title: Interfering with baffled B cells at the lupus tollway: Promises, successes, and failed expectations.
abstract: B cells play an important role in systemic lupus erythematosus by acting not only as precursors of autoantibody-producing cells but also as antigen-presenting, cytokine-secreting, and regulatory cells. Unopposed activation of B cells through their B-cell receptor for antigen, as seen in B cells lacking Lyn kinase, results in systemic autoimmunity. The B-cell activating factor of the TNF family (BAFF), nucleic acid-sensing Toll-like receptors (TLRs), and type I interferon can affect B-cell survival and decrease their threshold for activation. Herein we discuss both direct and indirect strategies aimed at targeting B cells in patients with lupus by blocking BAFF, type I interferon, or TLR7 to TLR9. Although BAFF-depleting therapy with belimumab achieved approval for lupus, other BAFF inhibitors were much less beneficial in clinical trials. Inhibitors of the B-cell receptor for antigen signaling and antibodies against type I interferon are in the pipeline. The TLR7 to TLR9 blocker hydroxychloroquine has been in use in patients with lupus for more than 50 years, but oligonucleotide-based inhibitors of TLR7 to TLR9, despite showing promise in animal models of lupus, have not reached the primary end point in a recent phase 1 trial. These data point toward possible redundancies in B-cell signaling/survival pathways, which must be better understood before future clinical trials are executed.
authors.affiliation: Division of Immunology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Namrata
authors.initials: N
authors.lastname: Singh
authors.affiliation: Division of Immunology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Bharat
authors.initials: B
authors.lastname: Kumar
authors.affiliation: Division of Immunology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Vijay
authors.initials: V
authors.lastname: Aluri
authors.affiliation: Division of Immunology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa. Electronic address: petar-lenert@uiowa.edu.
authors.forename: Petar
authors.initials: P
authors.lastname: Lenert
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D053264:B-Cell Activating Factor / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D000072377:Syk Kinase / Q000037:antagonists & inhibitors; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000276:immunology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000276:immunology
chemical_list: D053264:B-Cell Activating Factor; D007370:Interferon Type I; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; D051193:Toll-Like Receptors; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000606896:SYK protein, human; D000072377:Syk Kinase
keywords: B cells; B-cell receptor for antigen; Bruton tyrosine kinase; B cell activating factor; Lyn; Toll-like receptors; spleen tyrosine kinase; systemic lupus erythematosus; type I interferon