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Approximately 5% to 10% of patients with asthma have severe disease that is not effectively controlled by typical therapies. The existence of an autoantigen associated with severe asthma has been previously reported.We attempted to identify the autoantigen.Severe asthma was defined as patients having at least 1 severe asthmatic exacerbation requiring an emergency department visit or admission in the last year despite continuous typical therapies. Autoantibodies to airway epithelial cells (A549) were examined in sera from patients with severe asthma by immunoblot analysis.IgG autoantibodies to the 52-kd airway epithelial cell antigen were detected in sera from 32 of 78 patients with severe asthma (41%), 9 of 83 patients with mild-to-moderate asthma (11%), and 2 of 58 healthy controls (3%; P < .001). The 52-kd autoantigen was identified as α-enolase by mass spectrometry analysis and confirmed by using recombinant human α-enolase protein. The detection of IgG autoantibodies to α-enolase was the most significant indicator for distinguishing severe asthma from mild-to-moderate asthma, even after adjusting for the effects of other clinical variables, including age, sex, atopy, and FEV1 (adjusted odds ratio, 5.2; 95% CI, 2.1-12.9; P < .001).The α-enolase was identified as an autoantigen associated with severe asthma. Further studies are needed to determine the significance of this autoantigen in severe asthma.IgG autoantibodies to α-enolase could be a biological marker for severe asthma.