoid arthritis. Thus, FLCs are being investigated as a biomarker of immune activation, disease activity, and severity in these conditions. Our aim was to establish whether serum FLCs could be a marker of phenotypic variation or predict poor outcome in patients with usual and alpha-1-antitrypsin deficiency (A1ATD)-related COPD. MethodsWe measured FLC concentrations in 294 COPD patients with A1ATD-related and 85 patients with usual COPD using the Freelite serum FLC assay (The Binding Site Ltd, Birmingham, UK). We then compared combined (κ and λ) FLC (cFLC) concentrations in different subgroups defined by the presence of chronic bronchitis, colonisation of the lower respiratory tract, and subsequent mortality. In addition, we measured the estimated glomerular filtration rate (eGFR) of patients included in the study. FindingsOur preliminary data showed that in A1ATD-related COPD and usual COPD, cFLC concentrations were significantly higher in patients with chronic bronchitis than in those without bronchitis (p=0·008 vs p=0·047). Patients with A1ATD-related COPD who were chronically colonised with pathogenic organisms in their stable state also had significantly higher cFLC concentrations than did those who were not colonised (p=0·036). A multiple regression analysis showed that eGFR and the presence of chronic bronchitis significantly predicted cFLC concentrations in patients with A1ATD: renal function was the strongest predictor (β=−0·326, p<0·0001) followed by the presence of chronic bronchitis (β=0·147, p=0·01). A similar trend was seen in the usual COPD group although this did not meet statistical significance (eGFR β=−0·220, p=0·055; chronic bronchitis β=0·224, p=0·061). The 33 A1ATD patients who subsequently died also had significantly higher cFLC concentrations (p=0·005) than did those still alive. InterpretationThe higher cFLC concentrations in patients with A1ATD-related COPD who have chronic bronchitis and colonised lower respiratory tracts could mean that there is a greater adaptive immune response in these individuals. The drive behind this response might come directly from microorganisms or through self-perpetuating autoimmune events. Within the specialty of COPD clinical management, there is a move towards a more individualised approach to treating different clinical phenotypes. Measurement of serum FLCs might have a potential role as a biomarker to help stratify patients. The higher cFLC concentrations in patients with renal impairment is unsurprising in view of their renal clearance, but raised polyclonal FLCs have also been shown to be a predictor of mortality in the general population. Our mortality results suggest that FLCs could have a role in risk stratification for patients with COPD, but further investigation is needed. FundingGrifols Therapeutics.