Inhibitory activity of alpha-1-antitrypsin bound to human IgA

Musiani, Piero; Lauriola, Libero; Piantelli, Mauro

doi:10.1016/0009-8981(78)90101-8

Cited by 11 publications

(8 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, the early chromatographic elution peak of AAT at a high molecular mass was not attributable to the presence of covalently bound proteases or circulating polymerised AAT, but rather to AAT present in a high molecular weight complex with proteins involved in the complement system. The validity of these results is supported by the identification of previously characterised binding partners to AAT, including fibrinogen, apolipoprotein B-10024 and immunoglobulin light chains 25. Of interest, as AAT is an acute phase protein and can reach higher concentrations particularly during inflammation, its ability to bind proteins may have important implications for the regulation of inflammation.…”

Section: Discussionmentioning

confidence: 75%

Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency

O’Brien

Fee

Browne

et al. 2020

Thorax

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 75%

Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency

O’Brien

Fee

Browne

et al. 2020

Thorax

View full text Add to dashboard Cite

show abstract

“…Therefore, the thiol moiety of Cys 232 has a lower pK a value (6.8) than common thiol groups and is, thus, highly reactive under neutral pH conditions 66,67 . Accordingly, post‐translational modifications by, for example, glycosylation or cysteinylation as well as by nitric oxide are well‐known 68–70 . Therefore, we focused on this Cys 232 residue to investigate its alkylation by SM using μLC‐ESI MS/HR MS.…”

Section: Resultsmentioning

confidence: 99%

Identification of creatine kinase and alpha‐1 antitrypsin as protein targets of alkylation by sulfur mustard

Lüling

Schmeißer²,

Siegert

et al. 2020

Drug Testing and Analysis

View full text Add to dashboard Cite

Sulfur mustard (SM) is a toxic chemical warfare agent deployed in several conflicts within the last 100 years and still represents a threat in terroristic attacks and warfare. SM research focuses on understanding the pathophysiology of SM and identifying novel biomarkers of exposure. SM is known to alkylate nucleophilic moieties of endogenous proteins, for example, free thiol groups of cysteine residues. The two‐dimensional‐thiol‐differences in gel electrophoresis (2D‐thiol‐DIGE) technique is an initial proteomics approach to detect proteins with free cysteine residues. These amino acids are selectively labeled with infrared‐maleimide dyes visualized after GE. Cysteine residues derivatized by alkylating agents are no longer accessible for the maleimide–thiol coupling resulting in the loss of the fluorescent signal of the corresponding protein. To prove the applicability of 2D‐thiol‐DIGE, this technology was exemplarily applied to neat human serum albumin treated with SM, to lysates from human cell culture exposed to SM as well as to human plasma exposed to CEES (chloroethyl ethyl sulfide, an SM analogue). Exemplarily, the most prominent proteins modified by SM were identified by matrix‐assisted laser desorption/ionization time‐of‐flight (tandem) mass spectrometry, MALDI‐TOF MS(/MS), as creatine kinase (CK) from human cells and as alpha‐1 antitrypsin (A1AT) from plasma samples. Peptides containing the residue Cys282 of CK and Cys232 of A1AT were unambiguously identified by micro liquid chromatography‐electrospray ionization high‐resolution tandem‐mass spectrometry (μLC‐ESI MS/HR MS) as being alkylated by SM bearing the specific hydroxyethylthioethyl‐(HETE)‐moiety. Both peptides might represent potential biomarkers of SM exposure. This is the first report introducing these endogenous proteins as targets of SM alkylation.

show abstract

“…Subsequently, the complex (IgA/AAT/IgA/SC/J chain) is internalized via endocytosis and, through a vesicular mediated system, discharged into the lumen of bile ductules and ducts (Figure 4). AAT bound to IgA maintains its anti-protease activity and protects the immunoglobulins from proteolysis [31].…”

Section: Figurementioning

confidence: 99%

“…On the contrary, breastfed Pi ZZ newborns to a Pi MZ mother, can escape cholestasis as the mother's serum and milk concentration is sufficiently protective, due to capability of the mother's M fraction to raise AAT levels in blood, bile, and milk, in response to acute phase as well as to hormonal stimuli during pregnancy and lactation [10,34]. AAT bound to IgA maintains its anti-protease activity and protects the immunoglobulins from proteolysis [31].…”

Section: Figurementioning

confidence: 99%

Hepatic and Extrahepatic Sources and Manifestations in Endoplasmic Reticulum Storage Diseases

Callea

Francalanci

Giovannoni

2021

IJMS

View full text Add to dashboard Cite

Alpha-1-antitrypsin (AAT) and fibrinogen are secretory acute phase reactant proteins. Circulating AAT and fibrinogen are synthesized exclusively in the liver. Mutations in the encoding genes result in conformational abnormalities of the two molecules that aggregate within the rough endoplasmic reticulum (RER) instead of being regularly exported. That results in AAT-deficiency (AATD) and in hereditary hypofibrinogenemia with hepatic storage (HHHS). The association of plasma deficiency and liver storage identifies a new group of pathologies: endoplasmic reticulum storage disease (ERSD).

show abstract

Inhibitory activity of alpha-1-antitrypsin bound to human IgA

Cited by 11 publications

References 11 publications

Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency

Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency

Identification of creatine kinase and alpha‐1 antitrypsin as protein targets of alkylation by sulfur mustard

Hepatic and Extrahepatic Sources and Manifestations in Endoplasmic Reticulum Storage Diseases

Contact Info

Product

Resources

About