Pathogenic mechanism of intrathecally synthesized immunoglobulins in a mouse model of progressive multiple sclerosis

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Project Summary/Abstract Relapsing and progressive multiple sclerosis (MS) are characterized by an intrathecal synthesis of immunoglobulins (IIgS). This occurs throughout the disease and is the only widely agreed upon molecular diagnostic criteria for MS. A growing body of evidence also suggests that IIgS correlates with MS disease progression, although the pathological role of these antibodies remains to be determined. Cytotoxic activities in the central nervous system (CNS) are critical determinants of MS disease progression. Interestingly, antibodies can activate two distinct cytotoxic mechanisms: antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Therefore, I initially hypothesized that, in MS, IIgS triggers ADCC and CDC within the CNS, thereby accruing CNS damage and worsening disease progression. Thus, over the past few years, the primary goal of my work has been to define the cytotoxic activity of these Igs by using Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) as a model of progressive MS. Particularly, I have been focusing on CDC and the classical complement pathway. The first component of the classical complement pathway (C1q) recognizes and binds to Igs complexed to antigen and initiates the complement cascade, ultimately triggering CDC. Since the results of my studies suggest higher levels of C1q in the CNS indicate more severe clinical and pathological disease, I developed a refined working hypothesis. Thus, I now hypothesize that therapeutic inhibition of C1q in the CNS of TMEV-IDD mice will prevent disease progression by reducing neuroaxonal damage and neuroinflammation. I will test this hypothesis by accomplishing the following three aims: Aim 1 will demonstrate that anti-C1q treatment improves clinical outcomes. To accomplish this aim, TMEV- IDD mice will be treated with either an intraventricularly injected murine anti-C1q antibody (M1) or a systemically administered anti-C1q camelid VHH antibody (aka nanobody). Motor and cognitive outcomes will be evaluated. Aim 2 will demonstrate that anti-C1q treatment reduces neuroaxonal damage. To accomplish this aim, neuroaxonal damage in treated vs. untreated mice will be assessed throughout the disease by 1) measurement of cerebrospinal fluid (CSF) biomarkers of neuroaxonal damage, 2) histology, and 3) quantitative magnetic resonance imaging (MRI) techniques. Aim 3 will demonstrate that anti-C1q treatment reduces neuroinflammation. To accomplish this aim, neuroinflammation will be assessed in treated and untreated mice by 1) flow cytometry, 2) immunofluorescence, and 3) measurement of intrathecally produced inflammatory biomarkers. Overall, this work will provide compelling evidence for the significant role played by IIgs in PMS, thereby defining a new paradigm for its treatment.