Abstract: Chronic inflammatory demyelinating polyneuropathy (CIDP), a rare group of heterogeneous
autoimmune diseases targeting the peripheral nervous system, affects 10 in 100,000 individuals in the USA.
Patients with CIDP usually present with symmetric proximal and/or distal muscle weakness, sensory symptoms,
and may have a significant physical and socioeconomic burden. CIDP is considered responsive to
glucocorticoids, intravenous/subcutaneous immunoglobulin, and plasmapheresis; however, only 11% of patients
with CIDP achieve stable disease control without therapy, and 51% require continuous therapy. Sural nerve
biopsies in CIDP showed immunoglobulin and complement deposition on Schwann cells and compact myelin.
CIDP patients’ sera bind to nerves, and passive transfer of serum to animal models can cause demyelination
and slowing of nerve conduction velocity. While humoral mechanisms are critical to CIDP pathogenesis, many
aspects of disease pathomechanism remain unknown. In the majority of patients with CIDP, a definitive
autoantibody is not identified. Only recently, autoantibodies against nodal proteins, neurofascin 186 (NF186) and
gliomedin, and the paranodal proteins neurofascin 155 and contactin 1 were found to be pathogenic in a subclass
of CIDP, classified as autoimmune nodopathies (AIN). These autoantibodies in AIN are predominantly of IgG4
subtypes. AIN has distinct clinical phenotypes and responds better to B cell depletion therapy. The drivers of
these predominantly IgG4 autoantibodies and their pathogenic mechanisms remain unknown. This study will
address some key aspects of disease pathomechanism in CIDP and AIN. We will identify the phenotypes of the
B and T cell subsets that drive the immunopathology of CIDP and AIN. We will identify, isolate, and authenticate
highly specific autoantibody-producing B cells and comprehensively define their respective phenotypes at the
single-cell level by simultaneously profiling gene expression and full-length paired B-cell receptors. T follicular
helper cells have been implicated in other IgG4-mediated diseases, and we will investigate their role in IgG4-
mediated AIN. We will develop human monoclonal nodal/paranodal antibodies to define the antibody-mediated
pathomechanism by examining the requirement of monovalent autoantibody binding and the role of somatic
hypermutation in antibody affinity. We will also examine antibody-dependent cellular cytotoxicity and
phagocytosis. We will investigate the role of CD4+ T cells in selecting these specific autoantibody secreting B
cells. Lastly, we will use high-throughput state-of-the-art antigen discovery platforms to identify new antigen
targets in CIDP and validate the positive targets through well-established assays. Recently, new therapies have
become available for neuromuscular diseases targeting complement activation, neonatal Fc receptor inhibitors,
and B cell depletion, but treatment response to such therapies will depend on the underlying immunopathology.
This study will identify the underlying pathomechanism, help make a more informed decision regarding
therapeutic management, and improve patient care in CIDP and AIN.
