Abstract Details

Title Early B cell tolerance defects in anti-neurofascin 155 mediated chronic inflammatory demyelinating polyneuropathy

Topic Autoimmune Neurology

Presentation(s) S40 - Autoimmune Neurology: Stiff Person Syndrome/GAD65 Neurological Autoimmunity, CIDP, and MOGAD (4:18 PM-4:30 PM)

Poster/Presentation
Number 005

Objective To examine the role of B cell tolerance dysfunction in the immunopathology of anti-neurofascin 155 (NF-155) autoantibody-mediated chronic inflammatory demyelinating polyneuropathy (CIDP).

Background Autoantibodies against paranodal protein NF-155 are present in 5% of patients fulfilling CIDP diagnostic criteria. These patients have distinct clinical phenotypes and usually respond to B cell depletion therapy. However, the underlying B cell dysfunction driving the pathomechanism of NF-155-mediated CIDP remains unknown. In this study, we examined B cell tolerance dysfunction in patients with NF-155-mediated CIDP, which can lead to aberrant autoantibody production, and has been implicated in myasthenia gravis, neuromyelitis optica, and other autoimmune diseases.

Design/Methods Using a well-established approach, we generated recombinant monoclonal antibodies from single B cells from the new emigrant (NE) and mature naïve (MN) compartments from patients with NF-155-mediated CIDP. The frequency of polyreactive NE B-cell clones was measured by ELISA against dsDNA, insulin, and lipopolysaccharide, to assess the central B cell tolerance checkpoint defect. Similarly, the frequency of HEp-2 cell lysate-specific autoreactive MN B-cell clones was measured to identify a peripheral B cell tolerance checkpoint defect.

Results A total of 74 and 30 unique clones of monoclonal antibodies were generated from the NE and MN B cells of 3 patients with NF-155-mediated CIDP, respectively, and 47% (± 36.2%) clones from the NE B cells and 32.3% (± 13.2%) clones from the MN B cells were polyreactive, compared to expected 5-11% polyreactivity from healthy controls. Assessment of the peripheral tolerance checkpoint defect and phenotyping of the NE and MN B cells at the single-cell level by simultaneously profiling gene expression and full-length paired B-cell receptors is ongoing.

Conclusions This preliminary analysis suggests that CIDP associated with NF-155 may have early checkpoint tolerance defects. Further studies are warranted to understand the implication of such B cell dysfunction in the disease immunopathology.

Authors/Disclosures
Bhaskar Roy, MD, FAAN (Yale University) PRESENTER	Dr. Roy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion Pharmaceuticals. Dr. Roy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda Pharmaceuticals. Dr. Roy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for argenx. Dr. Roy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for argenx. Dr. Roy has stock in Cabaletta bio. . The institution of Dr. Roy has received research support from Martin Shubik Fund for IBM at Yale University. The institution of Dr. Roy has received research support from Abcuro Pharmaceuticals. The institution of Dr. Roy has received research support from Immunovant.
Abeer Obaid	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Amanda L. Hernandez, MD, PhD (University of Connecticut Medical School)	Dr. Hernandez-Jones has nothing to disclose.
Gianvito Masi, MD (Yale University)	Dr. Masi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen.
	No disclosure on file
	No disclosure on file
Richard J. Nowak, MD (Yale University School of Medicine)	Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion . Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for argenx. Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Nowak has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Immunovant . Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cabaletta Bio . Dr. Nowak has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Amgen. Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cour Pharma. Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Nowak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janseen . The institution of Dr. Nowak has received research support from UCB. The institution of Dr. Nowak has received research support from Alexion . The institution of Dr. Nowak has received research support from Janseen. The institution of Dr. Nowak has received research support from Immunovant . The institution of Dr. Nowak has received research support from argenx. The institution of Dr. Nowak has received research support from Amgen. Dr. Nowak has a non-compensated relationship as a Member of the Board of Directors with Myasthenia Gravis Foundation of America (MGFA) that is relevant to AAN interests or activities.
Luis Querol, MD, PhD (Hospital de la Santa Creu i Sant Pau)	Dr. Querol has received personal compensation in the range of $500-$4,999 for serving as a Consultant for CSL Behring. The institution of Dr. Querol has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for UCB. The institution of Dr. Querol has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Querol has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Johnson & Johnson. Dr. Querol has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. The institution of Dr. Querol has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Querol has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ArgenX. Dr. Querol has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Dr. Querol has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Querol has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Grifols. The institution of Dr. Querol has received research support from GBS-CIDP Foundation International. The institution of Dr. Querol has received research support from Grifols. The institution of Dr. Querol has received research support from ISCIII. The institution of Dr. Querol has received research support from CIBERER. The institution of Dr. Querol has received research support from UCB.
Kevin O'Connor (Yale University School of Medicine)	Kevin O'Connor has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Kevin O'Connor has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Kevin O'Connor has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Viela Bio. Kevin O'Connor has stock in Cabaletta.

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