Germinal centre autoantibody responses following heart transplantation

The development of humoral autoimmunity following organ transplantation is increasingly recognised, but of uncertain significance. I address the key question whether autoimmunity contributes independently to chronic graft rejection. In a MHC class II-mismatched murine model, I show that antinuclear autoantibody responses were initiated upon graft-versus-host allorecognition of recipient B cells by donor CD4 T cells transferred within the heart allograft. Rejected allografts displayed features of chronic humoral vascular rejection, with rejection mediated by long-lasting germinal centre (GC) responses, whose maintenance was dependent upon additional, cognate help from recipient T follicular helper (TFH) cells, and which diversified to encompass responses against vimentin autoantigen. Heart grafts transplanted into stable donor/ recipient mixed haematopoietic chimeras also provoked GC autoimmunity and were rejected with similar tempo, indicating that autoantibody can mediate graft damage despite host tolerance to alloantigen. An autonomous effector role for autoantibody was further suggested by the demonstration that F1 (BALB/c x C57BL/6) recipients reject parental BALB/c heart allografts, with rejection again dependent upon GC autoimmunity and help from recipient TFH cells. Thus GC autoantibody responses contribute to graft rejection independent of host adaptive alloimmunity, through a mechanism by which donor CD4 T cells initiate an auto reactive GC reaction that is then maintained and propagated by host TFH cells. The demonstration that one set of CD4 T cells triggers autoimmunity, but that a second subset of TFH cell is responsible for maintaining the response as a germinal centre reaction, has wider implications for our understanding of the pathogenesis of autoimmune disease.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Qureshi, Muhammad

Advisor dc:contributor.advisor

• Pettigrew, Gavin

• Germinal centre
• Transplant associated autoantibody responses

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/c60efc14-89cd-4d86-9a8f-3c448fbafd07/download
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

eng

Author Identifier

0000-0003-3724-9945

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/311074