The evolution of the autoantibody response in Graves’ disease

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.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2013

Author dc:creator

• Hargreaves, Chantal

Advisors dc:contributor.advisor

• Banga, Jasvinder-paul Singh
• Dunn-Walters, Deborah

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/b12a689c-e5d7-4478-b81a-40daa8b34a97

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/b12a689c-e5d7-4478-b81a-40daa8b34a97