Multiple sclerosis (MS) and other demyelinating disorders are neuroinflammatory disorders arising from yet still incompletely understood immune-mediated mechanisms. Among MS disease-implicated mechanisms, roles for T cells and B cells have been identified across the immune compartments of the peripheral circulation, the central nervous system, and the secondary lymphoid tissues. Here, we dissect the roles that some of these disease-implicated immune cells play both in health and in disease across compartments, including the peripheral blood, the cerebrospinal fluid, and tonsillar tissue, with a focus on pediatric populations, a relatively understudied patient population where identified immune signatures may more closely reflect those mechanisms involved at the onset of disease. We also place emphasis on comparing identified signatures in MS to a more recently identified, similar demyelinating disorder known as myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) in order to derive more disease-specific insight. We first explore the heterogeneity of B cells within secondary lymphoid tissue in children without demyelinating disorders and identify a novel subset of CCL4/CCL4-expressing activated B cells alongside novel transcription factors putatively implicated in B-cell maturation. We next identify particular immune features of T cells and B cells distinguishing MS from MOGAD and other disorders, across both the cerebrospinal fluid compartment and the peripheral blood compartment,. Among our findings, we find that the presence of antibody-secreting cells is an MS-unique feature in pediatric-onset MS CSF across demyelinating disorders, and a skew towards VLA-4+ Th17 cell phenotype in the circulation of pediatric patients with MS distinguishes their immune profiles from patients with MOGAD. Taken together, our studies identify multiple immune mechanisms of T cells and B cells across health and disease, with potential new avenues identified for mechanistic studies and insight into targetable disease-implicated pathways.