title: Aberrant B cell selection and activation in systemic lupus erythematosus.
abstract: The detrimental role of B lymphocytes in systemic lupus erythematosus (SLE) is evident from the high levels of pathogenic antinuclear autoantibodies (ANAs) found in SLE patients. Affirming this causative role, additional antibody-independent roles of B cells in SLE were appreciated. In recent years, many defects in B cell selection and activation have been identified in murine lupus models and SLE patients that explain the increased emergence and persistence of autoreactive B cells and their lowered activation threshold. Therefore, clinical trials with B cell depletion regimens in SLE patients were initiated but disappointingly the efficacy of B cell depleting agents proved to be limited. Remarkably however, a major breakthrough in SLE therapy was accomplished by blocking B cell survival factors rather then eliminating B cells. This surprising finding indicates that although SLE is a B cell-driven disease, the amplifying crosstalk between B cells and other cells of the immune system likely evokes the observed tolerance breakdown in B cells. Moreover, this implies that intelligent interception of pro-inflammatory loops rather then selectively silencing B cells will be key to the development of new SLE therapies. In this review, we will not only highlight the intrinsic B cell defects that facilitate the persistence of autoreactive B cells and their activation, but in addition we will focus on B cell extrinsic signals derived from T cells and innate immune cells that lower the activation threshold for B cells.
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, NL 3000 CA Rotterdam, The Netherlands.
authors.forename: Laurens P
authors.initials: LP
authors.lastname: Kil
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D060966:Clonal Selection, Antigen-Mediated / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D011947:Receptors, Antigen, B-Cell; D051193:Toll-Like Receptors