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Glucose-Regulated Protein 78 Autoantibodies Are Associated with Carotid Atherosclerosis in Chronic Obstructive Pulmonary Disease Patients.

ABSTRACT: Atherosclerosis prevalence is increased in chronic obstructive pulmonary disease (COPD) patients, independent of other risk factors. The etiology of the excess vascular disease in COPD is unknown, although it is presumably related to an underlying (if cryptic) systemic immune response. Autoantibodies with specificity for glucose-regulated protein 78 (GRP78), a multifunctional component of the unfolded protein response, are common in COPD patients and linked to comorbidities of this lung disease. We hypothesized anti-GRP78 autoreactivity might also be a risk factor for atherosclerosis in COPD patients. Carotid intima-medial thickness (cIMT) was measured in 144 current and former smokers by ultrasound. Concentrations of circulating IgG autoantibodies against full-length GRP78, determined by ELISA, were greater among subjects with abnormally increased cIMT (p < 0.01). Plasma levels of autoantibodies against a singular GRP78 peptide segment, amino acids 246-260 (anti-GRP78aa 246-260), were even more highly correlated with cIMT, especially among males with greater than or equal to moderate COPD (r s = 0.62, p = 0.001). Anti-GRP78aa 246-260 concentrations were independent of CRP, IL-6, and TNF-? levels. GRP78 autoantigen expression was upregulated among human aortic endothelial cells (HAECs) stressed by incubation with tunicamycin (an unfolded protein response inducer) or exposure to culture media flow disturbances. Autoantibodies against GRP78aa 246-260, isolated from patient plasma by immunoprecipitation, induced HAEC production of proatherosclerotic mediators, including IL-8. In conclusion, anti-GRP78 autoantibodies are highly associated with carotid atherosclerosis in COPD patients and exert atherogenic effects on HAECs. These data implicate Ag-specific autoimmunity in the pathogenesis of atherosclerosis among COPD patients and raise possibilities that directed autoantibody reduction might ameliorate vascular disease in this high-risk population.

SUBMITTER: Tran-Nguyen TK

PROVIDER: S-EPMC7430561 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Glucose-Regulated Protein 78 Autoantibodies Are Associated with Carotid Atherosclerosis in Chronic Obstructive Pulmonary Disease Patients.

Tran-Nguyen Thi K TK Chandra Divay D Yuan Kaiyu K Patibandla Phani K PK Nguyen Khanh T KT Sethu Palaniappan P Zhang Yingze Y Xue Jianmin J Mobley James A JA Kim Young-Il YI Shoushtari Ali A Leader Joseph K JK Bon Jessica J Sciurba Frank C FC Duncan Steven R SR

ImmunoHorizons 20200221 2

Atherosclerosis prevalence is increased in chronic obstructive pulmonary disease (COPD) patients, independent of other risk factors. The etiology of the excess vascular disease in COPD is unknown, although it is presumably related to an underlying (if cryptic) systemic immune response. Autoantibodies with specificity for glucose-regulated protein 78 (GRP78), a multifunctional component of the unfolded protein response, are common in COPD patients and linked to comorbidities of this lung disease. ...[more]

PMID: 32086320

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Project description:Background Heavy smokers perform worse on neuropsychological assessment than age-matched peers. However, traditional pulmonary measures of airflow limitation and hypoxemia explain only a modest amount of variance in cognition. The current objective was to determine whether carotid artery stiffness is associated with cognition in former smokers beyond the effects of amount of smoking and pulmonary function. Methods and Results Eighty-four former smokers including individuals across a spectrum of airflow limitation severity were included: 30 without chronic obstructive pulmonary disease (Global Initiative for Chronic Obstructive Lung Disease [GOLD] 0 with normal spirometry and lung computed tomography), 31 with mild-moderate chronic obstructive pulmonary disease (GOLD 1-2), and 23 with severe-very severe chronic obstructive pulmonary disease (GOLD 3-4). Participants completed questionnaires, spirometry, carotid ultrasonography, and neuropsychological testing. Multiple linear regression was used to determine whether carotid artery stiffness is associated with neuropsychological performance in 4 cognitive domains after adjusting for age, sex, pack-years of smoking, estimated premorbid intellectual functioning, and airflow limitation. Higher carotid artery β-stiffness index was associated with reduced executive functioning-processing speed in the fully adjusted model (β=-0.49, SE=0.14; P=0.001). Lower premorbid intellectual function, male sex, and presence of airflow limitation (GOLD 1 or 2 and GOLD 3 or 4) were also associated with worse executive functioning-processing speed. β-Stiffness index was not significantly associated with performance in other cognitive domains. Conclusions Carotid artery stiffness is associated with worse performance on executive functioning-processing speed in former smokers beyond the effects of aging, amount of past smoking, severity of airflow limitation, and hypoxemia. Future research should examine whether carotid stiffness can be used to identify former smokers at risk for subsequent cognitive impairment.

Project description:AIM:To assess the frequency of carotid artery disease (CAD) and lower extremities artery disease (LEAD) in patients with chronic obstructive pulmonary disease (COPD) and their relation to the severity of airflow limitation and the level of C-reactive protein (CRP). METHODS:We performed a cross-sectional study including 60 patients with COPD (52 male, 8 female), aged 40 to 80 years, initially diagnosed according to the actual criteria. Also, 30 subjects in whom COPD was excluded, matched to COPD patients by sex, age, body mass index and smoking status, served as controls. All study subjects completed questionnaire and underwent pulmonary evaluation (dyspnea severity assessment, baseline and post-bronchodilator spirometry, gas analyses, and chest X-ray), angiological evaluation by Doppler ultrasonography and measurement of serum CRP level. RESULTS:We found a statistically significant difference between the frequency of carotid plaques in COPD patients as compared to their frequency in controls (65% vs 30%; P = 0.002). The mean value of intima-media thickness (IMT) in COPD patients with CAD was significantly higher than its mean value in controls (0.8 ± 0.2 vs. 0.7 ± 0.2; P = 0.049). IMT value in COPD patients with CAD was significantly related to the degree of airflow limitation, i.e. to the degree of FEV1 decline (P = 0.000), as well as to the serum CRP level (P = 0.001). We found a statistically significant difference between the frequency of COPD patients with LEAD as compared to the frequency of LEAD in controls (78.3% vs 43.3%; P = 0.001). According to the Fontaine classification, COPD patients with LEAD were categorized in the stages I, IIA and IIB (53.3%, 30% and 16.7%, respectively), whereas all controls with LEAD were categorized in the Fontaine stage I. Among COPD patients with LEAD there was significant association between disease severity and clinical manifestations due to the vascular changes (P = 0.001) and serum CRP level (P = 0.001). CONCLUSION:Our findings suggest higher prevalence and higher severity of vascular changes in COPD patients as compared to their prevalence and severity in non-COPD subjects. Prevalence and severity of vascular changes in COPD patients were significantly related to the severity of airflow limitation and serum CRP levels.

Dataset Information

Glucose-Regulated Protein 78 Autoantibodies Are Associated with Carotid Atherosclerosis in Chronic Obstructive Pulmonary Disease Patients.

Publications

Glucose-Regulated Protein 78 Autoantibodies Are Associated with Carotid Atherosclerosis in Chronic Obstructive Pulmonary Disease Patients.

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