The roles of anti-GM1 complex antibodies in autoimmune neuropathies

QR180 Immunology

Meehan, Gavin Robertson ; Guillain-Barre Support Group of the United Kingdom (GUILL) ; Willison, Hugh

University:University of Glasgow

Department:Institute of Infection Immunity and Inflammation

关键词: Autoimmune, neuropathy, multifocal motor, sulfatide, GM1, ganglioside, Guillain-Barre syndrome, antibody, complex, concentration, dependent, independent, BO1, BO3, BR1, DO1, SM1, WO1, GAME, GAME-M2, GAME-M5, GAME-M6, GAME-M7, GAME-G1, GAME-G3;   

Others  :  http://theses.gla.ac.uk/7145/1/2015MeehanPhD.pdf

来源: University of Glasgow

【 摘 要 】

Anti-ganglioside antibodies have been implicated in autoimmune neuropathiesfor several decades. They are thought to elicit injury through binding to sites inthe peripheral nervous system, where they activate the complement pathway toinduce cell death. Patient serum is therefore regularly screened for theseantibodies to aid in the diagnosis of various conditions. Recent work has foundthat complexes composed of gangliosides and other glycolipids can improve thedetection of these antibodies beyond the signals detected to the singleganglioside species.In MMN research, complexes comprised of GM1 and GalC have been found tosignificantly enhance antibody detection in patient sera. In certain patients,however, antibody binding was only detected against these complexes and notthe single antigens. This led some researchers to hypothesise that anunidentified class of antibody may have arisen that binds specifically to a neoepitopeformed by the combination of the two glycolipids. It has also beenhypothesised that that this complex may be the true target of immune mediatedattack in MMN.This thesis sought to address this hypothesis by either cloning these antibodiesdirectly from patient serum or through active immunisations with mice. Analysisof previously generated human monoclonal antibodies indicated that theirbehaviours were modified by complexes containing particular gangliosides orglycolipids. Furthermore, the antibodies behaviours were found to diverge, whenthey were screened against complexes comprised of gangliosides and differentconcentrations of accessory lipids. These findings suggested that the accessorylipids were interacting with the ganglioside headgroups to modify thepresentation of different binding epitopes. This indicated that conformationalmodulation, rather than neo-epitope formation, may be responsible for complexenhancementCloning antibodies from patient sera was unsuccessful but examination of thescreening techniques suggested that the appearance of complex-dependentantibodies may have been an artefact. Attempts to induce complex-specificresponses in mice were similarly unsuccessful but several anti-ganglioside andanti-sulfatide antibodies were created. The subsequent chapters focused on thecharacterisation of these antibodies and indicated that most of them bound wellto solid-phase assays, cells and tissue and may therefore be of use in futurestudies.Taken together, the data from this thesis suggests that complex-dependentantibodies may not exist but are merely low concentrations of anti-gangliosideantibodies that are cis-enhanced by particular lipids. Future work shouldtherefore focus on assessing how the ganglioside microenvironment modifiesepitope presentation and how this affects the binding capabilities of antigangliosideantibodies.