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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
immunology and microbiology
Mass spectrometric characterization of circulating and functional antigens derived from piperacillin in patients with cystic fibrosis
Journal of Immunology, Volume 187, No. 1, Year 2011
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Description
A mechanistic understanding of the relationship between the chemistry of drug Ag formation and immune function is lacking. Thus, mass spectrometric methods were employed to detect and fully characterize circulating Ags derived from piperacillin in patients undergoing therapy and the nature of the drug-derived epitopes on protein that can function as an Ag to stimulate T cells. Albumin modification with piperacillin in vitro resulted in the formation of two distinct haptens, one formed directly from piperacillin and a second in which the dioxopiperazine ring had undergone hydrolysis. Modification was time and concentration dependent, with selective modification of Lys541 observed at low concentrations, whereas at higher concentrations, up to 13 out of 59 lysine residues were modified, four of which (Lys190, Lys 195, Lys432, and Lys541) were detected in patients' plasma. Piperacillin-specific T lymphocyte responses (proliferation, cytokines, and granzyme B release) were detected ex vivo with cells from hypersensitive patients, and analysis of incubation medium showed that modification of the same lysine residues in albumin occurred in situ. The antigenicity of piperacillin-modified albumin was confirmed by stimulation of T cells with characterized synthetic conjugates. Analysis of minimally modified T cell-stimulatory albumin conjugates revealed peptide sequences incorporating Lys190, Lys432, and Lys541 as principal functional epitopes for T cells. This study has characterized the multiple haptenic structures on albumin in patients and showed that they constitute functional antigenic determinants for T cells. Copyright © 2011 by The American Association of Immunologists, Inc.
Authors & Co-Authors
Whitaker, Paul
United Kingdom, Leeds
St James's University Hospital
Meng, Xiaoli
United Kingdom, Liverpool
University of Liverpool
United Kingdom, Oxford
Nihr Oxford Health Biomedical Research Centre
Lavergne, Sidonie N.
United Kingdom, Liverpool
University of Liverpool
United States, Urbana
University of Illinois Urbana-champaign
El-Ghaiesh, Sabah
United Kingdom, Liverpool
University of Liverpool
Egypt, Tanta
Tanta University
Monshi, Manal
United Kingdom, Liverpool
University of Liverpool
Saudi Arabia, Riyadh
King Fahad Medical City
Earnshaw, Caroline
United Kingdom, Liverpool
University of Liverpool
Peckham, Daniel Gavin
United Kingdom, Leeds
St James's University Hospital
Gooi, Jimmy Hock Chye
United Kingdom, Leeds
St James's University Hospital
Conway, Steve
United Kingdom, Leeds
St James's University Hospital
Pirmohamed, Munir
United Kingdom, Liverpool
University of Liverpool
United Kingdom, Oxford
Nihr Oxford Health Biomedical Research Centre
Jenkins, Rosalind E.
United Kingdom, Liverpool
University of Liverpool
Naisbitt, Dean John
United Kingdom, Liverpool
University of Liverpool
Park, B. Kevin
United Kingdom, Liverpool
University of Liverpool
Statistics
Citations: 100
Authors: 13
Affiliations: 6
Identifiers
Doi:
10.4049/jimmunol.1100647
ISSN:
00221767
e-ISSN:
15506606