Autoantibodies in patients with chronic obstructive pulmonary disease

Abstract

Rationale: Adaptive immune responses are present in patients with chronic obstructive pulmonary disease (COPD), and it has been postulated that these processes could be autoreactive.

Objectives: To ascertain if humoral autoimmunity could play a role in COPD pathogenesis.

Methods: Circulating IgG autoantibodies were detected by immunofluorescence and immunoprecipitation. Immunohistochemistry and immunofluorescence were used to evaluate intrapulmonary IgG and complement (C3) deposition in human lung explants. Autoantibody pathogenicity was also investigated with an antibody-dependent cell-mediated cytotoxicity assay.

Measurements and main results: The prevalence of anti-HEp-2 epithelial cell autoantibodies in 47 smokers/former smokers with COPD (GOLD stages 1-4) was greater than among 8 subjects with a smoking history but normal spirometry and 21 healthy control subjects who had never smoked (68 vs. 13 vs. 10%, respectively; P < 0.0001). Antibodies against primary pulmonary epithelial cells were found in 12 of 12 patients with COPD versus 3 of 12 never-smoked control subjects (P < 0.001). Self-antigens immunoprecipitated from 34 of 35 (97%) of COPD plasmas (vs. 0/12 never-smoked controls). Antibodies against a particular 130-kD autoantigen (n = 7) were associated with decreased body mass index (23.2 +/- 2.1 vs. 29.5 +/- 1.0 kg/m(2), P = 0.007). Intrapulmonary immune complexes were present in six of six and C3 was seen in five of six COPD lung explants, unlike zero of six and one of six normals, respectively. Cytotoxicity of pulmonary epithelial cells by allogeneic mononuclear cells also increased 46% after incubation with COPD plasmas (n = 10), compared with identical treatments with eight normal specimens (P = 0.03).

Conclusions: IgG autoantibodies with avidity for pulmonary epithelium, and the potential to mediate cytotoxicity, are prevalent in patients with COPD. Autoreactive adaptive immune responses may be important in the etiology of this disease.

Figure 1.

Antiepithelial autoantibodies in patients with chronic obstructive pulmonary disease (COPD). (A) The prevalence of autoantibodies detected by indirect immunofluorescence is much greater among subjects with COPD and abnormal expiratory airflow obstruction (GOLD stages 1–4) than in either healthy normal control subjects with no smoking history (NS Controls) or current or ex-smokers with normal spirometry (S Controls). Numbers of subjects in each population are denoted within columns. (B) Prevalences of antiepithelial autoantibodies among subjects with COPD and abnormal spirometry. Numbers of subjects in each population are denoted within columns. These respective prevalences (GOLD 1–4) are 62, 71, 73, and 64%. (C) Distributions of autoantibody fluorescence patterns among those subjects with COPD who had IgG autoantibodies detected by indirect immunofluorescence. (D) Predominant fluorescence patterns, clockwise from bottom left: speckled, nucleolar, mixed (both speckled and nucleolar), and negative specimens.

Figure 2.

Detection of autoantibodies in patients with chronic obstructive pulmonary disease (COPD) by immunoprecipitation. (A) Multiple bands depicting cellular antigens precipitated by autoantibodies are evident in the representative COPD specimens (composite figure). Molecular weight marker is denoted by kD. Specimens from representative never-smoked control subjects are denoted by Control. Each lane depicts an individual subject specimen. The locations of the most prevalent autoantigens (62, 75, 115, 130) are denoted by arrows. (B) Body mass indexes (BMI) were significantly decreased among the seven subjects with COPD and antibodies against the 130-kD autoantigen, compared with the 28 patients lacking humoral responses to this particular antigen.

Figure 3.

IgG deposition in lung explants. Immunohistochemical images of explanted sections to evaluate IgG deposition (dark red–brown). Left panels: photomicrographs of representative chronic obstructive pulmonary disease (COPD) lungs showing IgG deposition within alveolar septa and small airway walls. Top right is a normal control. Bottom right is an isotype antibody control. Images are ×20 original magnification.

Figure 4.

Complement (C3) deposition and antibody-dependent cell-mediated cytotoxicity mediated by chronic obstructive pulmonary disease (COPD) autoantibodies. (A) C3 stains red against the blue cellular background in alveolar septa of two representative COPD lung sections (left panels) compared with those from normal subjects (right panels). (B) Incubation of human primary airway epithelial cells with plasmas from COPD patients (n = 10) enhances allogeneic cytotoxicity compared with effects of plasmas from normal control subjects (n = 8).