SFEBES2009 Poster Presentations Thyroid (59 abstracts)
Clonal relationships between TSH receptor stimulating antibodies illustrate the effect of hypermutation on antibody function
J Gilbert 1, , C Padoa 2, , S Larsen 2 , C Hampe 4 , E Dagdan 2 , L Hegedus 5 , D Dunn-Walters 2 & JP Banga 2
1King’s College Hospital Foundation Trust, London, UK; 2King’s College London, School of Medicine, London, UK; 3Department of Chemical Pathology, WITS Medical School, Johannesburg, South Africa; 4Department of Medicine, University of Washington, Seattle, Washington, USA; 5Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark.
There is a paucity of information regarding the genetic and somatic mutation events that lead to the production of pathogenic thyroid stimulating antibodies (TSAbs) in Graves’ disease. We have previously isolated two murine monoclonal antibodies (KSAb1 and KSAb2) with potent TSAb activity that demonstrate subtle differences in their interaction with the thyrotropin receptor (TSHR). Analyses of the variable region genes of the heavy and light chains of these TSAbs were performed and the TSAb properties of the cloned genes were confirmed by expression as recombinant Fabs (rFabs). Both TSAbs used the same rearrangement of germ line genes, were clonally related and derived from the same naïve precursor B cell. The heavy chain genes demonstrated a greater degree of conservation, sharing 21 mutation events before diverging. A further eight mutations were unique to KSAb1 and five mutations unique to KSAb2. In contrast, the light chain genes evolved separately following the germ line gene rearrangement. Light chain swaps were subsequently performed, followed by rFab preparation, which continued to demonstrate TSAb activity. This suggests that the heavy chain genes may play the predominant role in the observed pathogenic TSAb activity.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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