Your browser doesn't support javascript.
loading
Circulating Truncated Alpha-1 Antitrypsin Glycoprotein in Patient Plasma Retains Anti-Inflammatory Capacity.
Reeves, Emer P; Dunlea, Danielle M; McQuillan, Karen; O'Dwyer, Ciara A; Carroll, Tomás P; Saldova, Radka; Akepati, Prithvi Reddy; Wormald, Mark R; McElvaney, Oliver J; Shutchaidat, Vipatsorn; Henry, Michael; Meleady, Paula; Keenan, Joanne; Liberti, Derek C; Kotton, Darrell N; Rudd, Pauline M; Wilson, Andrew A; McElvaney, Noel G.
Afiliación
  • Reeves EP; Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; emerreeves@rcsi.ie.
  • Dunlea DM; Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
  • McQuillan K; Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
  • O'Dwyer CA; Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
  • Carroll TP; Alpha-1 Foundation Ireland, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
  • Saldova R; GlycoScience Group, National Institute for Bioprocessing Research and Training, Mount Merrion, Dublin, Ireland.
  • Akepati PR; Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118.
  • Wormald MR; Department of Biochemistry, Oxford Glycobiology Institute, University of Oxford, Oxford OX1 3QU, United Kingdom; and.
  • McElvaney OJ; Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
  • Shutchaidat V; Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
  • Henry M; National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
  • Meleady P; National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
  • Keenan J; National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
  • Liberti DC; Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118.
  • Kotton DN; Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118.
  • Rudd PM; Alpha-1 Foundation Ireland, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
  • Wilson AA; Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118.
  • McElvaney NG; Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
J Immunol ; 202(8): 2240-2253, 2019 04 15.
Article en En | MEDLINE | ID: mdl-30796179
Alpha-1 antitrypsin (AAT) is an acute phase protein that possesses immune-regulatory and anti-inflammatory functions independent of antiprotease activity. AAT deficiency (AATD) is associated with early-onset emphysema and chronic obstructive pulmonary disease. Of interest are the AATD nonsense mutations (termed null or Q0), the majority of which arise from premature termination codons in the mRNA coding region. We have recently demonstrated that plasma from an AATD patient homozygous for the Null Bolton allele (Q0bolton ) contains AAT protein of truncated size. Although the potential to alleviate the phenotypic consequences of AATD by increasing levels of truncated protein holds therapeutic promise, protein functionality is key. The goal of this study was to evaluate the structural features and anti-inflammatory capacity of Q0bolton-AAT. A low-abundance, truncated AAT protein was confirmed in plasma of a Q0bolton-AATD patient and was secreted by patient-derived induced pluripotent stem cell-hepatic cells. Functional assays confirmed the ability of purified Q0bolton-AAT protein to bind neutrophil elastase and to inhibit protease activity. Q0bolton-AAT bound IL-8 and leukotriene B4, comparable to healthy control M-AAT, and significantly decreased leukotriene B4-induced neutrophil adhesion (p = 0.04). Through a mechanism involving increased mRNA stability (p = 0.007), ataluren treatment of HEK-293 significantly increased Q0bolton-AAT mRNA expression (p = 0.03) and Q0bolton-AAT truncated protein secretion (p = 0.04). Results support the rationale for treatment with pharmacological agents that augment levels of functional Q0bolton-AAT protein, thus offering a potential therapeutic option for AATD patients with rare mutations of similar theratype.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alfa 1-Antitripsina / Codón sin Sentido / Deficiencia de alfa 1-Antitripsina / Alelos Límite: Adult / Female / Humans / Male Idioma: En Revista: J Immunol Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alfa 1-Antitripsina / Codón sin Sentido / Deficiencia de alfa 1-Antitripsina / Alelos Límite: Adult / Female / Humans / Male Idioma: En Revista: J Immunol Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos