| Abstract: |
B lymphocyte stimulator (BLyS) is a newly identified monocyte-specific TNF family cytokine. It has been implicated in the development of autoimmunity, and functions as a potent costimulator with antiimmunoglobulin M in B cell proliferation in vitro. Here we demonstrate that BLyS prominently enhances the humoral responses to both T cell-independent and T cell-dependent antigens, primarily by attenuation of apoptosis as evidenced by the prolonged survival of antigen-activated B cells in vivo and in vitro. BLyS acts on primary splenic B cells autonomously, and directly cooperates with CD40 ligand (CD40L) in B cell activation in vitro by protecting replicating B cells from apoptosis. Moreover, although BLyS alone cannot activate the cell cycle, it is sufficient to prolong the survival of naive resting B cells in vitro. Attenuation of apoptosis by BLyS correlates with changes in the ratios between Bcl-2 family proteins in favor of cell survival, predominantly by reducing the proapoptotic Bak and increasing its prosurvival partners, Bcl-2 and Bcl-xL. In either resting or CD40L-activated B cells, the NF-κB transcription factors RelB and p50 are specifically activated, suggesting that they may mediate BLyS signals for B cell survival. Together, these results provide direct evidence for BLyS enhancement of both T cell-independent and T cell-dependent humoral immune responses, and imply a role for BLyS in the conservation of the B cell repertoire. The ability of BLyS to increase B cell survival indiscriminately, at either a resting or activated state, and to cooperate with CD40L, further suggests that attenuation of apoptosis underlies BLyS enhancement of polyclonal autoimmunity as well as the physiologic humoral immune response. |
| Keywords: |
unclassified drug; proto-oncogene proteins; nonhuman; t lymphocyte; t-lymphocytes; animal cell; mouse; animals; mice; cell survival; cells, cultured; cell cycle; cell division; protein bcl 2; apoptosis; cd40 ligand; animal experiment; membrane proteins; immunoglobulin enhancer binding protein; bcl-x protein; mice, inbred balb c; mice, inbred c57bl; b-lymphocytes; transcription factors; cytokine; lymphocyte activation; tumor necrosis factor-alpha; nf-kappa b; autoimmunity; serum albumin, bovine; humoral immunity; proto-oncogene proteins c-bcl-2; antibody formation; tumor necrosis factor; immunoglobulin m antibody; antibodies, bacterial; bcl-2; nitrophenols; bcl-2 homologous antagonist-killer protein; transcription factor relb; cd40; pneumococcal vaccines; glycoprotein gp 39; b lymphocyte activation; protein bcl x; b-cell activating factor; humans; female; priority journal; article; nf-kappa b p50 subunit; b lymphocyte stimulator; nuclear factor κb; primary b cell; 2,4-dinitrophenol; gamma-globulins
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