The evolution of the autoantibody response in Graves’ disease
type: CreativeWork
description: Graves’ disease (GD) is an antibody-mediated autoimmune disease caused by thyroid stimulating antibodies (TSAbs) activating the thyrotropin receptor (TSHR). Both genetic and environmental factors contribute to pathogenesis and one such factor is the infectious agent, Yersinia enterocolitica. Two high affinity TSAbs, (KSAbl, lgG2t>/K; KSAb2, IgGaa/K), developed from an experimental murine model of GD, share common germline Ig genes and thus are derived from the same precursor B cell clone which diversified through somatic hypermutation. The shared germline genes were expressed as recombinant (r) Fab germline and did not display measurable binding to TSHR in three assay systems: radioreceptor assay, flow cytometry and cAMP stimulation bioassay. Hence the precursor B cell clone was not endowed with autoreactive potential. To assess the individual contribution of KSAbl’s heavy and light chains to TSHR reactivity chimeric rFab constructs were created. The interaction and stimulation of TSHR was dependent on the mature heavy chain. Significantly, antigen recognition studies of rFab germline, KSAbl and KSAb2 showed binding to OmpA, OmpC and OmpF of Y. enterocolitica. Our findings raise the possibility that the clonal expansion of B cell populations that acquire autoreactivity in the periphery may be associated with the porin proteins of Y. enterocolitica.
abstract: Graves’ disease (GD) is an antibody-mediated autoimmune disease caused by thyroid stimulating antibodies (TSAbs) activating the thyrotropin receptor (TSHR). Both genetic and environmental factors contribute to pathogenesis and one such factor is the infectious agent, Yersinia enterocolitica. Two high affinity TSAbs, (KSAbl, lgG2t>/K; KSAb2, IgGaa/K), developed from an experimental murine model of GD, share common germline Ig genes and thus are derived from the same precursor B cell clone which diversified through somatic hypermutation. The shared germline genes were expressed as recombinant (r) Fab germline and did not display measurable binding to TSHR in three assay systems: radioreceptor assay, flow cytometry and cAMP stimulation bioassay. Hence the precursor B cell clone was not endowed with autoreactive potential. To assess the individual contribution of KSAbl’s heavy and light chains to TSHR reactivity chimeric rFab constructs were created. The interaction and stimulation of TSHR was dependent on the mature heavy chain. Significantly, antigen recognition studies of rFab germline, KSAbl and KSAb2 showed binding to OmpA, OmpC and OmpF of Y. enterocolitica. Our findings raise the possibility that the clonal expansion of B cell populations that acquire autoreactivity in the periphery may be associated with the porin proteins of Y. enterocolitica.
author: Hargreaves, Chantal
language: eng
date published: 2013-2-1
date modified: 2026-07-24T02:44:37Z
provider: King's College London
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: King's College London