B Cells As Therapeutic Targets In Autoimmune Neurological Disorders

Marinos C Dalakas

Disclosures

Nat Clin Pract Neurol. 2008;4(10):557-567. 

In This Article

Roles of B Cells in the Immune Response: Neurological Aspects

In the context of autoimmune neurological disorders, B cells have traditionally been associated with the production of autoantibodies from plasma cells, the end products of B-cell differentiation.[2,3,4,5] In several neurological diseases, including myasthenia gravis and certain neuropathies, the autoantibodies are pathogenetic, exerting a direct effect on self antigens either by functioning as neutralizing antibodies or by activating and fixing complement on the targeted tissues (Figure 1A). Autoantibodies and immune complexes can also activate Fc receptors on macrophages or dendritic cells, leading to the production of cytokines, which cause further tissue injury (Figure 1A). In most autoimmune neurological disorders, however, the autoantibodies are directed against cytosolic antigens and might not be directly involved in tissue injury. In such cases, B cells might still participate in the autoimmune process through antibody-independent mechanisms that include antigen presentation, costimulation, cytokine production, and coordination of T-cell functions (Figure 1A-D).[4,6]

Figure 1.

B-cell functions in neurological disorders. The figure shows the four main functions of B cells through which they contribute to the pathology of immune-mediated neurological conditions. (A) Production of antibodies that cause tissue damage either via complement activation or antibody-dependent-cell mediated cytotoxicity. (B) Acting as antigen-presenting cells, which results in clonal expansion of cytotoxic T cells and cytokine production. (C) Production of proinflammatory cytokines, such as IL-6, TNF and IL-10, which activate macrophages and T cells and enhance tissue damage. (D) De novo formation and maintenance of ectopic germinal centers in the intermeningeal spaces (neolymphogenesis). Abbreviations: IL = interleukin; LTβR = lymphotoxin-β receptor; LTβ = lymphotoxin-β; TNF = tumor necrosis factor.

A proof-of-principle that activated B cells are fundamental for coordinating T-cell functions was provided by the observation that B-cell-depleted mice exhibit a dramatic decrease in numbers of CD4+ and CD8+ T cells, and a tenfold inhibition of memory CD8+ T cells.[7,8] An important function of B cells is their ability to present antigenic peptides, in the context of major histocompatibility complex class II molecules on their surface, to the T-cell receptors of CD4+ cells, leading to expansion of antigen-specific T cells (Figure 1B).[1,2,3,4,5,6] B cells are 100-1,000 times more potent in antigen presentation than are the other antigen-presenting cells, such as macrophages or dendritic cells,[9] and they are especially effective at presenting low concentrations of antigen. Activated B cells are also as efficient as T cells at producing cytokines—most notably interleukins (IL-1, IL-4, IL-6, IL-10, IL-12, IL-23 and IL-16), tumor necrosis factor (TNF) and the chemokines macrophage inflammatory protein 1α (MIP1α) and MIP1β.[10,11] These inflammatory mediators modulate the migration of dendritic cells, activate macrophages, exert a regulatory role on T-cell functions, and provide feedback stimulatory signals for further B-cell activation (Figure 1C). Some cytokines might theoretically exert an inhibitory role in the immune process, although this has not been clearly established in human diseases.

An additional role of B cells that is relevant to neurology is their involvement in de novo formation and maintenance of ectopic lymphoid structures, a process termed neolymphogenesis.[6] This is accomplished through the actions of β-lymphotoxin, a TNF family member molecule that is expressed on the surface of B cells (Figure 1D). Ectopic follicular structures are found in the meningeal compartment in patients with various neuroinflammatory conditions, as discussed below. The multiple contributions of B cells to the complexity of the autoimmune process make B cells attractive targets for therapeutic interventions that extend beyond the traditional effects on antibody production.

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