Sputum autoantibodies in severe eosinophilic asthma.

The persistence of eosinophils in sputum despite high doses of corticosteroids indicates disease severity in asthma. Chronic inflamed airways over time may lose tolerance to immunogenic entities released upon frequent eosinophil degranulation, which further contributes to disease severity and necessitates increase in maintenance corticosteroids.To investigate the possibility of a polyclonal autoimmune event in asthmatic airways, and identify associated clinical and molecular characteristics.Presence of autoantibodies against eosinophil peroxidase (EPX) and anti-nuclear antibodies (ANAs) was investigated in eosinophilic asthmatics maintained on high dose corticosteroids and/or prednisone. The ability of sputum immunoglobulins to induce eosinophil degranulation in vitro was assessed. In addition, the associated inflammatory micro-environment in patients with detectable autoantibodies was examined.We report a "polyclonal" autoimmune event occurring in the airways of prednisone-dependent asthmatics with increased eosinophil activity and/or recurrent pulmonary infections, evident by the concomitant presence of sputum anti-EPX and ANAs of the IgG subtype. Extensive cytokine profiling of the sputum revealed a Th2-dominated micro-environment (eotaxin-2, IL-5, IL-18, IL-13), and increased signalling molecules that support the formation of ectopic lymphoid structures (B-cell activating factor, B-cell attracting chemokine-1). Immunoprecipitated sputum immunoglobulins from patients with increased autoantibodies triggered eosinophil degranulation in vitro, with release of extensive histone-rich extracellular-traps; an event unsuppressed by dexamethasone possibly contributing to the steroid-unresponsive nature of these eosinophilic patients.This study identifies an "autoimmune" endotype of severe asthma that can be identified by the presence of sputum autoantibodies against EPX and autologous cellular components.