COPD is associated with production of autoantibodies to a broad spectrum of self-antigens, correlative with disease phenotype

Abstract

The role of autoimmune pathology in development and progression of chronic obstructive pulmonary disease (COPD) is becoming increasingly appreciated. In this study, we identified serum autoantibody reactivities associated with chronic bronchitis or emphysema, as well as systemic autoimmunity and associated lung disease. Using autoantigen array analysis, we demonstrated that COPD patients produce autoantibodies reactive to a broad spectrum of self-antigens. Further, the level and reactivities of these antibodies, or autoantibody profile, correlated with disease phenotype. Patients with emphysema produced autoantibodies of higher titer and reactive to an increased number of array antigens. Strikingly, the autoantibody reactivities observed in emphysema were increased over those detected in rheumatoid arthritis patients, and included similar reactivities to those associated with lupus. These findings raise the possibility that autoantibody profiles may be used to determine COPD risk, as well as provide a diagnostic and prognostic tool. They shed light on the heterogeneity of autoantibody reactivities associated with COPD phenotype and could be of use in the personalization of medical treatment, including determining and monitoring therapeutic interventions.

Fig. 1

COPD patients have serum autoantibodies reactive to healthy lung tissue. Purified IgG fractions from serum of representative healthy smokers (left), and chronic bronchitis (middle) and emphysema (right) patients were used to stain serial sections of non-smoker lung tissue. Brown coloration indicates immunoreactivity. Hematoxylin counterstain

Fig. 2

Severe COPD is associated with multiple autoantibody reactivities. Autoantigen reactivities of serum antibodies from patients diagnosed with GOLD stage III/IV COPD (n = 16) were compared with normal subjects. Shown are reactivities from array of 70 antigens that were significantly increased in the disease group. Statistical significance calculated using Mann–Whitney test for populations with unequal variance (one-tailed, all listed are p ≤ 0.05, **p ≤ 0.01)

Fig. 3

Autoantigen reactivity of serum antibodies are increased in emphysema relative to subjects with chronic bronchitis. Represented are the mean serum antibody reactivities to individual antigens (each dot denotes an antigen, crosshairs = SEM) of the chronic bronchitis versus emphysema groups as fold increase over normal (a). The diagonal line represents a slope of 1, and is illustrative of relative correlation. Dots falling along the diagonal reflect reactivities that are increased in both subject groups, while those removed from the diagonal are more likely to reflect variation. Relatively more autoantigen reactivity is observed in sera from emphysematous patients. Large colored dots (a) are re-illustrated below (b) as examples of variation in chronic bronchitis and emphysema antibody reactivities (*p ≤ 0.05, **p ≤ 0.01)

Fig. 4

Autoimmunity-associated ILD shows autoantibody profile variability, including reduced reactivity to array antigens. Mean reactivities to individual antigens compared from patient groups: SLE and SLE-ILD (a), RA and RA-ILD (c). The colored antigens found to be significantly different with autoimmunity-associated ILD are reillustrated for SLE (b). Aggrecan (c, green dot) reactivity is illustrated as individual subjects’ normalized MFI (d)

Fig. 5

Emphysema is characterized by less antibody autoreactivity than SLE, and greater than RA. Mean reactivities to individual antigens compared from patient groups: all SLE and emphysema (a), all RA and emphysema (b). Large black dots represent antigens that had statistically significant difference (p ≤ 0.05) between patient groups. The 18 antigens that varied between RA and emphysema were all increased in emphysema (b). The 7 that differed between SLE and emphysema included 4 increased in SLE, and 3 increased in emphysema (c) (*p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001)