CNS Demyelinating Autoimmunity Targeting Water Channel Complexes

Project: Research project

Project Details


DESCRIPTION (provided by applicant): Water channels are a newly recognized target for CNS inflammatory autoimmune demyelinating diseases. Neuromyelitis optica (NMO; aka optic spinal multiple sclerosis [MS]) is a devastating disease that disproportionally affects non-Caucasians. It is characterized by recurrent episodes of optic neuritis and transverse myelitis, resulting in blindness and paraplegia in most patients, and it is frequently misdiagnosed as MS. Contrary to traditional teaching, NMO is not rare. It is the first MS-like disease for which a specific antigen has been identified--the astrocytic water channel aquaporin-4 (AQP4). This discovery represents a seismic shift from historic emphasis on the oligodendrocytes and myelin. An autoantibody specific for AQP4 (NMO/AQP4-IgG) is a clinically validated serum biomarker that distinguishes relapsing NMO from MS, which has no distinguishing biomarker and calls for different therapies. We suspect that a significant proportion of patients who are severely disabled (i.e., blind or paraparetic) from presumed MS, particularly African Americans, carry a misdiagnosis and will prove to be NMO/AQP4-IgG seropositive. Despite the high sensitivity and specificity of NMO/AQP4-IgG for NMO, the relationship of serum level to disease severity has not been established. We anticipate that qualitative and quantitative bioassays corresponding to distinctive pathologic outcomes of NMO/AQP4-IgG interacting with AQP4 in living target cells may predict clinical outcome. Our cumulative clinical, therapeutic and immunopathologic observations suggest that NMO patients who test negative for NMO/AQP4-IgG nevertheless have an antibody-mediated disorder. Our preliminary data support the existence of alternative pathogenic NMO-IgGs targeting novel components of the astrocytic AQP4/dystroglycan complex. We aim to 1) determine the prevalence of NMO/AQP4-IgG in serum of ethnically diverse patient cohorts and store DNA for future use in genetic correlative analyses; 2) assess the predictive and prognostic value of immunochemical, functional (complement activation, AQP4 downregulation and coupled glutamate transporter downregulation) and biosensor NMO/AQP4-IgG assays (indicative of antibody concentration and affinity) and 3) search for and validate novel IgG biomarkers (NMO-IgG X1, X2, ...) as the potential basis of NMO in apparently seronegative patients. Knowledge of the frequency of AQP4 autoimmunity, correlation with ethnicity and frequency of MS misdiagnosis will impact health care delivery and economics. Positive correlations of NMO/AQP4-IgG (titer, concentration/affinity and functional in vitro effects) with clinical or radiologic outcomes are anticipated to reveal prognostic antibody profiles as basis for appropriate therapy. Advanced serological interpretive insights, coupled with identification of alternative diagnostic markers (i.e., new NMO-IgGs reactive with AQP4 partner proteins in the dystroglycan complex) may lead to formulation of individual patient-specific NMO therapies.
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