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In-depth characterization of B-cell dysfunction in chronic inflammatory demyelinating polyneuropathy

Award Number: R01NS132860
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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In-depth characterization of B-cell dysfunction in chronic inflammatory demyelinating polyneuropathy - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $410,581 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/31/2026	NON-COMPETING CONTINUATION	$410,581
														Subtotal = $410,581

Issue Date FY: 2025 ( Subtotal = $377,245 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/26/2025	NON-COMPETING CONTINUATION	$377,245
														Subtotal = $377,245

Issue Date FY: 2024 ( Subtotal = $414,898 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/29/2024	NEW	$414,898
														Subtotal = $414,898

Grand Total All Awards = $1,202,724

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In-depth characterization of B-cell dysfunction in chronic inflammatory demyelinating polyneuropathy

Award Number: R01NS132860

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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