BAFF selectively enhances the survival of plasmablasts generated from human memory B cells

• Published in: The Journal of clinical investigation 2003-07, Vol.112 (2), p.286-297
• Main Authors: Avery, Danielle T, Kalled, Susan L, Ellyard, Julia I, Ambrose, Christine, Bixler, Sarah A, Thien, Marilyn, Brink, Robert, Mackay, Fabienne, Hodgkin, Philip D, Tangye, Stuart G
• Format: Article
• Language: English
• Subjects: ADP-ribosyl Cyclase - biosynthesis; ADP-ribosyl Cyclase 1; Antigens; Antigens, CD - biosynthesis; Apoptosis; Autoimmune diseases; B-Cell Activating Factor; B-Cell Activation Factor Receptor; B-Cell Maturation Antigen; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biomedical research; CD40 Ligand - metabolism; Cell Differentiation; Cell Division; Cell Line; Cell Separation; Cell Survival; Cells; Cloning; Flow Cytometry; Homeostasis; Humans; Immunologic Memory; Interleukin-10 - biosynthesis; Interleukin-2 - biosynthesis; Lupus; Membrane Glycoproteins; Membrane Proteins - metabolism; Membrane Proteins - physiology; Microscopy, Fluorescence; Models, Biological; Neuropeptides - physiology; Nuclear Proteins - physiology; Protein Binding; Receptors, Tumor Necrosis Factor - metabolism; Signal transduction; Spleen - cytology; Time Factors; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci18025

The generation of Ig-secreting cells (ISCs) from memory B cells requires interactions between antigen-specific (Ag-specific) B cells, T cells, and dendritic cells. This process must be strictly regulated to ensure sufficient humoral immunity while avoiding production of pathogenic autoantibodies. BAFF, a member of the TNF family, is a key regulator of B cell homeostasis. BAFF exerts its effect by binding to three receptors - transmembrane activator of and CAML interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). To elucidate the contribution of BAFF to the differentiation of B cells into ISCs, we tracked the fate of human memory B cells stimulated with BAFF or CD40L. BAFF and CD40L significantly increased the overall number of surviving B cells. This was achieved via distinct mechanisms. CD40L induced proliferation of nondifferentiated blasts, while BAFF prevented apoptosis of ISCs without enhancing proliferation. The altered responsiveness of activated memory B cells to CD40L and BAFF correlated with changes in surface phenotype such that expression of CD40 and BAFF-R were reduced on ISCs while BCMA was induced. These results suggest BAFF may enhance humoral immunity in vivo by promoting survival of ISCs via a BCMA-dependent mechanism. These findings have wide-ranging implications for the treatment of human immunodeficiencies as well as autoimmune diseases.