B lymphocyte stimulator (BLyS): a therapeutic trichotomy for the treatment of B lymphocyte diseases.
B Lymphocyte Stimulator (BLyS protein) is a member of the tumor necrosis factor (TNF) family of ligands and functions as an essential in vivo regulator of B lymphocyte homeostasis. As such, changes in systemic BlyS protein expression caused by disruption of the gene encoding BLyS or administration of neutralizing soluble receptors have resulted in profound losses in mature B cell numbers and impaired humoral immunity. A similar phenotype has been observed in A/WySnJ mice that express a truncated BLyS receptor and are thus defective in BLyS signal transduction. In contrast, overexpression of BLyS protein in BLyS-transgenic mice results in B cell hyperplasia, hypergammaglobulinemia, and development of autoimmune-like disease. The ability of BLyS to regulate both the size and repertoire of the peripheral B cell compartment raises the possibility that BLyS and antagonists thereof may form the basis of a therapeutic trichotomy. As an agonist, BLyS protein may enhance humoral immunity in congenital or acquired immunodeficiencies such as those resulting from viral infection or cancer therapy. BLyS-specific antagonists (antibodies or soluble receptors) that inhibit the biological activity of BLyS may be effective therapies for those autoimmune diseases characterized by polyclonal hypergammaglobulinemia and elevated autoantibody titers. Finally, the specificity of BLyS for B-lineage cells raises the possibility that BLyS may be used as a targeting vehicle for delivery of a cytotoxic or cytolytic signal to neoplastic B-lineage cells expressing one or more of the three known BLyS receptors. This review discusses the therapeutic potential of BLyS in the context of BLyS structure, function and receptor specificity.
Nardelli
Bernardetta
B
Human Genome Sciences, Inc., Rockville, MD, USA. bernardetta_nardelli@hgsi.com
Moore
Paul A
PA
Li
Yuling
Y
Hilbert
David M
DM
D000818:Animals; D000917:Antibody Formation; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D006402:Hematologic Diseases / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; C120197:BLyS receptor; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; C435926:TNFRSF13C protein, human; C505719:TNFSF13B protein, human; D014409:Tumor Necrosis Factor-alpha