B Cells Are Multifunctional Players in Multiple Sclerosis Pathogenesis: Insights from Therapeutic Interventions

Abstract

Multiple sclerosis (MS) is a severe disease of the central nervous system (CNS) characterized by autoimmune inflammation and neurodegeneration. Historically, damage to the CNS was thought to be mediated predominantly by activated pro-inflammatory T cells. B cell involvement in the pathogenesis of MS was solely attributed to autoantibody production. The first clues for the involvement of antibody-independent B cell functions in MS pathology came from positive results in clinical trials of the B cell-depleting treatment rituximab in patients with relapsing-remitting (RR) MS. The survival of antibody-secreting plasma cells and decrease in T cell numbers indicated the importance of other B cell functions in MS such as antigen presentation, costimulation, and cytokine production. Rituximab provided us with an example of how clinical trials can lead to new research opportunities concerning B cell biology. Moreover, analysis of the antibody-independent B cell functions in MS has gained interest since these trials. Limited information is present on the effects of current immunomodulatory therapies on B cell functions, although effects of both first-line (interferon, glatiramer acetate, dimethyl fumarate, and teriflunomide), second-line (fingolimod, natalizumab), and even third-line (monoclonal antibody therapies) treatments on B cell subtype distribution, expression of functional surface markers, and secretion of different cytokines by B cells have been studied to some extent. In this review, we summarize the effects of different MS-related treatments on B cell functions that have been described up to now in order to find new research opportunities and contribute to the understanding of the pathogenesis of MS.

New Insights into the Role of IL-1β in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

“…Immune cell invasion of the CNS in MS induces both demyelination and axon loss, and involves communication between the invading leukocytes and astrocytes, glia, and neurons. Autoreactive CD4 + T cells play an important role in driving MS pathology, although γδ T cells, CD8 + T cells, and B cells also appear to contribute to disease (1–5). How autoreactive T H cells acquire pathogenicity and how they mediate CNS damage remain important outstanding questions.…”

Activation of human B cells negatively regulates TGF-β1 production

“…While memory B cells are more easily activated to produce proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6, and granulocyte macrophage-colony stimulating factor (GM-CSF), naïve B cells preferentially secrete the regulatory cytokine IL-10 [6, 17]. Although the current data support the conceptual idea of a prominent involvement of activated proinflammatory B cells in MS pathogenesis, accumulating experimental and clinical findings indicate that not all B cells play a pathogenic role in MS [20]. Defects in regulatory B cell functions have been documented in MS patients [13, 17, 21–23], suggesting that a disrupted balance between proinflammatory and suppressive B cell properties may be particularly relevant to the regulation of CNS autoimmunity.…”

Update on Disease-Modifying Therapies for Multiple Sclerosis

“…However, the pathogenesis of MS in this patient subset is probably different from RRMS. There is unlikely to be a phase III trial of rituximab in MS because of the development of new CD20 monoclonals likely to be licensed specifically for the MS indication 31 35 97…”