Author ORCID Identifier
Date of Award
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Francesca Gilli Ph.D.
Multiple sclerosis (MS) is a clinically heterogeneous neurological condition characterized by neuroinflammation and neurodegeneration. Relapsing-remitting MS, defined by inflammatory attacks, is the most common initial form of MS and there are currently 23 FDA-approved treatments for these patients. These therapies work primarily by reducing inflammation in the CNS; they do not work well in progressive disease. Therefore, an unmet medical need exists for effective therapeutic options to treat progressive MS (PMS).
In MS, intrathecal immunoglobulins synthesis (IIgS) correlates with disease progression. My goals for this dissertation were to establish the pathological role of IIgS and identify new potential therapeutic targets for PMS. To investigate this, I used a mouse model of relapsing-remitting MS, rEAE, and a virally induced model of PMS, TMEV-IDD, along with a range of methodologies such as microarray, real-time PCR, immunofluorescent microscopy, immunoassays and behavior analyses.
I first demonstrated that, in contrast to rEAE, TMEV-IDD has high levels of IIgS along with demyelination, axonal injury, and neuronal death. In TMEV-IDD mice, IIgS also correlated with disability. After investigating possible effector mechanisms of IIgS, I found evidence for the pathological involvement of the complement system. I demonstrated that TMEV-IDD relies more on activating the classical complement pathway while protecting from acute relapses in rEAE. Overall, my studies showed in TMEV-IDD higher levels of CNS C1q, the initiating protein of the classical complement pathway, along with more severe clinical and pathological disease. The classic complement pathway represents a link between IIgS and MS progression. Canonically, activation of C1q requires binding immune-complexes. Therefore, increased IIgS could over-activate the classical complement cascade. Using inhibitory molecules and two treatment options designed to overcome the BBB, intraventricular infusion of a murine anti-C1q antibody with an Alzet Osmotic Pump and a modified anti-C1q nanobody, I demonstrated that C1 antagonization reduces neuroaxonal damage and neuroinflammation, improving disease outcomes in TMEV-IDD but not rEAE.
In conclusion, I showed that TMEV-IDD replicates IIgS as is observed in PMS, that IIgS is linked to an overactivation of the classical complement pathway, and that C1q antagonization represents a valid therapeutic strategy in progressive but not acute neuroinflammation.
DiSano, K.D., Linzey, M.R., Royce, D.B. et al. Differential neuro-immune patterns in two clinically relevant murine models of multiple sclerosis. J Neuroinflammation 16, 109 (2019). https://doi.org/10.1186/s12974-019-1501-9
Linzey M, DiSano K, Welsh N, Pachner A and Gilli F (2022) Divergent complement system activation in two clinically distinct murine models of multiple sclerosis. Front. Immunol. 13:924734. doi: 10.3389/fimmu.2022.924734
Linzey, Michael R., "Complement system in multiple sclerosis: its role in disease course and potential as a therapeutic target" (2023). Dartmouth College Ph.D Dissertations. 212.