Neuroimmunology is the discipline that specializes in the care of people with multiple sclerosis (PwMS) and related diseases. It is one of the most dynamic fields of clinical neurology, with means to treat PwMS increasing steadily since the early 1990’s. In MS, neurological disability accumulation is driven by two clinically distinct processes: relapses and progression. Relapses are defined as episodes of acute or subacute focal neurological deficits followed by varying degrees of recover. They are the most conspicuous initial clinical manifestations of MS in most patients, but their frequency decreases with time, becoming sparse after 10 to 15 years of disease evolution. Progression is defined as slow neurological disability accumulation occurring independently of relapses and MRI signs of acute focal inflammatory disease activity. It is an insidious process that is difficult to identify clinically, especially early in the disease course, as it may be masked by relapses. Its rate increases with time, becoming the major process driving disability accumulation later in the disease course in a majority of PwMS. All currently available disease modifying therapies (DMTs) are modulators of the peripheral immune system, targeting relapses and acute focal inflammatory disease activity with varying degrees of efficacy. Treatments specifically targeting progression are lacking, although this process contributes overwhelmingly to long-term physical and cognitive disability. Evaluating new drugs to reduce progression rate requires robust tools to quantify this process over the relatively short time frame of clinical trials. Such tools are lacking, but there are promising candidates. The absence of drugs to significantly slow progression and its devastating effect on the life of PwMS is a reality I witness daily in clinical practice. In the last years, I have thus focused my research on identifying and evaluating candidate body fluid biomarkers of progression, as well as on developing tools to measure these biomarkers. It is a challenging endeavor because the physiopathological underpinnings of progression are poorly understood and likely manifold. Several biomarkers will probably be needed to capture this complexity. In this thesis, I start by giving an overview of clinical, immunological, and pathological aspects of MS. I then give an overview of the state of knowledge of one of the most promising body fluid candidate biomarker of progression, as a background to the published manuscripts I selected for the body of this thesis. Finally, I discuss the challenges ahead, provide an overview of a research project I am currently working on thanks to the support of the Fondation privée des Hôpitaux Universitaires de Genève and the Fondation Schmidheiny, and present a new project I would like to start shortly in collaboration with the laboratory of Professor Jean-Charles Sanchez