Résumés disponibles (92) :

BAS Mathilde (INSERM U995 - Lennart MARS)
Session :

 

@mail :  mathilde.bas@inserm.fr      tél. :  0679663221


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Titre de la communication :
Do sugars dictate the pathogenicity of auto-antibodies in Multiple Sclerosis ?
Auteurs (et leurs adresses) de la communication :
Mathilde BAS (mathilde.bas@inserm.fr)
Résumé de la communication :
Introduction
The \"fragment crystallizable\" (Fc) region of antibodies (Abs) orchestrates their function by binding to Fc-receptors (FcRs) and complement. N-glycosylation of Asn297 in the Fc-domain modifies this binding-affinity endowing Abs to selectively engage pro- or anti-inflammatory FcRs. Here we study the impact of Fc-glycosylation on the pathogenicity of myelin-reactive Abs, that can be detected in Multiple Sclerosis, and Neuromyelitis Optica.

Methods
We cloned a pathogenic monoclonal Ab (mAb) called 8-18C5 that is specific for Myelin Oligodendrocyte Glycoprotein (MOG). Different glycovariants of this mouse IgG1 were created via Fc-mutagenesis and production in distinct cell-lines. The variants are being validated (purity, integrity, binding to MOG, Fc-glycosylation), their FcR-binding profile was determined in vitro and their pathogenicity was assessed in Experimental Autoimmune Encephalomyelitis (EAE). To this end, 50 µg of 8-18C5 variants were injected in C57Bl/6 mice 7 days after MOG35-55 immunisation.

Results
The native 8-18C5 mAb binds complement and pro-inflammatory FcRs resulting in the acceleration and aggravation of EAE. Two notable variants were identified. Producing 8-18C5 in an hypofucosylating cell-line (HFCL) increased its pathogenicity in EAE. Introducing a single amino-acid deletion in the Fc-domain resulted in a loss of binding to pro-inflammatory FcRs, except FcRn. In EAE, this 8-18C5-del variant not only lost its pathogenicity but even reduced the severity of EAE relative to the PBS control group.

Discussion
This is the first study to address the impact of Fc-glycosylation on a mAb response. Preliminary data indicates that the variant produced in HFCL augments its pathogenicity, probably due to hypofucosylation. A second variant was identified that reduced disease severity in association to a loss of binding to pro-inflammatory FcRs. This study will provide unprecedented insights into the cellular immune responses induced by the Fc-glycovariants.

BAS Mathilde (INSERM U995 - Lennart MARS)