Novel autoantigens immunogenic in COPD patients

Leidinger, Petra; Keller, Andreas; Heisel, Sabrina; Ludwig, Nicole; Rheinheimer, Stefanie; Klein, Veronika; Andrès, C.; Hamacher, Jürg; Huwer, Hanno; Stephan, B.; Stehle, Ingo; Lenhof, Hans‐Peter; Meese, Eckart

doi:10.1186/1465-9921-10-20

Cited by 44 publications

(36 citation statements)

References 29 publications

(29 reference statements)

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“…The increased prevalence of anti-elastin antibodies in a subset of patients with COPD with severe pulmonary emphysema (5) has been contradicted by more recent publications (33)(34)(35)(36). However, autoantibodies to several unidentified epithelial cell proteins (6) and general tissue proteins (37) have also been demonstrated, as well as antibodies in the serum of patients with COPD directed against a number of peptide epitopes from a peptide array (8). In addition, a very recent publication has reported the increased presence of anti-endothelial cell autoantibodies in COPD (9).…”

Section: Discussionmentioning

confidence: 97%

“…Serum autoantibodies against elastin (5) and bronchial epithelial cells along with corresponding IgG and complement (C3) deposition (6) have been observed in COPD lung. It has therefore been proposed that cigarette smoke-derived antigens may be responsible for driving this disease process in COPD (6)(7)(8)(9), but until now this has not been investigated. In addition, complement activation in the lung, which is usually direct evidence of autoimmune activation, has not been examined in COPD, particularly in progressive disease (1,10).…”

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confidence: 99%

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Oxidative Stress–induced Antibodies to Carbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease

Kirkham

Caramori

Casolari

et al. 2011

Am J Respir Crit Care Med

162

119

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Rationale: There is increasing evidence for the presence of autoantibodies in chronic obstructive pulmonary disease (COPD). Chronic oxidative stress is an essential component in COPD pathogenesis and can lead to increased levels of highly reactive carbonyls in the lung, which could result in the formation of highly immunogenic carbonyl adducts on "self" proteins. Objectives: To determine the presence of autoantibodies to carbonylmodified protein in patients with COPD and in a murine model of chronic ozone exposure. To assess the extent of activated immune responses toward carbonyl-modified proteins. Methods: Blood and peripheral lung were taken from patients with COPD, age-matched smokers, and nonsmokers with normal lung function, as well as patients with severe persistent asthma. Mice were exposed to ambient air or ozone for 6 weeks. Antibody titers were measured by ELISA, activated compliment deposition by immunohistochemistry, and cellular activation by ELISA and fluorescenceactivated cell sorter. Measurements and Main Results: Antibody titer against carbonylmodified self-protein was significantly increased in patients with Global Initiative for Chronic Obstructive Lung Disease stage III COPD compared with control subjects. Antibody levels inversely correlated with disease severity and showed a prevalence toward an IgG1 isotype. Deposition of activated complement in the vessels of COPD lung as well as autoantibodies against endothelial cells were also observed. Ozone-exposed mice similarly exhibited increased antibody titers to carbonyl-modified protein, as well as activated antigen-presenting cells in lung tissue and splenocytes sensitized to activation by carbonylmodified protein.Conclusions: Carbonyl-modified proteins, arising as a result of oxidative stress, promote antibody production, providing a link by which oxidative stress could drive an autoimmune response in COPD.Keywords: COPD; autoimmunity; oxidative stress; carbonyl Chronic obstructive pulmonary disease (COPD) is currently a leading cause of morbidity and mortality worldwide (1), with the main cause being long-term cigarette smoking in the western world (1, 2). Inflammation and remodeling of the small airways are major determinants for the progression and severity of COPD, as defined by the decline in FEV 1 (3). Accumulation of inflammatory mucous exudates in the lumen and infiltration of the wall by innate and adaptive inflammatory immune cells, such as CD4 1 cells, CD8 1 cells, B cells, macrophages, and neutrophils, and the formation of lymphoid follicles are all features of the observed inflammation that correlate with the severity of COPD (3, 4).Previous studies have suggested that autoimmune mechanisms may contribute to the pathogenesis of COPD. Serum autoantibodies against elastin (5) and bronchial epithelial cells along with corresponding IgG and complement (C3) deposition (6) have been observed in COPD lung. It has therefore been proposed that cigarette smoke-derived antigens may be responsible for driving this disease process in COPD (...

