Abstract : Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system (CNS). The role of B-lymphocytes in MS pathogenesis remains unclear, since they have been described to have pathogenic and regulatory effects, and also to be involved in remyelination process. To better understand the mechanisms underlying MS, we used the well-studied animal model, known as experimental autoimmune encephalomyelitis (EAE) induced by the encephalitogenic peptide 139-151 of the myelin proteolipid (PLP139-151) in females SJL/J mice, which presents at least one relapsing/remitting episode. Unlike SJL/J model, females B10.S (congenic for the H2 complex) do not develop the clinical signs characteristics of the EAE after active immunization. Thus, B10.S mice are considered as resistant to the disease induction. The experimental approach carried out in the susceptible/resistant EAE models highlighted the involvement of the B-cell homeostasis on the physiopathology of the autoimmune responses. These observations were confirmed in patients with MS, which showed altered B-cell subsets balance during the early phases of the disease. In fact, transitional B cells, also known as late-immature B cells, showed quantitative (cell numbers) and qualitative (a particular activation status and an increased expression of several adhesion molecules involved in the leukocyte extravasation) modifications. These characteristics, exclusively found in transitional B cells from patients with MS, were associated to their ability to home the central nervous system. Altogether these findings highlighted that B-cell involvement in MS pathogenesis may not be exclusively restricted to memory B cells.