Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency
| Autor: | Michael Henry, Cormac McCarthy, Emer P. Reeves, Paula Meleady, Oliver J. McElvaney, Karen McQuillan, Mark Logan, Mark P Murphy, Noel G. McElvaney, Michael Emmet O'Brien, Tomás P. Carroll, Niall Browne, Laura T. Fee |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Pulmonary and Respiratory Medicine congenital hereditary and neonatal diseases and abnormalities Blotting Western chemical and pharmacologic phenomena Enzyme-Linked Immunosorbent Assay Comorbidity Severity of Illness Index Mass Spectrometry Statistics Nonparametric 03 medical and health sciences 0302 clinical medicine Reference Values In vivo alpha 1-Antitrypsin Deficiency Severity of illness medicine Humans Respiratory system Aged 030304 developmental biology Analysis of Variance 0303 health sciences rare lung diseases Alpha 1-antitrypsin deficiency Complement component 3 business.industry Case-control study Complement C3 Middle Aged Respiration Disorders medicine.disease Complement system emphysema Treatment Outcome Respiratory Research Pulmonary Emphysema 030228 respiratory system Case-Control Studies alpha 1-Antitrypsin alpha1 antitrypsin deficiency Immunology Biomarker (medicine) Female business Biomarkers |
| Zdroj: | Thorax |
| ISSN: | 1468-3296 0040-6376 |
| Popis: | IntroductionAlpha-1 antitrypsin (AAT) deficiency (AATD) is associated with early onset emphysema. The aim of this study was to investigate whether AAT binding to plasma constituents could regulate their activation, and in AATD, exploit this binding event to better understand the condition and uncover novel biomarkers of therapeutic efficacy.MethodsTo isolate AAT linker proteins, plasma samples were separated by size exclusion chromatography, followed by co-immunoprecipitation. AAT binding proteins were identified by mass spectrometry. Complement turnover and activation was determined by ELISA measurement of C3, C3a and C3d levels in plasma of healthy controls (n=15), AATD (n=51), non-AATD patients with obstructive airway disease (n=10) and AATD patients post AAT augmentation therapy (n=5).ResultsDirect binding of complement C3 to AAT was identified in vivo and in vitro. Compared with healthy controls, a breakdown product of C3, C3d, was increased in AATD (0.04 µg/mL vs 1.96 µg/mL, p=0.0002), with a significant correlation between radiographic pulmonary emphysema and plasma levels of C3d (R2=0.37, p=0.001). In vivo, AAT augmentation therapy significantly reduced plasma levels of C3d in comparison to patients not receiving AAT therapy (0.15 µg/mL vs 2.18 µg/mL, respectively, p=0.001).DiscussionResults highlight the immune-modulatory impact of AAT on the complement system, involving an important potential role for complement activation in disease pathogenesis in AATD. The association between plasma C3d levels and pulmonary disease severity, that decrease in response to AAT augmentation therapy, supports the exploration of C3d as a candidate biomarker of therapeutic efficacy in AATD. |
| Databáze: | OpenAIRE |
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