Abstract Details

Title Mechanisms underlying contribution of IgG4 autoantibodies to neurofascins in autoimmune demyelinating neuropathies

Topic Autoimmune Neurology

Presentation(s) S21 - Autoimmune Neurology: Novel Diagnostic and Predictive Biomarkers and Immunopathologic Mechanisms of Disease (4:03 PM-4:14 PM)

Poster/Presentation
Number 004

Objective

To determine the pathogenic mechanisms of autoantibodies to neurofascins.

Background Mechanisms by which autoantibodies against cell adhesion molecules expressed on myelinated axons may contribute to injury and neurological diseases are poorly understood. Autoantibodies to Neurofascin 155 (NF155) define a subset of patients with severe acquired demyelinating neuropathy and are usually of the IgG4 subclass. IgG4, unlike other IgG subtypes, undergoes hemi-antibody exchange making each antibody bi-specific (functionally monovalent), such that crosslinking and internalization of the target antigen is unlikely. At the paranode, NF155 interacts with contactin/Caspr complex, an association necessary for anchoring myelin to the axon. NF155 is also known to dimerize in vitro, though the functional implications of this interaction are not well understood. We hypothesize that IgG4 autoantibodies disrupt important heterophilic and homophilic interactions of NF155 which, in turn, may disrupt the function of the protein.

Design/Methods Using cell-based assay screening, we confirmed the presence NF155 autoantibodies in a subset of patients with demyelinating neuropathy. A solid phase binding assay was used to test the effect of NF155 autoantibodies on the binding of NF155 to contactin, Caspr, and neurofascin in vitro.

Results We identified 4 cases of acquired demyelinating neuropathy harboring serum autoantibodies to NF155. IgG4 autoantibodies to NF155 were found in all cases, and typically comprised the predominant subtype. In binding assays, NF155 bound contactin and neurofascin with nanomolar affinity, while NF155 and Caspr did not appear to directly interact. Antibodies to neurofascin had a very modest effect on the interaction of NF155 with contactin; however, these neurofascin antibodies modulated homophilic neurofascin interactions.

Conclusions Our results suggest that inhibition of important protein-protein interactions is a possible mechanism of NF155 IgG4 autoantibodies and that homophilic NF155 interactions may play an as yet undefined role in myelination. Future work will focus on further characterizing homophilic NF155 interactions.

Authors/Disclosures
Kristina R. Patterson, MD, PhD (Horizon Therapeutics) PRESENTER	Dr. Patterson has received personal compensation for serving as an employee of Amgen. Dr. Patterson has stock in Amgen.
	No disclosure on file
Amit Bar-Or, MD, FRCPC (University of Pennsylvania)	Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche Genentech. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merk/EMD Serono. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for cabaletta. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck/EMD Serono. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi/Genzyme. The institution of Dr. Bar-Or has received research support from Novartis. The institution of Dr. Bar-Or has received research support from Biogen. The institution of Dr. Bar-Or has received research support from Roche/Genentech.
Eric Lancaster, MD, PhD (The University of Pennsylvania, Dept. of Neurology)	Dr. Lancaster has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for merck. Dr. Lancaster has received intellectual property interests from a discovery or technology relating to health care. Dr. Lancaster has received personal compensation in the range of $50,000-$99,999 for serving as a Expert and Witness with US Vaccine Injury Compensation Program.

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