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Oxidative Stress–induced Antibodies to Carbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease

Kirkham

Caramori

Casolari

et al. 2011

Am J Respir Crit Care Med

162

119

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“…Further validation will need to be done to determine the performance characteristics against an appropriate cohort of asymptomatic patients. The high rate of misclassifications within the resected nonneoplastic group may be partially accounted for by the fact that specific inflammatory conditions, such as interstitial lung disease, COPD, and asthma, has been reported to induce the production of autoantibodies (41)(42)(43)(44)(45) that may be common to the autoantibodies found in patients with NSCLC. However, whether these autoantibodies are produced before or during carcinogenesis is not known at this time and it may follow that a subset of these targets may provide a means to early disease detection.…”

Section: Discussionmentioning

confidence: 99%

Development of a Multiplexed Tumor-Associated Autoantibody-Based Blood Test for the Detection of Non–Small Cell Lung Cancer

Farlow

Patel

Basu

et al. 2010

Clinical Cancer Research

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Purpose: Non-small cell lung cancer (NSCLC) has an overall 5-year survival of <15%; however, the 5-year survival for stage I disease is over 50%. Unfortunately, 75% of NSCLC is diagnosed at an advanced stage not amenable to surgery. A convenient serum assay capable of unambiguously identifying patients with NSCLC may provide an ideal diagnostic measure to complement computed tomography-based screening protocols.Experimental Design: Standard immunoproteomic method was used to assess differences in circulating autoantibodies among lung adenocarcinoma patients relative to cancer-free controls. Candidate autoantibodies identified by these discovery phase studies were translated into Luminex-based "direct-capture" immunobead assays along with 10 autoantigens with previously reported diagnostic value. These assays were then used to evaluate a second patient cohort composed of four discrete populations, including: 117 NSCLC (81 T 1-2 N 0 M 0 and 36 T 1-2 N 1-2 M 0 ), 30 chronic obstructive pulmonary disorder (COPD)/ asthma, 13 nonmalignant lung nodule, and 31 "normal" controls. Multivariate statistical methods were then used to identify the optimal combination of biomarkers for classifying patient disease status and develop a convenient algorithm for this purpose.Results: Our immunoproteomic-based biomarker discovery efforts yielded 16 autoantibodies differentially expressed in NSCLC versus control serum. Thirteen of the 25 analytes tested showed statistical significance (Mann-Whitney P < 0.05 and a receiver operator characteristic "area under the curve" over 0.65) when evaluated against a second patient cohort. Multivariate statistical analyses identified a six-biomarker panel with only a 7% misclassification rate.Conclusions: We developed a six-autoantibody algorithm for detecting cases of NSCLC among several high-risk populations. Population-based validation studies are now required to assign the true value of this tool for identifying early-stage NSCLC. Clin Cancer Res; 16(13); 3452-62. ©2010 AACR.Lung cancer remains the leading cause of cancer death nationwide, with ∼160,000 deaths predicted in the United States in 2009 (1). Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancers and has a poor overall 5-year survival rate of ∼15% (2-4). This low survival rate is largely attributed to the fact that >75% of patients present with local or distant metastasis at diagnosis, which are associated with a 21% and 3% 5-year survival, respectively (2,3,5). In contrast to these dismal figures, stage I disease is associated with a 50% to 67% 5-year survival but accounts for only 15% of patients (2). This suggests that if patients could be diagnosed at an earlier stage, when a complete surgical resection offers the greatest potential for a cure, the mortality associated with this disease could be reduced.To that end, considerable efforts have been undertaken to produce an effective screening method for early NSCLC. In the 1950s, trials of chest X-rays alone or in combination with sputum analysis were com...

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“…With respect to the autoantigens that may drive autoimmunity, the presence of autoantibodies against HEp-2 epithelial cells [16,17], bronchial epithelial cells [16], endothelial cells [16,18], elastin [14], cytokeratin 18 [19] and several immunogenic peptides [20] has been demonstrated in patients with COPD. It should be noted, however, that we [21] and others [22][23][24] could not demonstrate this anti-elastin autoantibody response in COPD.…”

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confidence: 99%

Differential switching to IgG and IgA in active smoking COPD patients and healthy controls

et al. 2012

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Several studies have demonstrated the presence of B-cell follicles and autoantibodies in chronic obstructive pulmonary disease (COPD). It is unclear against which antigens this B-cell response is directed and whether it contributes to development or worsening of disease.We assessed different B-cell subsets in blood and lung tissue from COPD patients and controls, and compared differences in B-cell responsiveness to stimulation with lung-specific antigens.Active smoking induced an adaptive immune response with relatively high levels of (classswitched) memory B-cells in blood and immunoglobulin (Ig)G memory B-cells in the lung. COPD smokers showed more switching to IgG, whereas healthy smokers switched more to IgA. COPD patients had higher levels of memory B-cells in the lung and stimulation with lung-specific antigens induced higher numbers of anti-decorin antibody-producing cells in COPD patients compared with healthy controls.Differential switching to IgG and IgA indicates that the adaptive immune response to smoke differs between COPD patients and healthy controls. A higher level of memory B-cells in the lungs of COPD patients may reflect an antigen-specific immune response, which could be directed against decorin, as suggested by the induction of anti-decorin antibody-producing cells in response to antigen-specific stimulation in COPD patients.

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Novel autoantigens immunogenic in COPD patients

Cited by 44 publications

References 29 publications

Oxidative Stress–induced Antibodies to Carbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease

Oxidative Stress–induced Antibodies to Carbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease

Development of a Multiplexed Tumor-Associated Autoantibody-Based Blood Test for the Detection of Non–Small Cell Lung Cancer

Differential switching to IgG and IgA in active smoking COPD patients and healthy controls

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