Early B cell tolerance defects in anti-neurofascin 155 mediated chronic inflammatory demyelinating polyneuropathy
Bhaskar Roy1, Abeer Obaid2, Sarah Ohashi2, Carmina Coppola2, Sameeran Das2, Amanda Hernandez3, Gianvito Masi3, Lorena Martin-Aguilar4, Maria Cinta Lleixà4, Richard J. Nowak3, Luis A Querol Gutierrez4, Kevin C. O'Connor3
1Neurology, Yale University, 2Immunobiology, 3Neurology, Yale School of Medicine, 4Institut de Recerca Biomèdica Sant Pau
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.